[Federal Register Volume 68, Number 50 (Friday, March 14, 2003)]
[Proposed Rules]
[Pages 12405-12497]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-5204]



[[Page 12405]]

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Part II





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Parts 310, 312, et al.



Safety Reporting Requirements for Human Drug and Biological Products; 
Proposed Rule

Federal Register / Vol. 68, No. 50 / Friday, March 14, 2003 / 
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 312, 314, 320, 600, 601, and 606

[Docket No. 00N-1484]
RIN 0910-AA97


Safety Reporting Requirements for Human Drug and Biological 
Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its pre- and postmarketing safety reporting regulations for human drug 
and biological products to implement definitions and reporting formats 
and standards recommended by the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and by the World Health 
Organization's (WHO's) Council for International Organizations of 
Medical Sciences (CIOMS); codify the agency's expectations for timely 
acquisition, evaluation, and submission of relevant safety information 
for marketed drugs and licensed biological products; require that 
certain information, such as domestic reports of medication errors, be 
submitted to the agency in an expedited manner; clarify certain 
requirements; and make other minor revisions. FDA is also proposing to 
amend its postmarketing annual reporting regulations for human drug and 
licensed biological products by revising the content for these reports. 
FDA is taking this action to strengthen its ability to monitor the 
safety of human drugs and biological products. The intended effect of 
these changes is to further worldwide consistency in the collection of 
safety information and submission of safety reports, increase the 
quality of safety reports, expedite FDA's review of critical safety 
information, and enable the agency to protect and promote public 
health. These proposed changes would be an important step toward global 
harmonization of safety reporting requirements and additional efforts 
are underway within the Department of Health and Human Services to 
harmonize the reporting requirements of U.S. Federal agencies (e.g., 
FDA and the National Institutes of Health (NIH) are continuing to work 
together to address the best ways to streamline information sharing and 
harmonize, to the extent possible, the safety reporting requirements of 
the two agencies).

DATES: Submit written comments by July 14, 2003. Submit written 
comments on the collection of information by April 14, 2003.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852, e-mail: [email protected] or to the Internet 
at http://www.accessdata.fda.gov/scripts/oc/dockets/comments/commentdocket.cfm. FAX written comments on the information collection 
provisions to the Office of Information and Regulatory Affairs, Office 
of Management and Budget (OMB), New Executive Office Bldg., 725 17th 
St. NW., rm. 10235, Washington, DC 20503, Attn: Stuart Shapiro, Desk 
Officer for FDA, 202-395-6974.

FOR FURTHER INFORMATION CONTACT:
     For information concerning human drug products: Audrey A. Thomas, 
Center for Drug Evaluation and Research (HFD-7), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-5626.
    For information concerning human biological products: Miles Braun, 
Center for Biologics Evaluation and Research (HFM-220), Food and Drug 
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-
6079.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Previous Safety Reporting Rulemaking and Current Guidances
II. Introduction
    A. Persons Subject to the Safety Reporting Regulations
    1. Premarketing Expedited Safety Reporting Regulations
    2. Postmarketing Safety Reporting Regulations
    3. Terms Used in This Document
    B. Rationale for This Proposal
    1. International Standards
    2. Quality of Postmarketing Safety Reports
    3. New Postmarketing Expedited Safety Reports
    a. Medication errors
    b. Unexpected SADRs with unknown outcome
    c. Always expedited reports
    d. Blood and blood component safety reports
    4. Bioavailability and Bioequivalence Studies Not Subject to an 
Investigational New Drug Application (IND)
    C. New Safety Reporting Abbreviations
    D. Highlights of Proposed Changes to FDA's Safety Reporting 
Regulations
III. Description of the Proposed Rule
    A. Definitions
    1. Suspected Adverse Drug Reaction (SADR)
    2. A Life-Threatening SADR
    3. Serious SADR, Nonserious SADR, and SADR With Unknown Outcome
    4. Contractor
    5. Minimum Data Set and Full Data Set for an Individual Case 
Safety Report
    6. Active Query
    7. Spontaneous Report
    8. Medication Error
    9. Company Core Data Sheet, Company Core Safety Information 
(CCSI), Listed SADR, Unlisted SADR, and Unexpected SADR
    10. Data Lock Point and International Birth Date
    B. IND Safety Reports
    1. Review of Safety Information
    2. Written IND Safety Reports
    a. Minimum data set
    b. Serious and unexpected SADRs
    c. Information sufficient to consider product administration 
changes
    d. Reporting format
    3. Telephone Safety Reports
    4. IND Safety Reporting for Drugs Marketed in the United States
    5. Investigator Reporting
    C. Postmarketing Safety Reporting
    1. Prescription Drugs Marketed for Human Use Without an Approved 
Application
    2. Review of Safety Information
    3. Reporting Requirements
    4. Request for Alternative Reporting Frequency
    5. Determination of Outcome, Minimum Data Set, and Full Data Set
    6. Spontaneous Reports and Reports From Clinical Trials
    7. Lack of Efficacy Reports
    D. Postmarketing Expedited Reports
    1. Serious and Unexpected SADRs
    2. Information Sufficient to Consider Product Administration 
Changes
    3. Unexpected SADRs With Unknown Outcome
    4. Always Expedited Reports
    5. Medication Errors
    6. Followup Reports
    7. Supporting Documentation
    8. Scientific Literature
    9. Contractors and Shared Manufacturers
    10. Prescription Drugs Marketed for Human Use Without an 
Approved Application
    11. Class Action Lawsuits
    12. Blood and Blood Component Safety Reports
    E. Postmarketing Periodic Safety Reporting
    1. Traditional Periodic Safety Reports (TPSRs)
    a. Narrative summary and analysis of individual case safety 
reports
    b. Individual case safety reports
    c. Increased frequency reports
    d. Safety-related actions to be taken
    e. Summary tabulations
    f. History of safety-related actions taken
    g. Location of safety records
    h. Contact person
    2. Periodic Safety Update Reports (PSURs)
    a. Title page, table of contents, and introduction
    b. Worldwide marketing status
    c. Actions taken for safety reasons

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    d. Changes to CCSI
    e. Worldwide patient exposure
    f. Individual case safety reports
    i. Line listings
    ii. Summary tabulations
    g. Safety studies
    h. Other information
    i. Overall safety evaluation
    j. Conclusion
    k. Appendices
    i. Company core data sheet
    ii. U.S. labeling
    iii. Spontaneous reports submitted to the applicant by an 
individual other than a health care professional
    iv. SADRs with unknown outcome
    v. Class action lawsuits
    vi. Lack of efficacy reports
    vii. Information on resistance to antimicrobial drug products
    viii. Medication errors
    ix. U.S. patient exposure
    x. Location of safety records
    xi. Contact person
    3. Interim Periodic Safety Reports (IPSRs)
    4. Semiannual Submission of Individual Case Safety Reports
    5. Reporting Requirements
    a. Reporting intervals
    b. Submission date
    c. Cover letter
    d. International birth date for combination products
    F. Reporting Format
    1. Forms Versus Narrative Format
    2. Medical Dictionary for Regulatory Activities (MedDRA)
    3. Single Form for Each Identifiable Patient
    4. Contact Person
    5. Computer-Generated Facsimile of FDA Form 3500A or Vaccine 
Adverse Event Reporting System (VAERS) Form
    6. Other Revisions
    G. Patient Privacy
    H. Recordkeeping
    I. Abbreviated New Drug Application (ANDA) Products
    J. Postmarketing Approved New Drug Application (NDA) and 
Biologics License Application (BLA) Annual Reports
    K. Safety Reporting for In Vivo Bioavailability and 
Bioequivalence Studies
    L. Proposed Implementation Scheme
IV. Environmental Impact
V. Analysis of Impacts
    A. Background and Summary
    B. Market Failure
    C. Benefits
    1. Expanded Safety Information
    2. Improved Uniformity and Quality of Safety Information
    3. Potential Savings from Reduced SADR-Related Hospitalizations
    a. Reduced rate of SADR-related hospitalizations
    b. Reduced rate of in-hospital SADRs
    c. Indirect benefits of reducing the hospital costs of SADRs
    d. Sum of SADR-related costs
    4. Cost Savings and More Efficient Use of Resources
    a. Savings related to maintaining and building data bases of 
SADRs and intercompany transfers of drug safety data
    b. Savings related to greater ease in entering into intercompany 
agreements
    c. Savings related to eventual international harmonization to 
the PSUR format
    d. Potential savings in clinical trial management
    e. Leveraging specialized knowledge
    f. Total benefits
    D. Costs of Compliance
    1. Costs of New Recordkeeping and Reporting Requirements
    a. Number of reports
    b. New time burden
    i. Expedited reports
    ii. Followup reports
    iii. Blood products
    iv. IND and bioavailability/bioequivalence safety reports
    v. Semiannual submissions of postmarketing individual case 
safety reports
    vi. Postmarketing period safety reports (TPSR, PSUR, and IPSR)
    vii. Other reports
    c. Annual cost of the reporting and recordkeeping provisions
    2. Costs of MedDRA
    a. One-time costs
    i. Planning and coordination
    ii. Development of information technology support structure
    iii. Purchase or development of an autoencoder
    iv. Conversion of legacy safety data
    v. Training of personnel
    vi. Revision of standard operating procedures (SOPs)
    b. Recurring costs
    i. MedDRA core subscription
    ii. MedDRA versions and quarterly updates
    iii. Maintenance of existing dictionaries
    E. Small Business Analysis
    1. Need for and Objectives of the Rule
    2. Description and Estimate of Small Entities
    3. Projected Reporting, Recordkeeping, and Other Compliance 
Requirements
    a. Reporting and recordkeeping requirements
    b. Implementing MedDRA
    4. Alternatives and Steps to Minimize the Impact on Small 
Entities
    a. Do nothing
    b. Do not require a medical dictionary
    c. Do not require medication errors as expedited reports
    d. Do not require blood establishments to submit reports for all 
serious SADRs associated with blood collection and transfusion
    e. Do not require certain bioavailability and bioequivalence 
reports as expedited reports
    f. Waivers for economic hardship
    g. Small business outreach, training, and assistance
    F. Unfunded Mandates Reform Act of 1995
    G. References
VI. Paperwork Reduction Act of 1995
    A. Expedited Safety Reporting
    B. Periodic Safety Reports
    C. Other Reports
    D. Recordkeeping
VII. Executive Order 13132: Federalism

I. Previous Safety Reporting Rulemaking and Current Guidances

    FDA has undertaken a major effort to clarify and revise its 
regulations regarding pre- and postmarketing safety reporting for human 
drug and biological products. Since 1990, several rules and guidances 
have been issued regarding these regulations. Some of these guidances 
have been issued by international organizations (i.e., ICH and CIOMS), 
while others have been issued by FDA. In figure 1 of this document, FDA 
illustrates how these rules and guidances relate to the current 
proposed rule.

BILLING CODE 4160-01-P

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[GRAPHIC] [TIFF OMITTED] TP14MR03.000

BILLING CODE 4160-01-C

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    In the Federal Register of October 27, 1994 (59 FR 54046), FDA 
published a proposed rule to amend its expedited and periodic pre- and 
postmarketing safety reporting regulations for human drug and 
biological products (the October 1994 proposal). In the Federal 
Register of October 7, 1997 (62 FR 52237), FDA published a final rule 
amending its expedited pre- and postmarketing safety reporting 
regulations for human drug and biological products (the October 1997 
final rule). The October 1997 final rule implemented certain 
international standards recommended in an ICH guidance entitled 
``Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting'' (60 FR 11284, March 1, 1995) (the ICH E2A 
guidance). FDA is now proposing additional amendments to its expedited 
pre- and postmarketing safety reporting regulations based on 
recommendations in the ICH E2A guidance that were not included in the 
October 1994 proposal. Although the ICH E2A guidance pertains to 
expedited safety reporting during the premarketing phase of drug 
development, the agency has determined that many of the definitions and 
standards also should apply to FDA's expedited postmarketing safety 
reporting requirements.
    The proposed amendments to the postmarketing periodic safety 
reporting requirements in the October 1994 proposal were based on 
recommendations in a CIOMS II report issued in 1992 (``International 
Reporting of Periodic Drug-Safety Update Summaries'') (Ref. 28). As 
explained in the October 1997 final rule, the agency decided not to 
finalize these proposed amendments (62 FR 52237 and 52238) until FDA 
considered ICH's recommendations on this topic. These recommendations 
were published in an ICH final guidance entitled ``Clinical Safety Data 
Management: Periodic Safety Update Reports for Marketed Drugs'' 
''(PSURs) (the ICH E2C guidance) (62 FR 27470, May 19, 1997). After 
review of the ICH E2C guidance, FDA decided to repropose the 
postmarketing periodic safety reporting amendments in the October 1994 
proposal. These amendments are being reproposed in this rulemaking 
based on recommendations in the ICH E2C guidance and comments submitted 
in response to the October 1994 proposal.
    An addendum to the ICH E2C guidance has been prepared by ICH based 
on experience gained over the past 5 years in preparation of PSUR 
reports by companies and review of them by regulators (the ICH V1 draft 
guidance) (67 FR 79939; December 31, 2002). FDA is interested in 
harmonizing, to the extent possible, its postmarketing periodic safety 
reporting regulations with the recommendations in the ICH V1 draft 
guidance. In this regard, FDA is interested in comment from the public 
on whether the agency should implement these recommendations (e.g., 
permit use of summary bridging reports, include an executive summary in 
PSURs, permit use of different versions of reference safety information 
within a reporting interval or use of the version in effect at the end 
of the reporting interval).
    Some of the comments submitted in response to the October 1994 
proposal noted that several of the proposed amendments to the 
postmarketing periodic safety reporting regulations would result in 
duplicative reporting of information currently required in 
postmarketing approved new drug application (NDA) annual reports. The 
comments questioned the value of submitting similar information to FDA 
in two different reports and requested that the agency require 
inclusion of this information in either one report or the other, but 
not in both of them. In light of these comments, FDA is proposing to 
revoke the requirement for safety-related information in postmarketing 
approved NDA annual reports.
    In the Federal Register of December 2, 1998 (63 FR 66632), FDA 
issued a final rule amending its postmarketing approved NDA annual 
reports regulations to require reporting of specific information 
regarding studies in pediatric populations (the 1998 pediatric final 
rule). The 1998 pediatric final rule also required a new annual report 
for biological products with approved biologics license applications 
(BLAs) that contains the same type of information on studies of 
licensed biological products in pediatric populations. FDA is proposing 
to amend the annual reporting requirements for licensed biological 
products to revoke the requirement to submit safety-related information 
in these reports. This proposal is consistent with the proposed 
amendments to the postmarketing approved NDA annual reporting 
requirements.
    In the Federal Register of June 25, 1997 (62 FR 34166), FDA 
published a final rule revoking the postmarketing safety reporting 
requirement for submission of increased frequency reports in an 
expedited manner (the increased frequency reports final rule). These 
reports contained information regarding a significant increase in 
frequency of an adverse drug experience (synonymous with adverse 
experience) that is both serious and expected for marketed human drug 
and licensed biological products. FDA is now proposing to amend its 
regulations to require submission of increased frequency type 
information for marketed human drugs and licensed biological products 
in postmarketing periodic safety reports.
    In the Federal Register of August 27, 1997 (62 FR 45425), FDA 
published a notice of availability of a guidance for industry entitled 
``Postmarketing Adverse Experience Reporting for Human Drug and 
Licensed Biological Products; Clarification of What to Report'' (the 
clarification guidance of 1997). This guidance clarifies the agency's 
policy concerning certain postmarketing safety reporting requirements 
for human drugs and licensed biological products. The guidance: (1) 
Describes the information that should be obtained before an individual 
case safety report (i.e., FDA Form 3500A, CIOMS I Form, Vaccine Adverse 
Event Reporting System (VAERS) Form) of an adverse experience should be 
considered for submission to FDA; (2) clarifies how solicited safety 
information from planned contacts with patients should be handled; and 
(3) informs applicants that FDA will entertain waiver requests for 
periodic submission of individual case safety reports for adverse 
experiences that are determined to be nonserious and expected.
    FDA received 28 comments from medical centers, physicians, and 
consumers regarding the clarification guidance of 1997. All of these 
comments pertained to the item regarding waiver requests for periodic 
submission of individual case safety reports for adverse experiences 
that are determined to be nonserious and expected. The agency 
considered these comments in developing this proposed rule. All of the 
comments requested that FDA postpone granting these waivers until this 
new policy receives more complete public scrutiny and debate. The 
comments stated that the new waiver policy would deprive the public of 
access to important safety information about adverse reactions to 
approved drugs and biological products. The comments noted that, in 
some cases, adverse reactions classified as ``nonserious'' may, in 
fact, be related to very serious reactions. The comments also indicated 
that the new waiver policy provides industry with an incentive to 
classify serious reactions as ``nonserious'' so that the reactions 
would not have to be reported to FDA.
    Even though applicants may currently request waivers for submission 
of individual case safety reports for nonserious, expected adverse 
experiences, the agency should continue to receive information 
regarding these experiences. The clarification guidance

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of 1997 provides that summary tabulations of nonserious, expected 
adverse experiences be included in postmarketing periodic safety 
reports. If warranted, FDA could request submission of an individual 
case safety report for any nonserious, expected adverse experience. 
Thus, even if a waiver is granted, the agency will continue to receive 
sufficient information to monitor the safety of marketed drugs and 
licensed biological products. FDA is now proposing amendments to its 
postmarketing periodic safety reporting regulations that would require 
that nonserious, expected adverse experiences \1\ be submitted to the 
agency in summary tabulations consistent with the clarification 
guidance of 1997. At this time, FDA is also proposing to codify the 
other recommendations in the clarification guidance of 1997 (i.e., 
require a minimum data set for individual case safety reports, describe 
how solicited safety information from planned contacts with patients 
must be handled).
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    \1\ Adverse experiences are proposed to be called suspected 
adverse drug reactions (SADRs) in this proposed rule; see section 
III.A.1 of this document; the term ``adverse experiences'' or 
``adverse drug experiences'' will be used in this document when 
discussions pertain to FDA's current regulations and the term 
``SADR'' will be used in this document when discussions pertain to 
proposals in this rule.
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    In the Federal Register of March 12, 2001 (66 FR 14391), FDA 
published a notice of availability of a draft guidance for industry 
entitled ``Postmarketing Safety Reporting for Human Drug and Biological 
Products Including Vaccines'' (the draft guidance of 2001). The draft 
guidance of 2001 represents the agency's current thinking on reporting 
of postmarketing adverse drug experiences for human marketed drug and 
biological products including vaccines in accordance with FDA's 
postmarketing safety reporting regulations for these products in effect 
at the time the draft guidance of 2001 was issued. The draft guidance 
of 2001 consolidates the agency's existing guidances on this topic and 
revises them based on the October 1997 final rule and the increased 
frequency reports final rule. The draft guidance of 2001, once 
finalized, will replace FDA's guidances entitled ``Postmarketing 
Reporting of Adverse Drug Experiences'' (57 FR 61437, December 24, 
1992) (the guidance of 1992), ``Adverse Experience Reporting for 
Licensed Biological Products'' (the guidance of 1993), and the 
clarification guidance of 1997. The agency will issue a final guidance 
for industry on this topic after considering the comments received on 
the draft guidance of 2001.
    FDA is now proposing to codify certain expectations described in 
the draft guidance of 2001 to improve the quality of postmarketing 
safety reports submitted to the agency for human marketed drug and 
biological products, and also to clarify certain postmarketing safety 
reporting requirements. Once this proposed rule is finalized, the draft 
guidance of 2001, as finalized, will be updated to provide industry 
with assistance in fulfilling the new safety reporting requirements for 
human marketed drug and biological products.
    In June 2001, CIOMS issued a new report entitled ``Current 
Challenges in Pharmacovigilance: Pragmatic Approaches'' (CIOMS V 
report) (Ref. 29). This report provides recommendations for 
simplification, clarification, and harmonization of certain drug safety 
practices. Many of these recommendations serve to provide guidance for 
industry and would not be subject to requirements of individual 
regulatory authorities (e.g., FDA). Those that are the subject of our 
proposed rule are essentially consistent with what we are proposing. 
However, in some cases, there may be differences (see section III.A.6 
of this document for discussion of use of active query and written 
requests for acquisition of followup information).
    In the Federal Register of November 5, 1998 (63 FR 59746), FDA 
published an advance notice of proposed rulemaking announcing that it 
is considering a proposal to require persons subject to the 
postmarketing safety reporting regulations to submit postmarketing 
expedited individual case safety reports and individual case safety 
reports contained in postmarketing periodic safety reports to the 
agency electronically using a standardized medical terminology, 
standardized data elements, and electronic transmission standards 
recommended by the ICH. Under the auspices of ICH, standard medical 
terminology for regulatory purposes, MedDRA, the medical dictionary for 
regulatory activities (ICH M1), has been developed (63 FR 59746 at 
59748). On November 24, 1998, an international maintenance and support 
services organization (MSSO) was established to maintain and update 
MedDRA in response to medical/scientific advances and regulatory 
changes and to serve as the licensing agent for distribution of MedDRA. 
This proposed rule on safety reporting would require that postmarketing 
individual case safety reports be coded using MedDRA prior to 
submission to the agency. In a separate rulemaking, FDA plans to 
propose that postmarketing individual case safety reports be submitted 
to the agency electronically using standardized data elements and 
electronic transmission standards. The proposed amendments for 
electronic submissions are beyond the scope of this proposed rule.

II. Introduction

II.A. Persons Subject to the Safety Reporting Regulations

II.A.1. Premarketing Expedited Safety Reporting Regulations
    Section 312.32 (21 CFR 312.32), requires expedited reports of 
premarketing adverse experiences associated with the use of an 
investigational human drug or biological product (see table 1). 
Sponsors of INDs are subject to the premarketing expedited safety 
reporting regulations.

                       Table 1.--Currently Required Premarketing Expedited Safety Reports
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                                    Type of        21 CFR                               Persons with  reporting
        Safety report             information     section      Submission timeframe          responsibility
----------------------------------------------------------------------------------------------------------------
Written IND safety report....  [sbull] Serious      312.32  15 calendar days.........  Sponsors.
                                and unexpected
                                adverse
                                experience
                                associated with
                                the use of the
                                drug.
                               [sbull] Findings
                                from tests in
                                laboratory
                                animals that
                                suggest a
                                significant
                                risk for humans.
Telephone and facsimile        Unexpected fatal     312.32  7 calendar days..........  Sponsors.
 transmission safety report.    or life-
                                threatening
                                experience
                                associated with
                                the use of the
                                drug.
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[[Page 12411]]

II.A.2. Postmarketing Safety Reporting Regulations
    Sections 310.305, 314.80, 314.98, and 600.80 (21 CFR 310.305, 
314.80, 314.98, and 600.80) require expedited reports of postmarketing 
adverse drug experiences (see table 2). The following persons are 
subject to these postmarketing expedited safety reporting regulations:
    [sbull] Applicants with approved NDAs (Sec.  314.80) and 
abbreviated new drug applications (ANDAs) (Sec.  314.98);
    [sbull] Licensed manufacturers with approved BLAs (Sec.  600.80);
    [sbull] Manufacturers, packers, and distributors (also shared 
manufacturers, joint manufacturers, or any other participant involved 
in divided manufacturing for Sec.  600.80) whose name appears on the 
label of a product with an approved NDA, ANDA, or BLA (Sec. Sec.  
314.80, 314.98 and 600.80); and
    [sbull] Manufacturers, packers, and distributors whose name appears 
on the label of a prescription drug product marketed without an 
approved NDA or ANDA (Sec.  310.305). In this document, the term 
``applicant'' will be used instead of the term ``licensed 
manufacturer'' for persons with approved BLAs.

                                                Table 2.--Currently Required Postmarketing Safety Reports
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                                                                                                                                Persons with reporting
    Type of report           Safety report       Type of information       21 CFR section          Submission timeframe             responsibility
--------------------------------------------------------------------------------------------------------------------------------------------------------
Expedited report......  15-day Alert report...  Serious and            310.305, 314.80,       15 calendar days..............  Manufacturers \2\ and
                                                 unexpected adverse     314.98, 600.80.                                        applicants \3\.
                                                 drug experience \1\.
                        15-day Alert report-    New information for    310.305, 314.80,       15 calendar days..............  Manufacturers \2\ and
                         followup.               15-day Alert report.   314.98, 600.80.                                        applicants \3\.
                        Reports to              Serious adverse drug   310.305..............  5 calendar days...............  Packers and distributors.
                         manufacturer instead    experiences \1\.
                         of FDA.
                        Reports to applicant    Serious adverse        314.80, 314.98,        5 calendar days...............  Manufacturers, packers,
                         instead of FDA.         experiences \1\.       600.80.                                                and distributors (Sec.
                                                                                                                               Sec.   314.80, 314.98,
                                                                                                                               and 600.80) and joint
                                                                                                                               manufacturers, shared
                                                                                                                               manufacturers, or any
                                                                                                                               participant involved in
                                                                                                                               divided manufacturing
                                                                                                                               (Sec.   600.80).
Expedited report......  Blood safety report...  Fatalities...........  606.170..............  As soon as possible (oral or    Blood establishments.
                                                                                               written) and 7 days (written).
Periodic report.......  Periodic adverse drug   [sbull] Narrative      314.80, 314.98,        Quarterly for 3 years from the  Applicants.
                         experience report.      summary and analysis   600.80.                date of U.S. approval of the
                                                 of adverse drug                               application and then annually
                                                 experiences that                              thereafter.
                                                 occurred during the
                                                 reporting interval
                                                 including 15-day
                                                 Alert reports
                                                 previously submitted
                                                 to FDA \1\.
                                                [sbull] Individual
                                                 case safety report
                                                 for each adverse
                                                 drug experience not
                                                 submitted to FDA as
                                                 a 15-day Alert
                                                 report, excluding
                                                 reports from
                                                 postmarketing
                                                 studies, reports in
                                                 the scientific
                                                 literature, and
                                                 foreign marketing
                                                 experience \1\.
                                                [sbull] History of
                                                 actions taken..
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ For spontaneous reports, adverse drug experiences are submitted whether or not they are considered drug related; for study reports, adverse drug
  experiences are submitted if there is a reasonable possibility that the drug caused the adverse drug experience.
\2\ Section 310.305 also includes packers and distributors.
\3\ Sections 314.80 and 314.98 also include manufacturers, packers and distributors. Section 600.80 also includes manufacturers, packers, distributors,
  joint manufacturers, shared manufacturers, or any participant involved in divided manufacturing.

    Applicants with approved NDAs, ANDAs, and BLAs must also submit 
periodic reports of postmarketing adverse drug experiences under 
Sec. Sec.  314.80, 314.98 and 600.80 (see table 2). Manufacturers of 
prescription drug products marketed without an approved NDA or ANDA are 
not required to submit periodic reports of postmarketing adverse drug 
experiences (Sec.  310.305).
    Existing regulations, under Sec.  606.170 (21 CFR 606.170), require 
expedited reports of fatalities associated with

[[Page 12412]]

blood collection or transfusion (see table 2). The report must be 
submitted to FDA by the collecting facility in the event of a donor 
reaction and by the facility that performed the compatibility tests in 
the event of a transfusion reaction.
    Current safety reporting regulations under Sec. Sec.  310.305, 
314.80, 314.98, 600.80 and 606.170, as well as the provisions of this 
proposed rule, do not apply to voluntary reporting of adverse drug 
experiences to companies or regulatory authorities (e.g., FDA) by an 
individual (e.g., health care professional, consumer).
II.A.3. Terms Used in This Document
    The terms ``sponsors,'' ``manufacturers,'' and ``applicants'' are 
used in this proposed rule to describe, as appropriate, persons with 
safety reporting responsibilities. ``Sponsors'' is used to describe 
persons subject to the premarketing safety reporting regulations. 
``Manufacturers'' is used, unless otherwise specified, to describe 
persons subject to the postmarketing safety reporting regulations under 
Sec.  310.305 for prescription drug products marketed without an 
approved NDA or ANDA. ``Applicants'' is used to describe persons 
subject to the postmarketing safety reporting regulations under 
Sec. Sec.  314.80, 314.98, and 600.80 for products with an approved 
NDA, ANDA, or BLA; for Sec.  600.80, ``applicants'' includes 
participants involved in divided manufacturing.

II.B. Rationale for This Proposal

II.B.1. International Standards
    Many of the amendments that are being proposed in this rulemaking 
are intended to harmonize our safety reporting requirements with 
international standards developed by CIOMS and ICH (see table 4 of this 
document). These organizations were formed to facilitate international 
consideration of issues, particularly safety issues, concerning the use 
of global data in the development and use of drugs and biological 
products.
    The CIOMS working groups have been comprised of representatives 
from regulatory authorities, including FDA, and the pharmaceutical 
industry. These groups have worked to develop recommendations for 
standardization of international reporting of postmarketing adverse 
reactions by the pharmaceutical industry to regulatory authorities.
    ICH was organized to provide an opportunity for tripartite 
harmonization initiatives to be developed with input from regulatory 
and industry representatives. ICH has worked to promote the 
harmonization of technical requirements for the registration of 
pharmaceutical products among three regions: The European Union, Japan, 
and the United States. The six ICH sponsors are the European 
Commission; the European Federation of Pharmaceutical Industry 
Associations; the Japanese Ministry of Health and Welfare; the Japanese 
Pharmaceutical Manufacturers Association; FDA; and the Pharmaceutical 
Research and Manufacturers of America.
    One ICH initiative is to harmonize certain safety reporting 
requirements of the three regions. Through the ICH process, 
recommendations have been developed regarding the content, format, and 
reporting frequency for expedited and periodic safety reports for human 
drugs and biological products (the ICH E2A and E2C guidances). In 
addition, a standard medical terminology for regulatory purposes, 
MedDRA, has been developed (ICH M1). Worldwide implementation of this 
initiative is in process. FDA, which has been actively involved in the 
development of these recommendations, has implemented some of them (the 
October 1997 final rule) and is proposing to implement others in this 
rulemaking.
    FDA believes the changes recommended by ICH and CIOMS will result 
in more effective and efficient safety reporting to regulatory 
authorities worldwide. For example, postmarketing periodic safety 
reports are, for the most part, currently submitted to regulatory 
authorities in the three regions at different times with different 
formats and content. International harmonization efforts are beginning 
to decrease some of these differences, but harmonization of the format 
and content, as well as the reporting frequency, of these reports by 
all countries in the three regions is essential to eliminate 
unnecessary reporting burdens on industry so that companies can focus 
on the safety profiles of their products and not on the different 
reporting requirements of different regions. The PSUR recommended for 
postmarketing periodic safety reporting in the ICH E2C guidance 
provides regulatory authorities with a comprehensive overview of the 
safety profile of a product along with other relevant information such 
as estimates of worldwide patient exposure and worldwide marketing 
status of the product. In this rulemaking, FDA is proposing to require 
submission of PSURs for certain products (see sections III.E.2 and 
III.E.5.a of this document). FDA is also interested in receipt of 
additional information and is proposing to require that such 
information be submitted with these reports as appendices (e.g., copy 
of current U.S. approved labeling, information on medication errors, 
resistance to antimicrobial drug products and class action lawsuits) 
(see section III.E.2.k of this document). Thus, companies can prepare 
the same core document for all three regions and any additional 
information required by FDA would simply be attached to this document.
    Another international harmonization effort is standardization of 
medical terminology used for regulatory purposes. As noted previously, 
ICH has developed MedDRA for this purpose. Currently, companies use 
various medical terminologies for safety reporting purposes (e.g., 
WHO's Adverse Reaction Terminology (WHOART), Coding Symbols for a 
Thesaurus of Adverse Reaction Terms (COSTART), Japan's Adverse Reaction 
Terminology (J-ART)). The established terminologies have been 
criticized for a number of reasons, including: Lack of specificity, 
limited data retrieval options, and an inability to effectively handle 
complex combinations of signs and symptoms (syndromes). In addition, 
use of different terminologies at different stages in the development 
and use of products complicates data retrieval and analysis of 
information and makes it difficult to effectively cross-reference data 
through the lifetime of a product. Internationally, communication is 
impaired between regulatory authorities because of the delays and 
distortions caused by the translation of data from one terminology to 
another.
    Use of different terminologies also has significant consequences 
for pharmaceutical firms. Companies operating in more than one 
jurisdiction have had to adjust to subsidiaries or clinical research 
organizations that use different terminologies because of variations in 
data submission requirements. The difficulty of analyzing data 
comprehensively may be compounded by use of incompatible terminologies 
and could lead to delays in recognizing potential public health 
problems.
    For these reasons, it is critical that a single medical terminology 
be used internationally for coding postmarketing safety reports. FDA is 
proposing to use MedDRA for this purpose (see section III.F.2 of this 
document). MedDRA is the best choice because it was developed with 
input from regulatory authorities and industry and the problems 
associated with the other terminologies were taken into consideration 
during development of MedDRA. Some companies have begun to voluntarily

[[Page 12413]]

submit their postmarketing safety reports to FDA coded using MedDRA.
    Even though FDA is proposing to use MedDRA as the standard medical 
terminology for reporting purposes under this rule, the agency 
recognizes that alternative standard classification systems for 
clinical information exist in the United States and supports the 
national health data standardization initiatives underway in the United 
States under the Health Insurance Portability and Accountability Act.
    Although this proposed rule does not impose reporting requirements 
on health care providers, the agency recognizes that clinicians, 
medical centers, hospitals and others may report safety information to 
pharmaceutical companies. These third parties may employ clinical 
terminology standards that differ from those proposed here. Therefore, 
the agency invites comment on the unintended potential impact of this 
proposed rule on those parties not subject to FDA's safety reporting 
requirements. The agency also invites comment on the potential 
strategies and approaches for facilitating seamless cross-standard 
communications, such as mapping between alternative terminologies and 
MedDRA.
II.B.2. Quality of Postmarketing Safety Reports
    In light of the recommendations of ICH and CIOMS, FDA has reviewed 
its postmarketing safety reporting regulations for human drugs and 
licensed biological products and identified additional changes that the 
agency believes would further enhance surveillance of marketed 
products. Many of the postmarketing safety reports that FDA receives 
are complete and of very high quality. Others are incomplete, of 
mediocre or poor quality or both, making it difficult to ascertain the 
significance of these reports. In the latter cases, FDA is 
unnecessarily spending considerable amounts of time trying to collect 
additional information for the reports.
    To address this problem, FDA is proposing amendments to its 
postmarketing safety reporting requirements. For most of these 
amendments, a risk-based approach is being proposed (i.e., greater 
emphasis and effort would be required for reports of serious adverse 
drug experiences while less information would be required for 
nonserious adverse drug experiences (adverse drug experiences proposed 
to be called SADRs in this proposed rule; see section III.A.1 of this 
document)). For example, FDA is proposing that complete information be 
submitted for reports of serious SADRs (see section III.C.5 of this 
document). If complete information is not available, in some cases, a 
followup report would be required (e.g., for serious, unexpected SADRs) 
(see section III.D.6 of this document). On the other hand, for SADRs 
that are determined to be nonserious, not as much information would 
need to be acquired (see section III.C.5 of this document).
    Another amendment would require direct contact with the initial 
reporter of an SADR by a health care professional at the company for 
collection of certain postmarketing safety information (e.g., 
collection of followup information for a serious SADR) (see section 
III.A.6 of this document). Currently, some companies use this approach 
for collecting information, whereas others send the initial reporter a 
letter. The latter case is a passive approach which, in FDA's 
experience, results in limited acquisition of new information. In most 
cases, the initial reporter simply does not respond to the letter. 
Instead, using an active approach, as proposed by FDA, companies would 
more likely obtain the additional information needed for an SADR. Thus, 
use of this approach should result in submission of higher quality 
reports to FDA for review.
    Another amendment would require that a licensed physician at the 
company be responsible for the content of postmarketing safety reports 
submitted to FDA (see sections III.E.1.h, III.E.2.k.xi, and II.F.4 of 
this document). As in the previous examples, some companies currently 
use licensed physicians for this purpose, whereas others have their 
postmarketing safety reports prepared and submitted by clerical 
personnel with no health care training. The medical significance of 
postmarketing safety reports warrants review by a licensed physician. 
The agency believes that licensed physicians would ensure submission of 
high quality reports to FDA that articulately conveys all clinically 
relevant information associated with an SADR.
II.B.3. New Postmarketing Expedited Safety Reports
    FDA currently requires postmarketing expedited safety reports for 
serious and unexpected adverse drug experiences (adverse drug 
experiences proposed to be called SADRs in this proposed rule; see 
section III.A.1 of this document). To facilitate identification of 
significant safety problems, FDA is proposing that additional safety 
information be submitted expeditiously to the agency for marketed drugs 
and biological products. Some of this information is currently 
submitted to the agency but not in an expedited manner. In other cases, 
the information is not currently required to be submitted to the 
agency.
    II.B.3.a. Medication errors. In 1999, the Institute of Medicine 
(IOM) issued a report, ``To Err is Human: Building a Safer Health 
System,'' that cited studies and articles estimating the number of 
Americans dying each year as a result of medical mistakes to be between 
44,000 and 98,000 (Ref. 10). The IOM report concluded that preventable 
adverse drug events impose significant medical, personal, and economic 
costs to the United States.
    Requiring medication errors to be reported in an expedited manner 
to a centralized location would provide a systematic approach for 
collecting comprehensive information on these errors and result in 
timely assessment of the information. Various organizations and health 
care professional associations, including the 1999 IOM report, have 
advocated mandatory medication error reporting efforts, as well as 
encouragement of voluntary efforts, aimed at making sure the system 
continues to be made safer for patients. Such a system would provide 
the public with a higher level of protection by assuring that the most 
serious errors are investigated and reported, and that appropriate 
followup action is taken both by FDA and the company whose product is 
associated with the error. Second, it would provide companies with an 
incentive to improve patient safety regarding medication errors 
associated with their products. Finally, it would require that FDA and 
the pharmaceutical industry make some level of investment in preventing 
medication errors and improving patient safety. In some instances, 
information gathered through this type of a reporting system and 
analyzed for root causes can lead to various changes within the health 
care system to prevent or minimize recurrence.
    Currently, FDA maintains both a voluntary adverse event reporting 
system for health care professionals, through MedWatch (the Medical 
Products Reporting Program), and a mandatory adverse event reporting 
system for companies subject to the agency's postmarketing safety 
reporting regulations. Through these systems, FDA receives only about 
3,000 reports of medication errors annually. FDA believes that these 
safety reporting systems do not adequately address the nature and 
extent of problems caused by medication errors. In most cases, safety 
reports associated with a medication error are not identified in the 
report as being associated with an error. Instead, the report only 
highlights the effect of

[[Page 12414]]

the medication error (e.g., patient experienced a seizure). This 
information is not sufficient for FDA to identify medication errors 
that could be avoided in the future. For cases that involve a 
medication error, the safety report needs to be identified as a 
suspected medication error so that the report can be appropriately 
analyzed and addressed. FDA concludes that an explicit requirement for 
reporting medication errors by companies subject to the agency's 
postmarketing safety reporting regulations is needed to adequately 
assess and respond to the problem.
    FDA is therefore proposing to require that these companies submit 
to the agency expeditiously all domestic reports of actual and 
potential medication errors (see section III.D.5 of this document). FDA 
would review information about suspected medication errors to determine 
an appropriate risk management plan (e.g., changes to the proprietary 
name, labels, labeling or packaging of the drug or biological product 
or educational initiatives to protect public health). This proposal, 
which is consistent with one of the Department of Health and Human 
Services' major health initiatives, would allow FDA to form the 
framework for building a comprehensive risk assessment and management 
system for preventable SADRs. This proposal is also responsive to the 
1999 IOM report, which states that ``the Food and Drug Administration 
(FDA) should increase attention to the safe use of drugs in both pre- 
and postmarketing process'' by ``establishing appropriate responses to 
problems identified through post-marketing surveillance, especially for 
concerns that are perceived to require immediate response to protect 
the safety of patients.''
    II.B.3.b. Unexpected SADRs with unknown outcome. FDA is also 
proposing to require that companies subject to the agency's 
postmarketing safety reporting regulations submit to FDA in an 
expedited report SADRs that are unexpected and for which a 
determination of serious or nonserious cannot be made (i.e., SADR with 
unknown outcome) (see section III.D.3 of this document). This 
information is currently submitted to FDA, but, in most cases, not in 
an expedited manner. A company that receives a report of an adverse 
drug experience is able, in most cases, to determine if it is serious 
or nonserious (i.e., whether it meets the regulatory definition of 
serious), but in some cases, this may not be possible. Currently, most 
companies that are not able to make this determination designate the 
adverse drug experience as nonserious and include it in their next 
quarterly or annual postmarketing periodic safety report. In some of 
these cases, the adverse drug experience is, in fact, serious even 
though the company was not able to make this determination. FDA needs 
to receive reports of SADRs with unknown outcome expeditiously if the 
SADR is unexpected so that the agency can evaluate the report in light 
of other data and information available to FDA to attempt to determine 
if the SADR is serious. FDA would do this by comparing information on 
the unexpected SADR with unknown outcome with information on other 
similar unexpected SADRs with a known serious outcome that are on file 
with the agency.
    II.B.3.c. Always expedited reports. FDA is also proposing that 
companies subject to the agency's postmarketing safety reporting 
regulations always submit to FDA in an expedited report certain SADRs, 
which may jeopardize the patient or subject and/or require medical or 
surgical intervention to treat the patient or subject (e.g., 
ventricular fibrillation, liver necrosis, transmission of an infectious 
agent by an approved product) (see section III.D.4 of this document). 
Currently, all of these adverse drug experiences are submitted to the 
agency for review, but only some of them are submitted in an expedited 
safety report (i.e., if the adverse drug experience is serious and 
unexpected). FDA is proposing that all of them be submitted 
expeditiously whether the SADR is unexpected or expected and whether or 
not the SADR leads to a serious outcome. This is because of the medical 
gravity of these SADRs. For example, even though the labeling for a 
product indicates that ventricular fibrillation may be associated with 
use of the product and thus not subject to expedited reporting to FDA 
(i.e., SADR is expected), the agency needs to review each new report of 
ventricular fibrillation for this product as quickly as possible to 
ascertain if there is a qualitative or quantitative change in the 
nature of the SADR. Information from these reports could result in 
either new studies being undertaken to evaluate the SADR or appropriate 
regulatory action by FDA (e.g., labeling change, distribution of Dear 
Health Care Professional letter, restriction on distribution of 
product, withdrawal of product from the market).
    II.B.3.d. Blood and blood component safety reports. With regard to 
blood and blood components (e.g., red blood cells, plasma, platelets, 
cryoprecipitated AHF), FDA is proposing that blood establishments 
submit reports to the agency for all serious SADRs associated with 
blood collection and transfusion, in addition to their current 
requirement at Sec.  606.170(b) (21 CFR 606.170(b)) to submit reports 
of fatalities (see section III.D.12 of this document). This proposed 
safety reporting requirement would not impose significant new burdens 
on blood establishments. This is because under Sec.  606.170(a) (21 CFR 
606.170(a)) blood collection and transfusion facilities are currently 
required to conduct investigations and prepare and maintain reports of 
all adverse events associated either with the collection or transfusion 
of blood or blood components. The proposal would simply require that 
reports of serious SADRs that are currently maintained by the facility, 
be submitted to the agency within 45 calendar days of occurrence rather 
than only having these reports be reviewed by FDA at the time of an 
inspection. Thus, not all serious SADRs are reported to FDA for blood 
and blood components. FDA believes that it is critical that we receive 
all such reports to enhance donor safety and also to ensure the safety, 
purity and potency of blood and blood components for administration to 
patients.
    In the past, the agency has received some voluntary reports that 
have helped to identify errors in manufacturing and defects in products 
used to collect blood. For example, in 1997, FDA received reports from 
a blood establishment of allergic adverse reactions to red blood cells 
that had been leukoreduced using a bedside filtration method in 
hematology or oncology patients receiving multiple transfusions. The 
reactions were related to several lots of Hemasure Leukonet filters. 
The symptoms included bilateral conjunctival edema, severe headaches, 
eye pain, nausea sometimes associated with vomiting and joint pain. 
After investigation and analysis of the reports by FDA, the 
manufacturer discontinued production of the filter. Voluntary reporting 
of the adverse reactions by the blood establishment brought the issue 
to the attention of FDA. However, the time to resolution may have been 
shortened had these been required to be reported to FDA from all blood 
centers.
    With regard to the safety of donors, FDA review of adverse event 
reports is important and has resulted in detection and correction of 
problematic collection procedures. During an inspection, FDA field 
officers identified a blood collection center that had numerous donors 
with vasovagal reactions that required treatment by emergency medical 
personnel. In some of these cases, the donors had to be transported to 
a hospital emergency room for treatment. Upon investigation, FDA

[[Page 12415]]

determined that the center had failed to establish a lower limit for 
blood pressure measurements for donors as required by 21 CFR 640.3. Had 
these serious adverse events been required to be reported to FDA, 
immediate analysis of them is likely to have identified the problem 
sooner.
    Thus, required reporting of all serious SADRs related to blood 
collection and transfusion would enhance FDA's ability to take 
appropriate action to protect the blood supply more consistently. 
Currently, there is no assurance that FDA will receive reports of 
serious SADRs that have the potential to adversely affect both the 
donors and recipients of the nation's blood supply. Such information is 
essential for evaluating the agency's scientific and regulatory 
policies and for monitoring industry practices and their implications 
on blood safety.
    II.B.4. Bioavailability and Bioequivalence Studies Not Subject to 
an Investigational New Drug Application (IND).
    FDA is also proposing to amend its bioavailability and 
bioequivalence regulations under part 320 (21 CFR part 320) (see 
section III.K of this document). Under the existing regulations at 
Sec.  320.31, persons conducting a bioavailability or bioequivalence 
study in humans are only required to comply with the IND requirements 
of part 312 (21 CFR part 312) for certain products or for certain types 
of studies. This proposed rule would require submission of expedited 
safety reports for serious, unexpected adverse experiences (adverse 
experiences proposed to be called SADRs in this proposed rule; see 
section III.A.1 of this document) as prescribed under Sec.  312.32 for 
human bioavailability and bioequivalence studies that are not being 
conducted under an IND. FDA believes that bioavailability and 
bioequivalence studies that are not being conducted under an IND are, 
in general, safe. However, the agency is occasionally made aware of 
safety-related information associated with these types of studies. This 
information could either reflect a problem with the drug product being 
evaluated or with the study design being used. Timely review of 
serious, unexpected SADRs from these studies is critical to ensure the 
safety of study subjects. FDA would use this information to determine 
if the study design needs to be altered or if the study needs to be 
stopped.

II.C. New Safety Reporting Abbreviations

    Table 3 provides a list of new safety reporting abbreviations that 
are used in this document.

                                  Table 3.--New Safety Reporting Abbreviations
----------------------------------------------------------------------------------------------------------------
                                                                            Reference in section III of this
                 Phrase                           Abbreviation                          document
----------------------------------------------------------------------------------------------------------------
Company core safety information........  CCSI.........................  A.9
Interim periodic safety report.........  IPSR.........................  E.3
Medical dictionary for regulatory        MedDRA.......................  F.2
 activities.
Periodic safety update report..........  PSUR.........................  E.2
Suspected adverse drug reaction........  SADR.........................  A.1
Traditional periodic safety report.....  TPSR.........................  E.1
----------------------------------------------------------------------------------------------------------------

II.D. Highlights of Proposed Changes to FDA's Safety Reporting 
Regulations

    Specific changes to FDA's safety reporting requirements, as 
described in this proposed rule, are identified in table 4.

                 Table 4.--Highlights of Proposed Changes to FDA's Safety Reporting Requirements
----------------------------------------------------------------------------------------------------------------
                                   Proposed Change (reference in section III    Is the change based on ICH (ICH
         21 CFR Section                        of this document)                           guidance)?
----------------------------------------------------------------------------------------------------------------
Changes apply to: 310.305,        [sbull] ``Associated with the use of the     Yes (E2A)
 312.32, 314.80, 314.98, and       drug'' and ``adverse drug experience''
 600.80.\1\                        changed to ``suspected adverse drug
                                   reaction (SADR)'' and ``adverse
                                   experience'' changed to ``suspected
                                   adverse reaction (SAR)'' (A.1).
                                  [sbull] Minimum data set required for all    Yes (E2A)
                                   individual case safety reports of SADRs
                                   (A.5, B.2.a, C.5, E.4).
                                  [sbull] Reporting requirements for lack of   Yes (E2A and E2C)
                                   efficacy reports revised (B.2.c, C.7, D.2,
                                   E.1.c, E.2.h, E.2.k.vi).
                                  [sbull] Sources of safety information        No
                                   revised (B.1, C.2, D.8).
                                  [sbull] Individual case safety reports from  Yes (E2A)
                                   clinical trials based on opinion of either
                                   the sponsor/applicant or investigator
                                   (B.2.b, B.3, C.6).
                                  [sbull] Narrative format required for        No
                                   safety reports of overall findings or data
                                   in the aggregate (B.2.d, F.1).
Changes only apply to 312.32....  [sbull] Determination of a life-threatening  Yes (E2A)
                                   SADR based on opinion of either sponsor or
                                   investigator (A.2).
                                  [sbull] Expedited reports of findings from   Yes (E2A)
                                   tests in laboratory animals revised to
                                   include other information sufficient to
                                   consider product administration changes
                                   (B.2.c).
Changes only apply to 310.305,    New Safety Reports.........................  Yes (E2A)
 314.80, 314.98, 600.80.          [sbull] Expedited report for information
                                   sufficient to consider product
                                   administration changes (D.2).
                                  [sbull] Expedited report for unexpected      No
                                   SADRs with unknown outcome (A.3, D.3).

[[Page 12416]]

 
                                  [sbull] Always expedited reports for         No
                                   certain medically significant SADRs
                                   whether unexpected or expected and whether
                                   or not the SADR leads to a serious outcome
                                   (D.4).
                                  [sbull] Expedited report for medication      No
                                   errors (D.5).
                                  [sbull] 30-day followup report for initial   No
                                   serious and unexpected SADR reports,
                                   always expedited reports, and medication
                                   error reports that do not contain a full
                                   data set (D.6).
                                  Other Changes..............................  No
                                  [sbull] Active query required to acquire
                                   certain safety information (A.6, C.5, D.6,
                                   D.7).
                                  [sbull] Full data set required for reports   No
                                   of serious SADRs, always expedited
                                   reports, and medication error reports
                                   (A.5, C.5, D.1, D.4, D.5, E.4).
                                  [sbull] Safety reporting requirements for    No
                                   contractors and shared manufacturers (A.4,
                                   D.9).
Changes only apply to 310.305,    [sbull] Reporting requirements for           Yes (E2A and E2C)
 314.80, 314.98, and 600.80.       spontaneous reports codified (A.7, C.6).
                                  [sbull] Supporting documentation required    No
                                   for expedited reports concerning a death
                                   or hospitalization (D.7).
                                  [sbull] FDA request for submission of        No
                                   safety reports at times other than
                                   prescribed by regulations (C.4).
                                  [sbull] Individual case safety reports       Yes (M1)
                                   required to be coded using MedDRA (F.2)..
                                  [sbull] SADR information from class action   No
                                   lawsuits (A.7, E.1.e, E.2.k.v, E.3).
                                  [sbull] Contact person for postmarketing     No
                                   safety reports (E.1.h, E.2.k.xi, E.3, F.4).
                                  [sbull] Use of computer-generated facsimile  No
                                   of FDA Form 3500A or VAERS form permitted
                                   without approval by FDA (F.5).
                                  [sbull] Location of safety records (D.10,    No
                                   E.1.g, E.2.k.x, E.3).
                                  [sbull] FDA request for submission of        No
                                   safety related records (D.7, H)..
Changes only to apply to 314.80,  New or Revised Safety Reports..............  No
 314.98 and 600.80.               [sbull] Semiannual submission of certain     No
                                   spontaneously reported individual case
                                   safety reports (E.4, E.5.a).
                                  [sbull] TPSR, PSUR, or IPSR for              No
                                   applications approved prior to January 1,
                                   1998 (E.1, E.2, E.3, E.5.a).
                                  [sbull] PSUR/IPSR for applications approved  Yes (E2C)
                                   on or after January 1, 1998 (E.2, E.3,
                                   E.5.a).
                                  [sbull] PSUR/IPSR for pediatric use          No
                                   supplements (E.5.a).
                                  Other Changes..............................  Yes (E2C)
                                  [sbull] Periodicity of periodic safety
                                   reports (E.5.a, I).
                                  [sbull] Submission date for periodic safety  Yes (E2C)
                                   reports (A.10, E.5.b, I).
                                  [sbull] CCSI for determination of listed     Yes (E2C)
                                   and unlisted SADRs for certain periodic
                                   safety reports (A.9, E.2, E.3, E.4).
                                  [sbull] Information in addition to the       No
                                   minimum data set not required to be
                                   acquired for nonserious SADRs, except for
                                   nonserious SADRs resulting from a
                                   medication error, which require a full
                                   data set (A.3, C.5, E.4).
                                  [sbull] Individual case safety reports       No
                                   forwarded to applicant by FDA required to
                                   be included in comprehensive safety
                                   analysis (C.2).
                                  [sbull] Information on resistance to         No
                                   antimicrobial drug products (E.2.k.vii,
                                   E.3).
                                  [sbull] Number of copies of periodic safety  No
                                   reports required to be submitted to FDA
                                   (C.3).
Change only applies to 314.81     [sbull] Requirement to submit safety-        No
 and 601.28 \2\.                   related information in postmarketing
                                   annual report revoked (J).
Change only applies to 312.64(b)  [sbull] Investigator safety reporting        No
 \3\.                              requirements revised.
Change only applies to 320.31(d)  [sbull] Submission of expedited safety       No
 \4\.                              reports required for human bioequivalence
                                   and bioavailability studies which are
                                   exempt from submission of an IND (K).
Change only applies to 606.170    [sbull] All serious SARs required to be      No
 \5\.                              submitted to FDA for blood and blood
                                   products (D.12).
----------------------------------------------------------------------------------------------------------------
\1\ Section 310.305 describes postmarketing safety reporting regulations for prescription drug products marketed
  for human use without an approved application; Sec.   312.32 describes premarketing safety reporting
  regulations for investigational drugs and biological products; Sec.   314.80 describes postmarketing safety
  reporting regulations for human drugs with approved NDAs; Sec.   314.98 describes postmarketing safety
  reporting regulations for human drugs with approved ANDAs; and Sec.   600.80 describes postmarketing safety
  reporting regulations for human licensed biological products with approved BLAs.
\2\ Section 314.81 describes postmarketing annual reporting regulations for human marketed drugs with approved
  NDAs; Sec.   601.28 describes postmarketing annual reporting regulations for pediatric studies of human
  licensed biological products with approved BLAs.
\3\ Section 312.64(b) describes requirements for safety reporting to sponsors by investigators.
\4\ Section 320.31 (d) describes bioequivalence and bioavailability requirements for studies which are exempt
  from submission of an IND.
\5\ Section 606.170 describes safety reporting and recordkeeping requirements for blood and blood products.


[[Page 12417]]

III. Description of the Proposed Rule

III.A. Definitions

III.A.1. Suspected Adverse Drug Reaction (SADR)
    FDA's existing premarketing safety reporting regulations in Sec.  
312.32(a) define ``associated with the use of the drug'' to mean: 
``There is a reasonable possibility that the experience may have been 
caused by the drug.''
    FDA's existing postmarketing safety reporting regulations in 
Sec. Sec.  310.305(b), 314.80(a), and 600.80(a) define ``adverse drug 
experience (``adverse experience'' for Sec.  600.80(a))'' to mean:

    Any adverse event associated with the use of a drug 
(``biological product'' for Sec.  600.80(a)) in humans, whether or 
not considered drug (``product'' for Sec.  600.80(a)) related, 
including the following: An adverse event occurring in the course of 
the use of a drug (``biological'' for Sec.  600.80(a)) product in 
professional practice; an adverse event occurring from drug overdose 
(``from overdose of the product'' for Sec.  600.80(a)) whether 
accidental or intentional; an adverse event occurring from drug 
abuse (``from abuse of the product'' for Sec.  600.80(a)), an 
adverse event occurring from drug withdrawal (``from withdrawal of 
the product'' for Sec.  600.80(a)); and any failure of expected 
pharmacological action.

    Proposed Sec.  312.32(a) would replace the term ``associated with 
the use of the drug'' with the term ``suspected adverse drug reaction 
(SADR).'' Proposed Sec. Sec.  310.305(a) and 314.80(a) would replace 
the term ``adverse drug experience'' with the term ``suspected adverse 
drug reaction (SADR)'' (see section III.C.1 of this document regarding 
reorganization of Sec.  310.305). Proposed Sec.  600.80(a) would 
replace the term ``adverse experience'' with the term ``suspected 
adverse reaction (SAR).'' In this document the term ``adverse drug 
experience'' is synonymous with the term ``adverse experience'' and the 
abbreviation ``SADR'' will be used for both ``SADR'' and ``SAR,'' 
except when reference is only being made to an ``SAR,'' in which case 
the abbreviation ``SAR'' will be used. Proposed Sec. Sec.  310.305(a), 
312.32(a), 314.80(a), and 600.80(a) would also replace the definitions 
for ``associated with the use of the drug,'' ``adverse drug 
experience'' and ``adverse experience'' with the following definition 
for ``SADR'':

    A noxious and unintended response to any dose of a drug 
(``biological'' for proposed Sec.  600.80(a)) product for which 
there is a reasonable possibility that the product caused the 
response. In this definition, the phrase ``a reasonable 
possibility'' means that the relationship cannot be ruled out.

    The phrase ``the relationship cannot be ruled out'' clarifies which 
individual cases would be reported to FDA. Classifying a case as 
``probably related,'' ``possibly related,'' ``remotely related,'' or 
``unlikely related'' to the drug or biological product would signify 
that a causal relationship between the product and an adverse event 
could not be ruled out and, thus, the adverse event would be considered 
an SADR. For example, in some cases an adverse event may most probably 
have occurred as a result of a patient's underlying disease and not as 
a result of a drug or biological product the patient was taking, but it 
cannot usually be said with certainty that the product did not cause 
the adverse event. Therefore, such an adverse event would be classified 
as an SADR because there would be at least a ``reasonable possibility'' 
that the drug or biological product may have caused the adverse event. 
Of course, this classification would not establish causality 
(attributability) by itself, it would only indicate that causality 
could not be ruled out with certainty.
    These proposed changes are consistent with the ICH E2A guidance (60 
FR 11284 at 11285), which defines ``adverse drug reaction'' as:

    All noxious and unintended responses to a medicinal product 
related to any dose should be considered adverse drug reactions. The 
phrase ``response to medicinal products'' means that a causal 
relationship between a medicinal product and an adverse event is at 
least a reasonable possibility, i.e., the relationship cannot be 
ruled out.

    These proposed amendments would harmonize the agency's premarketing 
and postmarketing safety reporting definition for SADR, as well as 
safety reporting worldwide.
    Even though FDA has harmonized its proposed definition of SADR with 
the definition of adverse drug reaction recommended by ICH, the agency 
would like comment on an alternative definition for SADR: ``A noxious 
and unintended response to any dose of a drug product for which a 
relationship between the product and the response to the product cannot 
be ruled out''. The alternative and proposed definitions for SADR have 
the same meaning (i.e., a response to a product is an SADR unless one 
is sure that the product did not cause the response). The difference 
between these definitions is that the alternative definition of SADR 
does not include the phrase ``a reasonable possibility.'' This is 
because use of this phrase is potentially confusing. The phrase ``a 
reasonable possibility'' might be interpreted differently than the 
phrase ``the relationship cannot be ruled out.'' The agency defines ``a 
reasonable possibility'' as ``the relationship cannot be ruled out'' to 
be consistent with ICH. FDA seeks comment as to whether the agency 
should use the alternative definition of SADR instead of the proposed 
definition of SADR. The agency also requests comment from sponsors, 
manufacturers and applicants if their interpretation of these 
definitions is different than FDA's interpretation.
    As explained in the following paragraphs, FDA believes that the 
proposed definition of SADR would not affect the number of safety 
reports that are currently submitted to FDA from spontaneous sources, 
but it could increase the number of safety reports that would be 
submitted from clinical studies. FDA seeks comment as to whether use of 
the proposed or alternative definition of SADR would lead to 
significant increases in reporting to the agency beyond what FDA has 
identified in the following paragraphs. FDA is particularly interested 
in learning of examples of events beyond those identified by the agency 
that are not currently reported to FDA but would be required to be 
reported under these definitions.
    Although FDA is proposing to remove the definition for ``adverse 
drug experience'' from its postmarketing safety reporting regulations 
and replace it with the proposed definition for ``SADR,'' this change 
would not affect the number of safety reports from spontaneous sources 
that would be submitted to the agency because every spontaneous report 
currently must be submitted to FDA, irrespective of whether the 
manufacturer or applicant considers it to be drug related (see current 
definition of adverse drug experience at Sec. Sec.  310.305(c), 
314.80(c), and 600.80(c)). Under this proposed rule, every spontaneous 
report would continue to be submitted to FDA, because, for spontaneous 
reports, manufacturers and applicants would always be required to 
assume, for safety reporting purposes only, that there was at least a 
reasonable possibility in the opinion of the initial reporter that the 
drug or biological product caused the spontaneously reported event (see 
sections III.A.7 and III.C.6 of this document for the proposed 
definition of spontaneous report and for discussion of the proposed 
reporting requirement for SADRs from spontaneous sources).
    On the other hand, with regard to clinical studies of 
investigational and marketed drugs and biological products, the 
proposed definition of SADR is likely to result in an increase in the 
number of safety reports that are currently submitted to FDA from some

[[Page 12418]]

studies. Current regulations at Sec. Sec.  310.305(c)(1)(ii), 
312.32(c)(1), 314.80(e)(1), and 600.80(e)(1) require that serious, 
unexpected adverse experiences from a study be reported to FDA only if 
there is a reasonable possibility that the drug caused the adverse 
experience. The phrase ``reasonable possibility'' is typically 
interpreted by sponsors, manufacturers and applicants to mean that 
there is a possible causal relationship between an adverse experience 
and a drug or biological product. It would not include adverse 
experiences considered to be unlikely or remotely related to the 
product. The proposed definition of SADR maintains the phrase 
``reasonable possibility'' as part of the definition, but defines the 
phrase to mean that the relationship between a product and a response 
to the product cannot be ruled out. In some cases, this proposed change 
would result in submission of more safety reports to FDA. For example, 
under the current regulations if a sponsor or applicant concludes that 
the existence of a causal relationship between a drug and an adverse 
event is unlikely or remote, but not impossible, (e.g., because the 
event is a recognized consequence of the patient's underlying disease) 
it would not submit a safety report to FDA. In contrast, under the 
proposed rule, the sponsor or applicant would be required to submit a 
safety report to the agency for this SADR, because, although the 
relationship of the adverse event to the drug is unlikely or remote 
because of the patient's underlying disease, a causal relationship 
cannot, nonetheless, be ruled out. FDA is proposing the new definition 
for SADR to minimize situations in which an adverse event that proves 
ultimately to be due to a drug or biological product is not reported as 
soon as possible to the agency because the etiology of the adverse 
event is attributed to the patient's underlying disease by the sponsor, 
manufacturer or applicant (e.g., a patient's hepatic deterioration is 
judged to be related to the patient's viral hepatitis and not to the 
hepatotoxicity of the drug the patient received.)
    FDA recognizes, however, that particularly for those patients who 
have certain diseases (e.g., fatal diseases such as cancer), the 
proposed definition of SADR may result in submission of numerous safety 
reports to the agency for which the reported SADR is not informative as 
a single report because it is very likely to have been a consequence of 
the patient's disease. This would be true, for example, for most non-
acute deaths in a clinical trial evaluating a drug in cancer patients. 
These deaths would have to be reported to FDA as SADRs because a 
relationship between the drug and the deaths could not be ruled out 
with certainty. Because such ``over-reporting'' may make it more 
difficult for FDA and the sponsor, manufacturer or applicant to 
recognize adverse events that are really caused by a drug or biological 
product, the agency wants to minimize receipt of this type of safety 
report, but in a way that does not compromise receipt of useful safety 
reports that are perceived as remotely related to an administered drug 
or biological product but that occur, in fact, as a result of the 
product. If sponsors, manufacturers or applicants believe that, in a 
specific situation, there is an alternative way(s) to handle adverse 
events occurring during clinical studies that would minimize ``over-
reporting'' while assuring that reporting of SADRs would not be 
compromised, they are invited to propose any such alternative(s) 
reporting method to the agency. In such situations, if FDA does not 
oppose the proposed alternative reporting method, the sponsor, 
manufacturer or applicant would be permitted to report SADRs to the 
agency according to the alternative method. For example, one such 
alternative would be to include in study protocols or other 
documentation a list of known consequences of the disease that would 
not be submitted to FDA in an expedited manner as individual case 
safety reports (e.g., events that are the endpoints of the study). 
These adverse events would, however, be monitored by the sponsor, 
manufacturer, or applicant and, if they indicated in the aggregate by 
comparison to a control group or historical experience, that the 
product in the clinical study may be causing these events, the 
information would be submitted to FDA in an expedited manner as an 
information sufficient to consider product administration changes 
report (see sections III.B.2.c and III.D.2 of this document for 
discussion of this type of report). FDA invites comment from the public 
on this alternative and requests suggestions for other alternatives as 
well that would minimize ``over-reporting'' of uninformative events and 
assure submission of meaningful reports of unexpected events. FDA also 
invites comment on reporting of these types of clinical events that 
occur in studies not being conducted under an IND (e.g., drug or 
biological product is marketed in the United States for a particular 
indication and being investigated in a clinical trial abroad for the 
same or other indication).
    The proposed definition of SADR may result in submission to FDA of 
some reports from clinical studies and the scientific literature in 
which the reported SADR is suspected to be associated with the product, 
but, in fact, it is ultimately demonstrated not to be due to the 
product. This is also true for reports from spontaneous sources in 
which manufacturers and applicants must always assume, for safety 
reporting purposes, that there is at least a reasonable possibility 
that the drug or biological product caused the spontaneously reported 
event and submit the report to FDA. Thus, SADR reports are required to 
be submitted to FDA based on a suspected, not established, causal 
relationship between an adverse event and a drug. This type of 
reporting program allows the agency to determine more quickly which 
SADRs warrant regulatory action by FDA to protect public health (e.g., 
change in product labeling, withdrawal of product from the market). FDA 
receives hundreds of thousands of such reports each year, most of which 
do not result in any regulatory action. But for those reports that do 
represent a significant change in the benefit-to-risk profile of a 
product, this system is critical for developing a signal necessitating 
further evaluation of an SADR.
    Some members of the public have maintained that submission of 
voluntary SADR reports by health care professionals or consumers to 
manufacturers or to FDA might be discouraged because of concern that a 
person or entity might be implicated in a product liability action. In 
addition, industry has expressed its concern that these reports, taken 
out of context and used in a manner for which they were never intended, 
can create a product liability vulnerability. FDA is concerned that 
such liability misuse of these reports could imperil the credibility 
and functionality of this critical public health reporting system.
    Our current safety reporting regulations at Sec. Sec.  310.305(g), 
312.32(e), 314.80(k), and 600.80(l) provide manufacturers, applicants, 
and sponsors with a disclaimer that permits them to deny that the 
safety report or other information required to be submitted to FDA 
under these regulatory provisions constitutes an admission that the 
drug or biological product caused or contributed to an adverse effect. 
For example, Sec.  314.80(k) currently reads in pertinent part:

    Disclaimer. A report or information submitted by an applicant 
under this section (and any release by FDA of that report or 
information) does not necessarily reflect a

[[Page 12419]]

conclusion by the applicant or FDA that the report or information 
constitutes an admission that the drug caused or contributed to an 
adverse effect. An applicant need not admit, and may deny, that the 
report or information submitted under this section constitutes an 
admission that the drug caused or contributed to an adverse effect.

    Additionally, a ``disclaimer'' is included on the first page of the 
voluntary reporting form used by health care professionals and 
consumers, FDA Form 3500, stating ``Submission of a report does not 
constitute an admission that medical personnel or the product caused or 
contributed to the event.'' A similar disclaimer is included on the 
mandatory reporting form used by manufacturers and applicants, FDA Form 
3500A. In its notice of availability announcing FDA Form 3500 and 
3500A, the agency reiterated that ``Although the underlying information 
may be relevant to product liability issues, submitting the form 
itself, as is clearly stated on the form, does not constitute an 
admission that the product caused the adverse event'' (58 FR 31596 at 
31600, June 3, 1993).
    FDA seeks comment as to whether these ``disclaimers'' are 
sufficient to protect manufacturers, applicants, and sponsors, from the 
use of SADR reports in product liability actions. For instance, perhaps 
the agency should consider also prohibiting use of SADR reports the 
agency receives in product liability actions. Accordingly, FDA seeks 
comment on the need for any further action to promote submission of 
SADR reports to the agency and guard against their misuse, as well as 
FDA's legal authority to take any such action.
    FDA is proposing to remove the current provisions in Sec. Sec.  
310.305(c)(1)(ii), 314.80(e)(1), and 600.80(e)(1). The agency is 
proposing this amendment because the information contained in these 
paragraphs is included in the proposed definition of SADR.
III.A.2. A Life-Threatening SADR
    FDA's existing premarketing safety reporting regulations at Sec.  
312.32(a) define a life-threatening adverse drug experience as:

    Any adverse drug experience that places the patient or subject, 
in the view of the investigator, at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction that, 
had it occurred in a more severe form, might have caused death.

    FDA is proposing to amend this definition by adding the phrase ``or 
sponsor'' after the word ``investigator.'' Thus, reports of life-
threatening SADRs would be based on the opinion of either the 
investigator or sponsor. In some cases, the opinions of the 
investigator and sponsor may be discordant. In these situations, the 
sponsor would submit an IND safety report to FDA for the life-
threatening SADR and include in the report the reason(s) for any 
differences in opinions. This proposed revision is consistent with the 
ICH E2A guidance (60 FR 11286): ``Causality assessment is required for 
clinical investigation cases. All cases judged by either the reporting 
health care professional or the sponsor as having a reasonable 
suspected causal relationship to the medicinal product qualify as ADR's 
[adverse drug reactions].''

    FDA's existing postmarketing safety reporting regulations at 
Sec. Sec.  310.305(b), 314.80(a), and 600.80(a) define a ``life-
threatening adverse drug experience'' as:

    Any adverse [drug] experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the 
adverse [drug] experience as it occurred, i.e., it does not include 
an adverse [drug] experience that, had it occurred in a more severe 
form, might have caused death.

Proposed Sec. Sec.  310.305(a), 312.32(a), 314.80(a), and 600.80(a) 
would amend the premarketing and postmarketing definition of life-
threatening adverse drug experience by making minor revisions. FDA is 
proposing to move the phrase ``places the patient'' (``patient or 
subject'' for proposed Sec.  312.32(a)) before the phrase ``at 
immediate risk of death'' and also to replace the phrase ``adverse drug 
experience'' with the abbreviation ``SADR.''
III.A.3. Serious SADR, Nonserious SADR, and SADR With Unknown Outcome
    FDA's existing premarketing and postmarketing safety reporting 
regulations at Sec. Sec.  310.305(b), 312.32(a), 314.80(a), and 
600.80(a) define a serious adverse drug experience as:

    Any adverse [drug] experience occurring at any dose that results 
in any of the following outcomes: Death, a life-threatening adverse 
[drug] experience, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/ 
incapacity, or a congenital anomaly/birth defect. * * *

Proposed Sec. Sec.  310.305(a), 312.32(a), 314.80(a), and 600.80(a) 
would amend this definition by removing the phrase ``occurring at any 
dose,'' because the proposed definition of SADR includes the phrase 
``response to any dose of a drug (``biological'' for proposed Sec.  
600.80(a)) product'' and it is unnecessary to refer to ``any dose'' in 
both definitions. FDA is also proposing to amend this definition by 
replacing the phrase ``adverse drug experience'' with the abbreviation 
``SADR'' for consistency as proposed previously.

    Under proposed Sec. Sec.  310.305(a), 314.80(a), and 600.80(a), FDA 
would amend its postmarketing safety reporting regulations to define 
the term ``nonserious SADR'' to mean: ``Any SADR that is determined not 
to be a serious SADR.'' FDA is proposing to add this definition to 
clarify what constitutes a nonserious SADR. SADRs would only be 
classified as ``nonserious'' if manufacturers and applicants have 
determined that the reaction does not meet the definition of a serious 
SADR. If the outcome for an SADR is not known, a determination of 
seriousness cannot be made; the SADR would not default to a 
``nonserious'' designation, but would rather be classified as an ``SADR 
with unknown outcome'' as described below.
    Under proposed Sec. Sec.  310.305(a), 314.80(a), and 600.80(a), FDA 
would amend its postmarketing safety reporting regulations to define 
the term ``SADR with unknown outcome'' to mean: ``An SADR that cannot 
be classified, after active query, as either serious or nonserious.'' 
FDA is proposing to define this term to describe those SADRs for which 
an outcome (i.e., classification as either serious or nonserious) 
cannot be determined. FDA believes that, in most cases, manufacturers 
and applicants are usually able to determine the outcome of an SADR. 
However, in a few cases, this may not be possible, even after active 
query, and these SADRs would be designated as ``SADR with unknown 
outcome'' (see section III.A.6 of this document for proposed definition 
of active query).
III.A.4. Contractor
    Under proposed Sec.  310.305(a), FDA would amend its postmarketing 
safety reporting regulations to define the term ``contractor'' to mean:

    Any person (e.g., packer or distributor whether or not its name 
appears on the label of the product; licensee; contract research 
organization) that has entered into a contract with the manufacturer 
to manufacture, pack, sell, distribute, or develop the drug or to 
maintain, create, or submit records regarding SADRs or medication 
errors.

    Under proposed Sec.  314.80(a), the term ``contractor'' is defined 
as persons (e.g., manufacturer, packer, or distributor whether or not 
its name appears on the label of the product; licensee; contract 
research organization) that have entered into a contract with the 
applicant. Under proposed Sec.  600.80(a), the term ``contractor'' is 
defined as persons (e.g.,

[[Page 12420]]

manufacturer, joint manufacturer, packer, or distributor whether or not 
its name appears on the label of the product; licensee; contract 
research organization) that have entered into a contract with the 
applicant (includes participants involved in divided manufacturing). 
FDA would define this term to specify which contractors would be 
subject to the agency's postmarketing safety reporting requirements 
under proposed Sec. Sec.  310.305(c)(2)(xi), 314.80(c)(2)(x), and 
600.80(c)(2)(x) (see section III.D.9 of this document). Persons under 
contract to manufacture, pack, sell, distribute, or develop the drug or 
licensed biological product, or to maintain, create, or submit records 
regarding SADRs or medication errors (whether or not the medication 
error results in an SADR; see section III.A.8 of this document) would 
have postmarketing safety reporting responsibilities.
III.A.5. Minimum Data Set and Full Data Set for an Individual Case 
Safety Report
    Proposed Sec. Sec.  310.305(a), 312.32(a), 314.80(a), and 
600.80(a), would amend FDA's premarketing and postmarketing safety 
reporting regulations to define the term ``minimum data set.'' A 
``minimum data set'' for an individual case safety report of an SADR 
would include: an identifiable patient, an identifiable reporter, a 
suspect drug (biological for proposed Sec.  600.80(a)) product, and an 
SADR.
    Proposed Sec. Sec.  310.305(a), 314.80(a), and 600.80(a), would 
also amend FDA's postmarketing safety reporting regulations to define 
the term ``full data set.'' A ``full data set'' for a postmarketing 
individual case safety report would include:

    Completion of all the applicable elements on FDA Form 3500A (or 
the Vaccine Adverse Event Reporting System (VAERS) form for proposed 
Sec.  600.80(a)) (or on a Council for International Organizations of 
Medical Sciences (CIOMS) I form for reports of foreign SADRs) 
including a concise medical narrative of the case (i.e., an accurate 
summary of the relevant data and information pertaining to an SADR 
or medication error).

    The proposed rule would define these terms to clarify the type of 
information that manufacturers and applicants would be required to 
submit to FDA for SADRs and medication errors. The proposed rule would, 
as described below, require at least a minimum data set for all 
individual case safety reports, except for certain reports of 
medication errors (see sections III.B.2.a and III.C.5 of this 
document). In addition, a full data set would be required for 
postmarketing individual case safety reports of serious SADRs, always 
expedited reports, and medication error reports (see sections III.C.5, 
III.D.1, III.D.4, III.D.5, and III.E.4 of this document). Reports of 
nonserious SADRs with a minimum data set would include all safety 
information received or otherwise obtained by the manufacturer or 
applicant for the SADR. However, except for reports of nonserious SADRs 
resulting from a medication error, information in addition to the 
minimum data set would not be required to be acquired by the 
manufacturer or applicant (see sections III.C.5 and III.E.4 of this 
document). Manufacturers and applicants would be required to submit a 
full data set for reports of nonserious SADRs resulting from a 
medication error (see sections III.C.5 and III.D.5 of this document).
    As noted previously, for each individual case safety report, a 
suspect product would be required to be identified. Reports from 
blinded clinical studies (i.e., the sponsor and investigator are 
blinded to individual patient treatment) should be submitted to FDA 
only after the code is broken for the patient or subject that 
experiences an SADR. The blind should be broken for each patient or 
subject who experiences a serious, unexpected SADR unless arrangements 
have been made otherwise with the FDA review division that has 
responsibility for review of the IND (e.g., the protocol or other 
documentation clearly defines specific alternative arrangements for 
maintaining the blind). Exceptions to breaking the blind for a study 
usually involve situations in which mortality or certain serious 
morbidities are indeed the clinical endpoint of the study. This is 
consistent with the discussion of managing blinded therapy cases in the 
ICH E2A guidance (60 FR 11266):

    * * * Although it is advantageous to retain the blind for all 
patients prior to final study analysis, when a serious adverse 
reaction is judged reportable on an expedited basis, it is 
recommended that the blind be broken only for the specific patient 
by the sponsor even if the investigator has not broken the blind. * 
* * However, when a fatal or other ``serious'' outcome is the 
primary efficacy endpoint in a clinical investigation, the integrity 
of the clinical investigation may be compromised if the blind is 
broken. Under these and similar circumstances, it may be appropriate 
to reach agreement with regulatory authorities in advance concerning 
serious events that would be treated as disease-related and not 
subject to routine expedited reporting.

In addition to the exception for breaking the blind mentioned above, 
FDA is also interested in considering whether the blind should be 
broken for other serious SADRs that are not the clinical endpoint of 
the study, but occur at a rate high enough that the overall study blind 
would be threatened if each such case were individually unblinded. FDA 
invites comment from the public on how reporting of these SADRs should 
be handled.
III.A.6. Active Query
    Under proposed Sec. Sec.  310.305(a), 314.80(a), and 600.80(a), FDA 
would amend its postmarketing safety reporting regulations to define 
the term ``active query'' to mean:

    Direct verbal contact (i.e., in person or by telephone or other 
interactive means such as a videoconference) with the initial 
reporter of a suspected adverse drug reaction (SADR) or medication 
error by a health care professional (e.g., physician, physician 
assistant, pharmacist, dentist, nurse, any individual with some form 
of health care training) representing the manufacturer (applicant 
for proposed Sec. Sec.  314.80(a) and 600.80(a)). For SADRs, active 
query entails, at a minimum, a focused line of questioning designed 
to capture clinically relevant information associated with the drug 
product (licensed biological product for proposed Sec.  600.80(a)) 
and the SADR, including, but not limited to, information such as 
baseline data, patient history, physical exam, diagnostic results, 
and supportive lab results.

The agency would define this term to describe the process that 
manufacturers and applicants would be required to use to acquire safety 
information expeditiously. Active query would be used to:
    [sbull] Determine whether an SADR is serious or nonserious if the 
manufacturer or applicant is not able to immediately make this 
determination (see section III.C.5 of this document),
    [sbull] Obtain at least the minimum data set for all SADRs and the 
minimum information for medication errors that do not result in an SADR 
if the manufacturer or applicant is not able to immediately obtain this 
information (see section III.C.5 of this document),
    [sbull] Obtain a full data set for individual case safety reports 
of serious SADRs, always expedited reports, and medication error 
reports if a full data set is not available for the report (see section 
III.C.5 of this document), and
    [sbull] Obtain supporting documentation for a report of a death or 
hospitalization (e.g., autopsy report, hospital discharge summary) (see 
section III.D.7 of this document).
    Active query would entail direct verbal contact either in person or 
by telephone or other interactive means (e.g., a videoconference) with 
the initial reporter of an SADR or medication error. FDA believes that, 
in many cases, use of active query during initial contact with these 
reporters would provide

[[Page 12421]]

manufacturers and applicants with adequate safety information and could 
eliminate or decrease followup time expended by manufacturers, 
applicants, and the agency. The agency does not believe that it is 
sufficient for manufacturers and applicants just to send a letter to 
reporters of SADRs and medication errors requesting further 
information. These reporters could, however, submit written materials 
to manufacturers and applicants to clarify or provide support for 
verbal discussions.
    Even though the agency is not proposing that manufacturers and 
applicants request followup information for SADR and medication error 
reports in writing, the CIOMS V report describes instances when it 
might be appropriate to do so. FDA seeks comment as to whether the 
agency should permit written requests for followup information and, if 
so, in which situations should these requests be permitted.
    Active query would be conducted by a health care professional, such 
as a physician, physician's assistant, pharmacist, dentist, nurse, or 
any individual with some form of health care training. The agency 
believes that a health care professional would be able to understand 
better the medical consequences of a case and ask reporters of SADRs 
and medication errors appropriate questions to acquire more complete 
safety information effectively and rapidly.
    The proposed definition of active query would provide that, at a 
minimum, a focused line of questioning be used to acquire further 
information on SADRs. For this purpose, questions would be designed to 
capture clinically relevant information associated with the drug or 
licensed biological product and the SADR. This information would 
include, but would not be limited to, baseline data, patient history, 
physical exam, diagnostic results, and supportive lab results.
III.A.7. Spontaneous Report
    Under proposed Sec. Sec.  310.305(a), 314.80(a), and 600.80(a), FDA 
would amend its postmarketing safety reporting regulations to define 
the term ``spontaneous report'' to mean:

    A communication from an individual (e.g., health care 
professional, consumer) to a company or regulatory authority that 
describes an SADR or medication error. It does not include cases 
identified from information solicited by the manufacturer or 
contractor (applicant or contractor for proposed Sec.  314.80(a); 
applicant, shared manufacturer, or contractor for proposed Sec.  
600.80(a)), such as individual case safety reports or findings 
derived from a study, company-sponsored patient support program, 
disease management program, patient registry, including pregnancy 
registries, or any organized data collection scheme. It also does 
not include information compiled in support of class action 
lawsuits.

    The agency would define this term to clarify which reports would be 
considered ``spontaneous.'' Over the years, changes in marketing 
practices in the United States have led to expanded contacts between 
consumers and manufacturers, applicants, contractors, and shared 
manufacturers. This has resulted in the acquisition of new types of 
solicited safety information. Under the proposed rule, only unsolicited 
safety information from an individual, such as a health care 
professional or consumer, to a company or regulatory authority would be 
considered a ``spontaneous report.''
    Cases identified from information solicited by companies, such as 
individual case safety reports or findings obtained from a study, 
company-sponsored patient support program, disease management program, 
patient registry, including pregnancy registries, or any organized data 
collection scheme would not be considered spontaneous. Instead, safety 
information from these sources would be considered ``study'' 
information and would be handled according to the postmarketing safety 
reporting requirements for a ``study.'' As proposed, study information 
would be subject to reporting as discussed below:
    [sbull] Expedited reports for serious and unexpected SADRs from a 
study (see section III.D.1 of this document),
    [sbull] Expedited reports for information from a study that would 
be sufficient to consider product administration changes (see section 
III.D.2 of this document),
    [sbull] Expedited reports for an unexpected SADR with unknown 
outcome from a study (see section III.D.3 of this document),
    [sbull] Always expedited reports from a study (see section III.D.4 
of this document),
    [sbull] Medication error reports from a study (see section III.D.5 
of this document),
    [sbull] Summary tabulations of all serious SADRs from studies or 
individual patient INDs in PSURs (see section III.E.2.f.ii of this 
document), and
    [sbull] Discussion of important safety information from studies in 
PSURs and IPSRs (see sections III.E.2.g and III.E.3 of this document).
    The proposed rule would consider SADR information compiled in 
support of class action lawsuits to be neither spontaneous nor 
``study'' information. FDA believes that the vast majority of SADR 
information from class action lawsuits is duplicative (i.e., the same 
SADR information is reported by multiple individuals). In many cases, 
information in addition to the minimum data set is not available for 
these SADR reports and followup is unlikely to result in acquisition of 
new information. For these reasons, the agency is proposing to require 
in TPSRs, PSURs and IPSRs summary information for SADRs from class 
action lawsuits (see sections III.E.1.e, III.E.2.k.v, and III.E.3 of 
this document).
    Any safety information obtained from an individual (e.g., health 
care professional, consumer) who has initiated contact with a company 
or regulatory authority would be considered spontaneous. For example, 
if an individual calls a company and asks if a particular SADR has been 
observed with one of the company's drug or licensed biological products 
because the individual or someone the individual knows has experienced 
such an SADR, the call would be considered spontaneous. The agency 
would consider these calls spontaneous because the individual making 
the call has a belief or suspicion that the drug or licensed biological 
product may have caused the SADR.
    The proposed definition for spontaneous report is consistent with 
the definition of ``spontaneous report or spontaneous notification'' in 
the ICH E2C guidance (62 FR 27475)):

    An unsolicited communication to a company, regulatory authority, 
or other organization that describes an adverse reaction in a 
patient given one or more medicinal products and which does not 
derive from a study or any organized data collection scheme.

III.A.8. Medication Error
    Proposed Sec. Sec.  310.305(a), 314.80(a), and 600.80(a) would 
amend FDA's postmarketing safety reporting regulations to define the 
terms ``medication error,'' ``actual medication error,'' and 
``potential medication error.'' A ``medication error'' would be defined 
as:

    Any preventable event that may cause or lead to inappropriate 
medication use or patient harm while the medication is in the 
control of the health care professional, patient, or consumer. Such 
events may be related to professional practice, health care 
products, procedures, and systems including: Prescribing; order 
communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; 
monitoring; and use.


[[Page 12422]]


    An ``actual medication error'' would be defined as:

    A medication error that involves an identifiable patient whether 
the error was prevented prior to administration of the product or, 
if the product was administered, whether the error results in a 
serious SADR, nonserious SADR, or no SADR.

    A ``potential medication error'' would be defined as:

    An individual case safety report of information or complaint 
about product name, labeling, or packaging similarities that does 
not involve a patient.

    The proposed rule would define these terms to clarify what would be 
considered a medication error. The proposed definition for ``medication 
error'' was developed by the National Coordinating Council for 
Medication Error Reporting and Prevention, of which FDA is a member. 
FDA would not consider a case in which a patient deliberately took an 
overdose of a drug to be a ``medication error'' because the agency does 
not believe that this type of situation is ``preventable.'' Instead, it 
would be considered a ``non-accidental overdose.''
    The proposed definitions for actual and potential medication errors 
were developed by FDA. Actual medication errors involve an identifiable 
patient whether or not the product is administered and, if the product 
is administered, whether or not an SADR occurs. Potential medication 
errors do not involve a patient, but rather describe information or 
complaint about product name, labeling, or packaging similarities that 
could result in a medication error in the future.
III.A.9. Company Core Data Sheet, Company Core Safety Information 
(CCSI), Listed SADR, Unlisted SADR, and Unexpected SADR
    Proposed Sec. Sec.  314.80(a) and 600.80(a) would amend FDA's 
postmarketing safety reporting regulations to define the terms 
``company core data sheet,'' ``company core safety information 
(CCSI),'' ``listed SADR,'' and ``unlisted SADR.'' The ``company core 
data sheet'' would be defined as:

    A document prepared by the applicant containing, in addition to 
safety information, material relating to indications, dosing, 
pharmacology, and other information concerning the drug substance 
(biological product for proposed Sec.  600.80(a)). The only purpose 
of this document is to provide the company core safety information 
(CCSI) for periodic safety update reports (PSURs), interim periodic 
safety reports (IPSRs), and certain individual case safety reports--
semiannual submissions (i.e., if PSURs are submitted for the 
product).

    The ``CCSI'' would be defined as:

    All relevant safety information contained in the company core 
data sheet that the applicant proposes to include in the approved 
product labeling in all countries where the applicant markets the 
drug substance (biological product for proposed Sec.  600.80(a)). It 
is the reference information by which an SADR is determined to be 
``listed'' or ``unlisted'' for PSURs, IPSRs, and certain individual 
case safety reports--semiannual submissions (i.e., if PSURs are 
submitted for the product).

    A ``listed SADR'' would be defined as: ``an SADR whose nature, 
specificity, severity, and outcome are consistent with the information 
in the CCSI.''
    An ``unlisted SADR'' would be defined as: ``an SADR whose nature, 
specificity, severity, or outcome is not consistent with the 
information included in the CCSI.''
    The proposed rule would define these terms to help applicants 
determine which SADRs must be reported in PSURs, IPSRs, and certain 
individual case safety reports--semiannual submissions (i.e., if PSURs 
are submitted for the product) (see sections III.E.2, III.E.3, and 
III.E.4 of this document). For this purpose, the CCSI would be used as 
the reference document by which an SADR would be judged as ``listed'' 
or ``unlisted.''
    Company core data sheets would usually be prepared by applicants 
for a drug substance rather than a drug product because postmarketing 
PSURs and IPSRs would be based on a drug substance. Under the existing 
regulations at Sec.  314.3(b) (21 CFR 314.3(b)), a drug substance is 
defined as:

    An active ingredient that is intended to furnish pharmacological 
activity or other direct effect in the diagnosis, cure, mitigation, 
treatment, or prevention of disease or to affect the structure or 
any function of the human body, but does not include intermediates 
use[d] in the synthesis of such ingredient.

    Under these same regulations, a drug product is defined as:

a finished dosage form, for example, tablet, capsule, or solution, 
that contains a drug substance, generally, but not necessarily, in 
association with one or more other ingredients.

    Thus, drug substances refer to active moieties of drug products.
    In the United States, the company core data sheet would be used 
only to provide the CCSI for a drug or biological product to determine 
whether an SADR is listed or unlisted. Company core data sheets would 
not require approval from FDA, unlike the U.S. labeling for a marketed 
drug or licensed biological product which does require approval from 
FDA. Company core data sheets would not be used in the United States as 
the labeling for an approved drug or licensed biological product. FDA 
believes that preparation of a company core data sheet would not impose 
a new burden on most applicants because it codifies a common practice 
in the pharmaceutical industry (see the ICH E2C guidance, 62 FR 27470 
at 27472).
    Postmarketing PSURs may be submitted by applicants to multiple 
countries, and the drug or licensed biological product may have 
different approved labeling in the different countries. The CCSI for 
the product should not be a compilation of all the safety information 
contained in the various approved labelings for the product. Instead, 
the CCSI should contain the critical safety information for the product 
that would be relevant in all countries where the product is approved 
for marketing. In some cases, the CCSI and an approved labeling for the 
product would contain the same safety information (i.e., all the safety 
information in an approved labeling for the product is relevant in all 
countries where the product is approved for marketing or the product is 
only approved for marketing in one country). In other cases, an 
approved labeling for a product may contain more safety information 
than the CCSI for the product because the labeling may contain safety 
information specific to the country in which the product is approved 
for marketing (e.g., safety information regarding a specific indication 
for which the product is approved for marketing in one country but not 
other countries). In these cases, the use of the CCSI as the reference 
document for determining whether an SADR is listed or unlisted for the 
postmarketing PSURs may result in overreporting of some SADRs to FDA as 
``unlisted'' when they actually are ``expected'' by the approved U.S. 
labeling.
    This proposal would not affect the reference document used to 
determine expectedness (i.e., unexpected or expected SADR) for SADRs 
reported in premarketing IND safety reports, postmarketing expedited 
reports, postmarketing TPSRs, and certain postmarketing individual case 
safety reports--semiannual submissions (i.e., if TPSRs are submitted 
for the product) (see table 5 and sections III.B, III.D, III.E.1, and 
III.E.4 of this document). Under the existing regulations at Sec. Sec.  
310.305(b), 314.80(a), and 600.80(a), the definition of ``unexpected 
adverse drug experience'' designates the current approved labeling for 
the drug or licensed biological product as the reference document to be 
used to determine what would be considered

[[Page 12423]]

``unexpected.'' Proposed Sec. Sec.  310.305(a), 314.80(a), and 
600.80(a) would include in the definition of ``unexpected SADR'' the 
abbreviation ``U.S.'' before the word ``labeling'' to clarify that the 
approved U.S. labeling would be used to determine whether or not an 
SADR is ``unexpected.'' FDA would also amend this definition by 
replacing the word ``event'' with the word ``reaction'' and by 
clarifying that the phrase ``differ from the event because of greater 
severity or specificity'' refers to a ``labeled reaction.'' Under 
proposed Sec. Sec.  310.305(a), 312.32(a), 314.80(a), and 600.80(a), 
the agency would also replace the word ``listed'' with the word 
``included'' in the definition of ``unexpected SADR'' to minimize 
confusion with ``listed SADRs'' in the CCSI. FDA would also revise the 
sentence ``Unexpected, as used in this definition, refers to an SADR 
that has not been previously observed * * * rather than from the 
perspective of such reaction not being anticipated from the 
pharmacological properties of the drug product'' in this definition for 
clarity.

        Table 5.--Proposed Reference Documents for Safety Reports
------------------------------------------------------------------------
      Marketing status            Safety report      Reference document
------------------------------------------------------------------------
Premarketing................  IND safety report...  Investigator's
                                                     brochure. If not
                                                     available, risk
                                                     information in
                                                     general
                                                     investigational
                                                     plan or elsewhere
                                                     in the current
                                                     application.
Postmarketing...............  Expedited reports...  U.S. labeling.
                              TPSRs...............  U.S. labeling.
                              PSURs and IPSRs.....  CCSI.
                              Individual case
                               safety reports--
                               semiannual
                               submission:
                                 If TPSR is         U.S. labeling.
                                  submitted for
                                  the product.
                                 If PSUR is         CCSI.
                                  submitted for
                                  the product.
------------------------------------------------------------------------

    These proposed amendments are consistent with the ICH E2C guidance 
(62 FR 27470 at 27472):

    For purposes of periodic safety reporting, CCSI forms the basis 
for determining whether an ADR is already Listed or is still 
Unlisted, terms that are introduced to distinguish them from the 
usual terminology of ``expectedness'' or ``labeledness'' that is 
used in association with official labeling. Thus, the local approved 
product information continues to be the reference document upon 
which labeledness/expectedness is based for the purpose of local 
expedited postmarketing safety reporting.

    Under proposed Sec. Sec.  310.305(a), 312.32(a), 314.80(a), and 
600.80(a), FDA would include the following sentence in the definition 
of ``unexpected SADR:''

    SADRs that are mentioned in the U.S. labeling (investigator's 
brochure for proposed Sec.  312.32(a)) as occurring with a class of 
drugs (products for proposed Sec.  600.80(a)) but not specifically 
mentioned as occurring with the particular drug (product for 
proposed Sec.  600.80(a)) are considered unexpected.

    This information is currently included in the draft guidance of 
2001. FDA is now proposing to codify this information to clarify which 
SADRs would be considered ``unexpected.''
III.A.10. Data Lock Point and International Birth Date
    Proposed Sec. Sec.  314.80(a) and 600.80(a) would amend FDA's 
postmarketing safety reporting requirements to define the terms ``data 
lock point'' and ``international birth date.'' The ``data lock point'' 
would be defined as:

    The date designated as the cut-off date for data to be included 
in a postmarketing periodic safety report.

    The ``international birth date'' would be defined as:

    The date the first regulatory authority in the world approved 
the first marketing application for a human drug product containing 
the drug substance (human biological product for proposed Sec.  
600.80(a)).

    The agency would define these terms to help standardize the 
submission date (i.e., month and day of submission) for postmarketing 
periodic safety reports (i.e., PSURs, IPSRs, TPSRs, individual case 
safety reports--semiannual submissions). The data lock point would 
signify the end of a reporting period for data to be included in a 
specific postmarketing periodic safety report. The month and day of the 
international birth date would serve as a reference point for 
determining the data lock point. On the date of the data lock point, 
safety information that is available to applicants would be reviewed 
and evaluated prior to being submitted to FDA. Postmarketing periodic 
safety reports would be submitted to FDA within 60 days of the data 
lock point (see section III.E.5.b of this document). For example, for a 
drug or biological product approved by FDA on June 15 with a 6-month 
periodic reporting period and an international birth date of April 1, 
the first data lock point would be October 1, which is less than 6 
months after FDA approval, but is the 6-month anniversary of the 
international birth date. Therefore, the first postmarketing periodic 
safety report would cover the period from April 1 through October 1 
even though the product had only been approved in the United States on 
June 15. The second periodic report would cover the period from October 
2 through April 1.
    An international birth date would be determined and declared by 
applicants. Applicants would determine an international birth date for 
a product based on the date of approval of the first marketing 
application in the world for a human drug product containing the drug 
substance or a biological product. A single international birth date 
would encompass all different dosage forms, formulations, or uses 
(e.g., indications, routes of administration, populations) of a drug 
substance or licensed biological product. Thus, postmarketing periodic 
safety reports for different drug products containing the same drug 
substance would be submitted to FDA at the same time.
    The month and day of the international birth date would be used, as 
noted previously, to determine the data lock point (i.e., month and 
day) for postmarketing periodic safety reports. It would not, except as 
noted below, be used to determine the frequency for submission of these 
reports (i.e., 6-month intervals or multiples of 6 months). Instead, 
the date (i.e., year) of U.S. approval of the application for the drug 
or biological product (e.g., NDA, ANDA, BLA) would be used to determine 
the frequency for submission of postmarketing periodic safety reports 
to FDA (see section III.E.5.a of this document). The international 
birth date would be used to determine both the data lock point and 
reporting frequency for postmarketing periodic safety reports only when 
the U.S. approval date is used to determine the international birth 
date (e.g., FDA is the first

[[Page 12424]]

regulatory authority in the world to approve the human drug product 
containing the drug substance or biological product for marketing).
    The use of a standardized submission date (i.e., month and day), 
which is consistent with the ICH E2C guidance (62 FR 27470 at 27472), 
would enable applicants to submit a single core report (PSUR excluding 
appendices) to regulatory authorities worldwide. Currently, different 
regulatory authorities require submission of postmarketing periodic 
safety reports on varying time schedules. The submission of a single 
core report to multiple regulatory authorities would significantly 
reduce the time spent preparing these reports, thereby permitting more 
time for the evaluation of the medical significance of any safety 
information reported.

III.B. IND Safety Reports

III.B.1. Review of Safety Information
    Current IND safety reporting regulations in Sec.  312.32(b) require 
that sponsors promptly review all information relevant to the safety of 
the drug under investigation obtained or otherwise received by the 
sponsor from any source, foreign or domestic. Sources of information 
include any clinical or epidemiological investigations, animal 
investigations, commercial marketing experience, reports in the 
scientific literature, and unpublished scientific papers, and reports 
from foreign regulatory authorities that have not already been 
previously reported to FDA by the sponsor. FDA is proposing to amend 
this requirement by adding ``in vitro studies'' to the list of examples 
because some in vitro studies report relevant safety-related 
information (e.g., carcinogenicity studies performed in cell lines). 
FDA is also proposing to move the phrase ``commercial marketing 
experience'' to the end of the list and to revise it to read ``and 
reports of foreign commercial marketing experience for drugs that are 
not marketed in the United States'' to clarify that sponsors are not 
required to review safety information from commercial marketing 
experience for drugs that are marketed in the United States and are 
being further studied under an IND. Safety reports from commercial 
marketing experience for these drugs would be reviewed for safety 
information as prescribed by FDA's postmarketing safety reporting 
regulations (see section III.C.2 of this document). This proposed 
revision is consistent with existing regulations at Sec.  312.32(c)(4) 
and proposed amendments to Sec.  312.32(c)(4) described below (see 
section III.B.4 of this document). The proposed amendments would 
further clarify some of the types of safety information that must be 
examined to determine whether the information must be submitted in an 
IND safety report.
III.B.2. Written IND Safety Reports
    Current IND safety reporting regulations at Sec.  312.32(c)(1)(i) 
require sponsors to notify FDA and all participating investigators in a 
written IND safety report of any adverse experience associated with the 
use of the drug that is both serious and unexpected or any finding from 
tests in laboratory animals that suggests a significant risk for human 
subjects, including reports of mutagenicity, teratogenicity, or 
carcinogenicity. These written IND safety reports must be made as soon 
as possible and in no event later than 15 calendar days after the 
sponsor's initial receipt of the information. For clarity, FDA is 
proposing to amend Sec.  312.32(c)(1) by reorganizing and renumbering 
this paragraph.
    III.B.2.a. Minimum data set. FDA is proposing to amend Sec.  
312.32(c) to state that sponsors must not submit an IND safety report 
for an SADR to the agency if the report does not contain a minimum data 
set (i.e., identifiable patient, identifiable reporter, suspect drug or 
biological product, and SADR). If a minimum data set is not available, 
a sponsor would be required to maintain records of any information 
received or otherwise obtained for the SADR along with a record of its 
efforts to obtain a minimum data set for the IND safety report. This 
proposed amendment would clarify for sponsors that, at a minimum, 
certain information must be submitted to FDA for each IND safety report 
of an SADR to allow an initial evaluation of the significance of the 
SADR. This proposed revision is consistent with the ICH E2A guidance 
(60 FR 11284 at 11287):

    The minimum information required for expedited reporting 
purposes is: an identifiable patient; the name of a suspect 
medicinal product; an identifiable reporting source; and an event or 
outcome * * *.

    III.B.2.b. Serious and unexpected SADRs. FDA is also proposing to 
amend Sec.  312.32(c)(1)(i) by replacing the phrase ``any adverse 
experience associated with the use of the drug that is both serious and 
unexpected'' with the phrase ``any SADR that, based on the opinion of 
the investigator or sponsor, is both serious and unexpected, as soon as 
possible, but in no case later than 15 calendar days after receipt by 
the sponsor of the minimum data set for the serious, unexpected SADR.'' 
This proposed amendment would require that the determination of the 
possibility of causality (attributability) of an SADR to an 
investigational drug be based on the opinion of either the investigator 
or sponsor, which is consistent with the ICH E2A guidance (60 FR 11284 
at 11286):

    Causality assessment is required for clinical investigation 
cases. All cases judged by either the reporting health care 
professional or the sponsor as having a reasonable suspected causal 
relationship to the medicinal product qualify as ADR's.

    In situations in which a sponsor does not believe that there is a 
reasonable possibility that an investigational drug caused a response, 
but an investigator believes that such a possibility exists, the 
proposed rule would require that the sponsor submit a written IND 
safety report to FDA for the SADR. In the opposite situation, the same 
would also be true.
    The proposed rule would also require that written IND safety 
reports be submitted to FDA no later than 15 calendar days after 
receipt by the sponsor of the minimum data set for the serious, 
unexpected SADR. This proposed revision would clarify when the 15 
calendar day timeframe would begin. FDA expects sponsors to use due 
diligence to acquire immediately the minimum data set for a report and 
to determine the outcome (whether the SADR is serious or nonserious) 
and expectedness of an SADR upon initial receipt of the SADR. Sponsors 
should include in any written IND safety reports subsequently filed 
with FDA a chronological history of their efforts to acquire this 
information if there is a delay in obtaining the information (it is not 
necessary to include the chronological history in IND safety reports 
sent to investigators). This proposed amendment is consistent with the 
ICH E2A guidance (60 FR 11284 at 11286):

    Information for final description and evaluation of a case 
report may not be available within the required timeframes for 
reporting * * *. Nevertheless, for regulatory purposes, initial 
reports should be submitted within the prescribed time as long as 
the following minimum criteria are met: An identifiable patient; a 
suspect medicinal product; an identifiable reporting source; and an 
event or outcome that can be identified as serious and unexpected, 
and for which, in clinical investigation cases, there is a 
reasonable suspected causal relationship. * * *

    FDA is also proposing to amend Sec.  312.32(c)(1)(i) by removing 
the following sentence: ``Each notification shall be made as soon as 
possible and

[[Page 12425]]

in no event later than 15 calendar days after the sponsor's initial 
receipt of the information.'' The agency is proposing this revision 
because the information in this sentence is redundant with a provision 
of proposed Sec.  312.32(c)(1)(i).
    III.B.2.c. Information sufficient to consider product 
administration changes. Under proposed Sec.  312.32(c)(1)(ii), FDA 
would amend Sec.  312.32(c)(1)(i) by replacing the phrase ``Any finding 
from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity'' with the sentence:

    The sponsor must also notify FDA and all participating 
investigators in a written IND safety report of information that, 
based upon appropriate medical judgment, might materially influence 
the benefit-risk assessment of an investigational drug or that would 
be sufficient to consider changes in either product administration 
or in the overall conduct of a clinical investigation. The sponsor 
must submit this information to FDA and all participating 
investigators as soon as possible, but in no case later than 15 
calendar days after determination by the sponsor that the 
information qualifies for reporting under this paragraph. Examples 
of such information include any significant unanticipated safety 
finding or data in the aggregate from an in vitro, animal, 
epidemiological, or clinical study, whether or not conducted under 
an IND, that suggests a significant human risk, such as reports of 
mutagenicity, teratogenicity, or carcinogenicity or reports of a 
lack of efficacy with a drug product used in treating a life-
threatening or serious disease.

    This proposed amendment is consistent with the ICH E2A guidance (60 
FR 11284 at 11286):

    There are situations in addition to single case reports of 
``serious'' adverse events or reactions that may necessitate rapid 
communication to regulatory authorities; appropriate medical and 
scientific judgment should be applied for each situation. In 
general, information that might materially influence the benefit-
risk assessment of a medicinal product or that would be sufficient 
to consider changes in medicinal product administration or in the 
overall conduct of a clinical investigation represents such 
situations. Examples include:
    a. For an ``expected, serious ADR, [''] an increase in the rate 
of occurrence which is judged to be clinically important.
    b. A significant hazard to the patient population, such as lack 
of efficacy with a medical product used in treating life-threatening 
disease.
    c. A major safety finding from a newly completed animal study 
(such as carcinogenicity).

    In contrast to the ICH recommendations, the proposed rule would not 
require reports of an increase in the rate of occurrence of expected, 
serious SADRs to be submitted to the agency in an expedited manner. 
However, sponsors should report this information to FDA in their IND 
annual reports under Sec.  312.33(b)(1). Proposed Sec.  
312.32(c)(1)(ii) would be consistent with the increased frequency 
reports final rule that revoked the postmarketing safety reporting 
requirement for submission of increased frequency reports in an 
expedited manner. Although the increased frequency reports final rule 
pertains to postmarketing expedited safety reporting, FDA has decided 
to apply this rule to its requirements for premarketing expedited 
safety reports because of the limited reliability of increased 
frequency reports. See the increased frequency reports final rule (62 
FR 34166) for a discussion of the limited reliability of increased 
frequency reports. With regard to premarketing clinical trials in 
progress, FDA does not believe that baseline incidence rates would be 
available for serious expected SADRs which would make it difficult for 
sponsors to predict an increase in the rate of occurrence of these 
SADRs.
    III.B.2.d. Reporting format. Current IND safety reporting 
regulations at Sec.  312.32(c)(1)(i) require sponsors to submit written 
IND safety reports from animal or epidemiological studies in a 
narrative format. Proposed Sec.  312.32(c)(1)(iii) would amend these 
regulations by replacing the phrase ``reports from animal or 
epidemiological studies'' with the phrase ``reports of overall findings 
or data in the aggregate from published and unpublished in vitro, 
animal, epidemiological, or clinical studies.'' The proposed rule would 
require sponsors to submit reports of overall findings or data in the 
aggregate in a narrative format rather than on FDA Form 3500A because 
the form is designed for reporting safety information for an individual 
case.
III.B.3. Telephone Safety Reports
    Current IND safety reporting regulations at Sec.  312.32(c)(2) 
require sponsors to notify FDA by telephone or by facsimile 
transmission of any unexpected fatal or life-threatening experience 
associated with the use of an investigational drug as soon as possible 
but in no event later than 7 calendar days after the sponsor's initial 
receipt of the information. FDA is proposing to amend this requirement 
to read:

    The sponsor must also notify FDA by telephone or by facsimile 
transmission of any unexpected fatal or life-threatening SADR based 
on the opinion of the investigator or sponsor as soon as possible 
but in no case later than 7 calendar days after receipt by the 
sponsor of the minimum data set for the unexpected fatal or life-
threatening SADR.

    These proposed revisions are consistent, as described previously, 
with the proposed amendments to Sec.  312.32(c)(1)(i) for written IND 
safety reports and the ICH E2A guidance (60 FR 11284 at 11286).
III.B.4. IND Safety Reporting for Drugs Marketed in the United States
    Current IND safety reporting regulations at Sec.  312.32(c)(4) 
state that a sponsor of a clinical study of a marketed drug is not 
required to make a safety report for any adverse experience associated 
with the use of the drug that is not from the clinical study itself. 
FDA is proposing to amend this regulation by making the following 
revisions:

    A sponsor of a clinical study under an IND for a drug marketed 
in the United States is only required to submit IND safety reports 
to FDA (review division that has responsibility for the IND) for 
SADRs from the clinical study itself, whether from domestic or 
foreign study sites of the IND. The sponsor must also submit to FDA 
safety information from these clinical studies as prescribed by the 
postmarketing safety reporting requirements under Sec. Sec.  
310.305, 314.80, and 600.80 of this chapter.

    FDA is proposing this change to clarify, for sponsors investigating 
under an IND drugs and biological products that are already marketed in 
the United States, what SADRs must be reported in IND safety reports 
under Sec.  312.32. The agency notes that sponsors investigating under 
an IND drug and biological products that are not marketed in the United 
States are required, under Sec.  312.32, to report to FDA safety 
information obtained or otherwise received for the product from any 
source, domestic or foreign, including safety information from foreign 
commercial marketing experience (see section III.B.1 of this document). 
Proposed Sec.  312.32(c)(4) also clarifies that sponsors investigating 
under an IND drugs and biological products that are already marketed in 
the United States must submit safety information for these clinical 
studies as prescribed by the postmarketing safety reporting 
requirements in Sec. Sec.  310.305, 314.80, and 600.80.
III.B.5. Investigator Reporting
    Current investigator safety reporting regulations at Sec.  
312.64(b) state that the investigator shall promptly report to the 
sponsor any adverse effect that may reasonably be regarded as caused 
by, or probably caused by, the drug. If the adverse effect is alarming, 
the investigator shall report the adverse

[[Page 12426]]

effect immediately. FDA is proposing to revise this requirement as 
follows:

    An investigator must report to the sponsor any serious SADR (as 
defined in Sec.  312.32(a)) immediately and any other SADR (as 
defined in Sec.  312.32(a)) promptly unless the protocol or 
investigator's brochure specifies a different timetable for 
reporting the SADR.

    FDA is proposing this revision to be consistent with the proposed 
definition for SADR and to clarify what information investigators must 
submit to sponsors expeditiously.

III.C. Postmarketing Safety Reporting

III.C.1. Prescription Drugs Marketed for Human Use Without an Approved 
Application
    Current regulations (Sec.  310.305) require manufacturers, packers, 
and distributors of marketed prescription drug products that are not 
the subject of an approved NDA or ANDA to establish and maintain 
records of and report to FDA all serious, unexpected adverse drug 
experiences associated with the use of their drug products. The 
proposed rule would amend these regulations by revising the language in 
this section to be consistent with the language for the postmarketing 
expedited safety reporting requirements under Sec.  314.80. FDA is also 
proposing to reorganize and renumber Sec.  310.305 to be consistent 
with Sec.  314.80. FDA is proposing these revisions to harmonize, to 
the extent possible, the postmarketing expedited safety reporting 
requirements for human marketed drugs with approved applications (i.e., 
NDAs, ANDAs) and prescription drugs marketed for human use without an 
approved application.
III.C.2. Review of Safety Information
    Current postmarketing safety reporting regulations under Sec. Sec.  
314.80(b) and 600.80(b) require applicants to promptly review all 
safety information obtained or otherwise received from any source, 
foreign or domestic, including information derived from commercial 
marketing experience, postmarketing clinical investigations, 
postmarketing epidemiological/surveillance studies, reports in the 
scientific literature, and unpublished scientific papers. FDA is 
proposing to amend these regulations by adding ``animal and in vitro 
studies,'' ``electronic communications with applicants via the Internet 
(e.g., e-mail),'' and ``reports from foreign regulatory authorities 
that have not been previously reported to FDA by the applicant'' to the 
list of examples. FDA is proposing to add animal and in vitro studies 
to the list of examples because many of these studies report relevant 
safety-related information (e.g., carcinogenicity, mutagenicity, 
teratogenicity).
    FDA is proposing to add electronic communications with applicants 
via the Internet (e.g., e-mail) to the list of examples to clarify for 
applicants what safety information on the Internet would be required to 
be reviewed. An applicant would be required to review information 
received on an Internet site(s) that it sponsors, but would not be 
required to review Internet sites that it does not sponsor. However, if 
an applicant becomes aware of safety information on an Internet site 
that it does not sponsor, the applicant would be responsible for 
reviewing the information.
    FDA would not expect applicants to review safety data bases 
generated by foreign regulatory authorities. However, proposed 
Sec. Sec.  314.80(b)(1) and 600.80(b)(1) would require that any safety 
information acquired or received from a foreign regulatory authority be 
reviewed to determine whether the information must be reported to FDA. 
The agency is proposing these amendments to further clarify some of the 
types of safety information that must be examined to determine whether 
the information must be submitted in postmarketing safety reports.
    Proposed Sec.  310.305(b)(1) would amend FDA's postmarketing safety 
reporting regulations for prescription drugs marketed for human use 
without an approved application by adding the following sentence:

    Each manufacturer of a prescription drug product marketed for 
human use without an approved application must promptly review all 
safety information pertaining to its product obtained or otherwise 
received by the manufacturer from any source, foreign or domestic, 
including information derived from commercial marketing experience, 
postmarketing clinical investigations, postmarketing epidemiology/
surveillance studies, animal or in vitro studies, electronic 
communications with manufacturers via the Internet (e.g., e-mail), 
reports in the scientific literature, and unpublished scientific 
papers, as well as reports from foreign regulatory authorities that 
have not been previously reported to FDA by the manufacturer.

    This proposed amendment would further clarify some of the types of 
safety information that must be examined to determine whether the 
information must be submitted in postmarketing expedited safety reports 
(see section III.D of this document). This proposed revision would 
provide uniformity between FDA's safety reporting requirements for 
human marketed drugs with approved applications (i.e., NDAs, ANDAs) and 
prescription drugs marketed for human use without an approved 
application (i.e., without an approved NDA or ANDA).
    Current postmarketing safety reporting regulations in Sec. Sec.  
314.80(b) and 600.80(b) state that applicants are not required to 
resubmit to FDA safety reports forwarded to the applicant by FDA; 
however, applicants must submit all followup information on such 
reports. Proposed Sec. Sec.  314.80(b)(2) and 600.80(b)(2) would amend 
these regulations to state that individual case safety reports 
forwarded to the applicant by FDA must not be resubmitted to the agency 
by applicants. FDA is proposing this revision to prevent duplicate 
reports from being entered into the agency's safety reporting database. 
Applicants that inadvertently resubmit such reports to FDA will be 
informed not to do so in the future.
    Proposed Sec. Sec.  314.80(b)(2) and 600.80(b)(2) would also amend 
these regulations to require that applicants include information from 
individual case safety reports forwarded to the applicant by FDA in any 
comprehensive safety analysis subsequently submitted to the agency. 
This proposed amendment, which was discussed in the preamble but 
inadvertently omitted from the codified section of the October 1994 
proposal (59 FR 54046 at 54053), would clarify how safety information 
received from FDA must be handled.
    Current postmarketing safety reporting regulations at Sec. Sec.  
314.80(b) and 600.80(b) state that applicants must develop written 
procedures for the surveillance, receipt, evaluation, and reporting of 
postmarketing adverse drug experiences to FDA. FDA is proposing to 
amend this provision by adding the phrase ``and maintain'' after the 
phrase ``must develop.'' This proposed amendment would clarify that 
applicants must maintain records of the written procedures for review 
by FDA. FDA would review the written procedures either upon request by 
the agency (proposed Sec. Sec.  314.80(f) and 600.80(f)) or during 
inspections by the agency. FDA is also proposing to replace the phrase 
``adverse drug experiences'' with the phrase ``postmarketing safety 
information.'' For organizational purposes, FDA is proposing to move 
the written procedures provision to proposed Sec. Sec.  314.80(g) and 
600.80(g). FDA is proposing the same type of amendments to Sec.  
310.305.
    Current Sec.  314.80(b) applies to applicants having an approved 
application under Sec.  314.50 or, in the case of a 505(b)(2) 
application, an effective approved application. FDA is proposing to 
amend this provision by replacing the phrase ``under Sec.  314.50 or,

[[Page 12427]]

in the case of a 505(b)(2) application, an effective approved 
application'' with the phrase ``under section 505(c) of the act.'' 
Although NDAs, including those referred to in section 505(b)(2) of the 
Federal Food, Drug and Cosmetic Act (the act) (21 U.S.C. 355(b)(2)) are 
filed under section 505(b)(1) of the act, they are approved under 
section 505(c) of the act. FDA is proposing to use the phrase ``section 
505(c) of the act'' because it more appropriately references the cite 
for approval of NDAs.
    The agency is proposing to remove the phrase ``in the case of a 
505(b)(2) application, an effective approved application'' because FDA 
no longer issues approvals with a delayed effective date for 505(b)(2) 
applications, as it did at the time this regulation was issued. The 
agency now issues tentative approvals for 505(b)(2) applications when 
the (final) approval is blocked by patent or exclusivity rights. As 
described in the preamble to the final rule on ``Abbreviated New Drug 
Application Regulations; Patent and Exclusivity Provisions'' (59 FR 
50338 at 50351 to 50352, October 3, 1994), a 505(b)(2) application that 
has a tentative approval is not approved for marketing until a final 
approval letter for the drug product is received from FDA. Thus, 
applicants having a 505(b)(2) application with a tentative approval 
would not be subject to the postmarketing safety reporting requirements 
under Sec.  314.80 until final approval of the application is in 
effect. For consistency, FDA is proposing a similar change to Sec.  
314.98(a).
III.C.3. Reporting Requirements
    Current postmarketing safety reporting requirements at Sec. Sec.  
310.305(c), 314.80(c), and 600.80(c) state that persons subject to 
these requirements shall report to FDA adverse drug experience 
information as described under these sections. FDA is proposing to 
remove these provisions from its postmarketing safety reporting 
regulations because they are redundant (see proposed Sec. Sec.  
310.305(c), 314.80(c), and 600.80(c)).
    Current postmarketing safety reporting requirements at Sec. Sec.  
314.80(c) and 600.80(c) state that two copies of each report must be 
submitted to FDA. For drug products, proposed Sec.  314.80(c) would 
require that applicants submit to FDA two copies of each postmarketing 
expedited report and one copy of each postmarketing periodic safety 
report of an individual case safety reports--semiannual submission 
pertaining to its product (see tables 6 and 7 for proposed 
postmarketing expedited and periodic safety reports). For nonvaccine 
biological products, proposed Sec.  600.80(c) would require that 
applicants submit to FDA two copies of each postmarketing expedited 
report and each postmarketing periodic safety report of an individual 
case safety reports--semiannual submission pertaining to its product. 
For drugs and nonvaccine biologics, proposed Sec. Sec.  314.80(c) and 
600.80(c) would also require that one copy of a PSUR, IPSR, or TPSR be 
submitted to FDA along with one copy for each approved application for 
a human drug or licensed biological product (e.g., NDA, ANDA, BLA) 
covered by the report (see table 7 for proposed postmarketing periodic 
safety reports). For vaccines, proposed Sec.  600.80(c) would require 
that applicants submit to VAERS two copies of each safety report 
required under Sec.  600.80 and pertaining to its product. These 
proposed amendments would provide FDA with enough copies of safety 
reports for efficient review by the agency. Electronic submission of 
these reports will obviate the need for submission of two copies. At 
this time, manufacturers and applicants can voluntarily submit certain 
postmarketing safety reports in an electronic format (see Docket 92S-
0251 regarding postmarketing expedited and periodic individual case 
safety reports; available on the Internet at http://www.fda.gov/ohrms/dockets/dockets/92s0251/92s0251.htm). Capabilities for electronic 
submission of other postmarketing safety reports (e.g., safety reports 
for vaccines) will be available in the future.

                                                Table 6.--Proposed Postmarketing Expedited Safety Reports
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                             Persons with
      Expedited Safety Report                    Type of Information                Submission to FDA--        Reporting        Reference in Section III
                                                                                         Timeframe          Responsibility          of this Document
--------------------------------------------------------------------------------------------------------------------------------------------------------
Serious & unexpected SADRs........  Individual case safety reports...............  15 calendar days....  Manufacturers and     D.1
                                                                                                          applicants.
Information sufficient to consider  Information based upon appropriate medical     15 calendar days....  Manufacturers and     D.2
 product administration changes.     judgment. For example, any significant                               applicants.
                                     unanticipated safety finding or data in the
                                     aggregate from an in vitro, animal,
                                     epidemiological, or clinical study that
                                     suggests a significant human risk.
Unexpected SADRs with unknown       Individual case safety reports of unexpected   45 calendar days....  Manufacturers and     D.3
 outcome.                            SADRs for which a determination of serious                           applicants.
                                     or nonserious cannot be made..
Always expedited reports..........  Individual case safety reports of certain      15 calendar days....  Manufacturers and     D.4
                                     medically significant SADRs whether                                  applicants.
                                     unexpected or expected and whether or not
                                     the SADR leads to a serious outcome.
Medication errors.................  All domestic reports of medication errors,     15 calendar and days  Manufacturers and     D.5
                                     whether actual or potential..                                        applicants.
30-day followup...................  Followup report for initial serious and        30 calendar days....  Manufacturers and     D.6
                                     unexpected SADR reports, always expedited                            applicants.
                                     reports and medication error reports that do
                                     not contain a full data set.
15-day followup...................  New information for expedited or followup      15 calendar days....  Manufacturers and     D.6
                                     reports, except initial expedited reports                            applicants.
                                     for which 30-day followup reports must be
                                     submitted.
SADR reports to manufacturer......  All SADRs....................................  5 calendar days to    Contractors.........  D.9
                                                                                    manufacturer.
SADR reports to applicant.........  All SADRs....................................  5 calendar days to    Contractors and       D.9
                                                                                    applicant.            shared
                                                                                                          manufacturers.

[[Page 12428]]

 
Blood safety--oral or written.....  Fatalities...................................  As soon as possible.  Blood establishments  D.12
Blood safety--written.............  Fatalities...................................  7 calendar days       ....................  .........................
                                    All serious SARs except fatalities...........  45 calendar days....  ....................  .........................
--------------------------------------------------------------------------------------------------------------------------------------------------------


                            Table 7.--Proposed Postmarketing Periodic Safety Reports
----------------------------------------------------------------------------------------------------------------
                                                                           Persons with
    Periodic safety report       Type of information     Submission to       reporting      Reference in section
                                                        FDA--timeframe    responsibility    III of this document
----------------------------------------------------------------------------------------------------------------
Individual case safety          [sbull] Serious,       Every 6 months    Applicants......  E.4
 reports--semiannual             expected SADRs         after U.S.
 submission.                     (domestic and          approval of
                                 foreign) and           application.\3\.
                                 nonserious,
                                 unexpected SADRs
                                 (domestic) if TPSR
                                 is submitted for the
                                 product.\1\.
                                [sbull] Serious,
                                 listed SADRs
                                 (domestic and
                                 foreign) and
                                 nonserious, unlisted
                                 SADRs (domestic) if
                                 PSUR is submitted
                                 for the product.\2\.
TPSR--for applications          [sbull] Narrative      At 5, 7.5, 10,    Applicants......  E.1
 approved before January 1,      summary and analysis   12.5, and 15
 1998.\4\.                       of individual case     years after
                                 safety reports         U.S. approval
                                [sbull] Increased       of application
                                 frequency reports.     and then every
                                [sbull] Safety-         5 years
                                 related actions to     thereafter.\3\.
                                 be taken.
                                [sbull] Summary
                                 tabulations of
                                 individual case
                                 safety reports.
                                [sbull] History of
                                 safety-related
                                 actions taken.
                                [sbull] Location of
                                 safety records.
                                [sbull] Contact
                                 person information.
PSUR--for applications          Core Document          Every 6 months    Applicants......  E.2
 approved on or after January   [sbull] Introduction.   after U.S.
 1, 1998.                       [sbull] Worldwide       approval of
                                 marketing status.      application for
                                [sbull] Actions taken   2 years,
                                 for safety reasons.    annually for
                                [sbull] Changes to      the next 3
                                 CCSI.                  years, and then
                                [sbull] Worldwide       every 5 years
                                 patient exposure.      thereafter.\3\.
                                [sbull] Summary
                                 tabulations.
                                [sbull] Safety
                                 studies.
                                [sbull] Other
                                 information.
                                [sbull] Overall
                                 safety evaluation.
                                [sbull] Conclusion...
                                Appendices...........
                                [sbull] Company core
                                 data sheet.
                                [sbull] U.S. labeling
                                [sbull] Spontaneous
                                 reports from
                                 individuals other
                                 than health care
                                 professionals.
                                [sbull] SADRs with
                                 unknown outcome.
                                [sbull] SADRs from
                                 class action
                                 lawsuits.
                                [sbull] Lack of
                                 efficacy reports.
                                [sbull] Information
                                 on resistance to
                                 antimicrobial drug
                                 products.
                                [sbull] Medication
                                 errors.
                                [sbull] U.S. patient
                                 exposure.
                                [sbull] Location of
                                 safety records.
                                [sbull] Contact
                                 person.
IPSR--for applications          An ``abbreviated       At 7.5 and 12.5   Applicants......  E.3
 approved on or after January    PSUR;'' same           years after
 1, 1998.                        information as PSUR    U.S. approval
                                 excluding summary      of
                                 tabulations.           application.\3\.
----------------------------------------------------------------------------------------------------------------
\1\ Nonserious, expected SARs (domestic) and expected SARs with unknown outcome (domestic) would also be
  submitted for vaccines.
\2\ Nonserious, listed SARs (domestic) and listed SARs with unknown outcome (domestic) would also be submitted
  for vaccines.
\3\ The data lock point for the report would be the month and day of the international birth date or any other
  month and day agreed on by the applicant and FDA. The submission date for the report would be within 60
  calendar days of the data lock point.
\4\ A PSUR may be submitted in lieu of a TPSR if an applicant so desires.

    Current Sec. Sec.  310.305(c), 314.80(c), 314.98(b), and 600.80(c) 
provide mailing addresses for the submission of postmarketing safety 
reports. FDA is proposing to remove the mailing addresses from 
Sec. Sec.  310.305(c), 314.80(c), 314.98(b), and 600.80(c) because this 
information is provided in the draft guidance of 2001.

[[Page 12429]]

III.C.4. Request for Alternative Reporting Frequency
    FDA is proposing to amend its postmarketing safety reporting 
regulations at Sec. Sec.  310.305(c), 314.80(c), and 600.80(c) to state 
that, upon written notice, the agency may require, when appropriate, 
that manufacturers and applicants submit postmarketing safety reports 
(i.e., expedited, followup, or periodic safety reports) to FDA at times 
other than prescribed by the regulations (see tables 8 and 9 regarding 
proposed reporting frequencies for postmarketing safety reports). In 
most cases, FDA would not request alternative reporting periods for 
these safety reports. In some cases, however, FDA may need to receive 
reports more frequently (e.g., marketed product approved for a new 
indication, dosage form, or population) or less frequently (e.g., 
product on the market for over 30 years with no new safety concerns 
identified).

                Table 8.--Proposed Reporting Frequency for Postmarketing Expedited Safety Reports
----------------------------------------------------------------------------------------------------------------
Submit as soon as   Submit within 5    Submit within 7  Submit within 15  Submit within 30    Submit within 45
     possible        calendar days      calendar days     calendar days     calendar days       calendar days
----------------------------------------------------------------------------------------------------------------
[sbull] Blood      [sbull]            [sbull] Blood     [sbull] Serious   [sbull] 30-day    [sbull] Unexpected
 safety report--    Individual case    safety report--   and unexpected    followup report   SADR with unknown
 telephone          safety reports     written           SADR report       (D.6).            outcome (D.3).
 (fatality)         from contractors   (fatality)        (D.1).                             [sbull] Blood safety
 (D.12).\1\         to manufacturer    (D.12).          [sbull]                              report--written
                    (D.9).                               Information                         (all serious SARs
                   [sbull]                               sufficient to                       except fatalities)
                    Individual case                      consider                            (D.12).
                    safety reports                       product
                    from contractors                     administration
                    and shared                           changes (D.2).
                    manufacturers to                    [sbull] Always
                    applicant (D.9).                     expedited
                                                         report (D.4).
                                                        [sbull]
                                                         Medication
                                                         error report
                                                         (D.5).
                                                        [sbull] 15-day
                                                         followup report
                                                         (D.6).
----------------------------------------------------------------------------------------------------------------
\1\ References in parentheses refer to location in section III of this document.


                Table 9.--Proposed Reporting Frequency for Postmarketing Periodic Safety Reports
----------------------------------------------------------------------------------------------------------------
                                                   Submit at 0.5, 1,                              Submit at 10
    Persons with reporting      Submit every 6    1.5, 2, 3, 4, and 5     Submit at 7.5 and    years and every 5
        responsibility              months               years                12.5 years        years thereafter
----------------------------------------------------------------------------------------------------------------
Applicants with NDAs \1\ or    Individual case   PSUR (E.2)...........  IPSR (E.3)...........  PSUR.
 BLAs approved on or after 1/   safety reports--
 1/98 and applicants with       semiannual
 approved pediatric use         submission
 supplements.                   (E.4)\2\.
Applicants with NDAs or BLAs   Individual case   NA...................  TPSR (E.1) or IPSR...  TPSR or PSUR.
 approved before 1/1/98.        safety reports--
                                semiannual
                                submission.
----------------------------------------------------------------------------------------------------------------
\1\ Applicants with approved ANDAs would determine the type of postmarketing periodic safety report required to
  be submitted to FDA (i.e., TPSR, PSUR, IPSR) and the frequency of submission for these reports based on the
  U.S. approval date of the application for the innovator NDA product (see section III.I of this document).
\2\ References in parentheses refer to section III of this document.

    FDA is also proposing to amend its postmarketing safety reporting 
regulations at Sec. Sec.  314.80(c) and 600.80(c) to state that 
applicants who wish to submit postmarketing safety reports at times 
other than prescribed by these regulations may request a waiver for 
this purpose under Sec. Sec.  314.90 or 600.90. This proposed revision 
does not represent a new provision, but rather provides a cross-
reference to the existing waiver requirements under Sec. Sec.  314.90 
and 600.90.
    FDA is also proposing to amend its postmarketing periodic safety 
reporting regulations at Sec. Sec.  314.80(c)(2)(i) and 600.80(c)(2)(i) 
by removing the third and fourth sentences in these paragraphs. These 
sentences state that, upon written notice, FDA may request submission 
of periodic safety reports at different times than stated under 
Sec. Sec.  314.80(c)(2)(i) and 600.80(c)(2)(i) (e.g., following the 
approval of a major supplement). FDA is proposing to remove these 
sentences because this information would now be stated under proposed 
Sec. Sec.  314.80(c) and 600.80(c). This proposed revision represents 
an organizational change that clarifies that FDA may request a 
different time period for submission of not only postmarketing periodic 
safety reports, but also postmarketing expedited safety reports.
III.C.5. Determination of Outcome, Minimum Data Set, and Full Data Set
    Proposed Sec. Sec.  310.305(c)(1)(i)(A), 314.80(c)(1)(i)(A), and 
600.80(c)(1)(i)(A) would amend FDA's postmarketing safety reporting 
regulations to require that manufacturers and applicants immediately, 
upon initial receipt of an SADR report, determine the outcome for the 
SADR (whether the SADR is serious or nonserious) and at least the 
minimum data set for the individual case safety report (i.e., 
identifiable patient, identifiable reporter, suspect drug or biological 
product, and SADR). If the manufacturer or applicant is not able to 
immediately determine this information, active query would be required 
to be used by the manufacturer or applicant to obtain the information 
as soon as possible. FDA is proposing this change to clarify that 
timely acquisition of information is critical to determine whether an 
SADR must be submitted to FDA and, for those reactions that would be 
reported, whether the SADR would be submitted in a postmarketing 
expedited safety report or a postmarketing periodic safety report.
    Proposed Sec. Sec.  310.305(c)(1)(i)(A), 314.80(c)(1)(i)(A), and 
600.80(c)(1)(i)(A) would also require manufacturers and applicants to 
immediately determine the

[[Page 12430]]

minimum information for actual medication errors that do not result in 
an SADR and potential medication errors (minimum information described 
below and at proposed Sec. Sec.  310.305(c)(1)(iii)(B) and 
(c)(1)(iii)(C), 314.80(c)(1)(iii)(B) and (c)(1)(iii)(C), and 
600.80(c)(1)(iii)(B) and (c)(1)(iii)(C)). If the manufacturer or 
applicant is not able to immediately determine this information, active 
query would be required to be used by the manufacturer or applicant to 
obtain the information as soon as possible.
    Proposed Sec. Sec.  310.305(c)(1)(ii), 314.80(c)(1)(ii), and 
600.80(c)(1)(ii) would require manufacturers and applicants who are 
unable to immediately determine the outcome of an SADR (whether the 
SADR is serious or nonserious) to continue to use active query to 
attempt to determine the outcome within 30 calendar days after initial 
receipt of the SADR report by the manufacturer or applicant. The 
proposed rule would require that manufacturers and applicants maintain 
records of their efforts to obtain this information. These proposed 
revisions clarify that due diligence must be used to obtain the outcome 
for SADRs. Unknown outcomes should not be classified arbitrarily as 
nonserious SADRs. Instead, each of the outcomes in the definition of 
serious SADR should be considered as a possibility.
    Under proposed Sec. Sec.  310.305(c)(1)(iii)(A), 
314.80(c)(1)(iii)(A), and 600.80(c)(1)(iii)(A), individual case safety 
reports for SADRs that do not contain a minimum data set would not be 
submitted to the agency. Instead, the proposed rule would require that 
manufacturers and applicants maintain records of any information 
received or otherwise obtained for the SADR along with a record of 
their efforts to obtain a minimum data set for the individual case 
safety report. These proposed amendments are consistent with proposed 
revisions to the premarketing safety reporting regulations at proposed 
Sec.  312.32(c) (see section III.B.2.a of this document). This change 
would clarify that, at a minimum, certain information must be submitted 
to FDA to provide the agency with enough information to allow an 
initial evaluation of the significance of an SADR.
    Proposed Sec. Sec.  310.305(c)(1)(iii)(B), 314.80(c)(1)(iii)(B), 
and 600.80(c)(1)(iii)(B) would require that reports of actual 
medication errors that do not result in an SADR be submitted to FDA 
even though the report does not contain a minimum data set (i.e., does 
not have an SADR). In these cases, individual case safety reports would 
be required to contain at least an identifiable patient, an 
identifiable reporter, and a suspect drug or biological product.
    Proposed Sec. Sec.  310.305(c)(1)(iii)(C), 314.80(c)(1)(iii)(C), 
and 600.80(c)(1)(iii)(C) would require that reports of potential 
medication errors be submitted to FDA even though the report does not 
contain a minimum data set (i.e., does not have an identifiable patient 
or an SADR). In these cases, individual case safety reports would be 
required to contain at least an identifiable reporter and a suspect 
drug or biological product.
    FDA is requiring submission of individual case safety reports for 
actual medication errors that do not result in an SADR and potential 
medication errors because of their potential significance and the need 
for intervention to minimize future errors. For example, if an adult is 
given the wrong medication, no SADR may occur, but if the same error 
occurs with a child, an SADR may occur. Also, if an error is prevented 
prior to administration of a product, this information could be used to 
prevent the error from occurring in other situations. For example, the 
proprietary name, label, labeling or packaging of the product could be 
changed if sufficient evidence suggests such a change is warranted, or 
education announcements could be communicated to health care 
professionals and/or consumers.
    Proposed Sec. Sec.  310.305(c)(1)(iv), 314.80(c)(1)(iv), and 
600.80(c)(1)(iv) state that, for reports of serious SADRs, always 
expedited reports, and medication error reports, manufacturers and 
applicants would be required to submit a full data set for the report 
(see section III.D.4 of this document for discussion of always 
expedited reports and section III.D.5 of this document for discussion 
of medication error reports). If a full data set is not available for 
the report, the manufacturer or applicant would be required to use 
active query to obtain this information. If a full data set is not 
available, after active query, the manufacturer or applicant would 
provide the following information:
    [sbull] All safety information, received or otherwise obtained, for 
the report;
    [sbull] The reason(s) for their inability to acquire a full data 
set; and
    [sbull] Documentation of their efforts to obtain a full data set 
(i.e., description of unsuccessful steps taken to obtain this 
information).

In some cases, the agency has received incomplete safety reports for 
serious SADRs, making interpretation of their significance difficult. 
This proposed amendment would require submission of complete 
information for reports of serious SADRs, always expedited reports, and 
medication error reports, which would facilitate their expeditious 
review.
    Proposed Sec. Sec.  310.305(c)(1)(v), 314.80(c)(1)(v), and 
600.80(c)(1)(v) state that:

    For a serious SADR that was not initially reported to the 
manufacturer (applicant for proposed Sec. Sec.  314.80(c)(1)(v) and 
600.80(c)(1)(v)) by a health care professional (e.g., report from a 
consumer), the manufacturer (applicant for proposed Sec. Sec.  
314.80(c)(1)(v) and 600.80(c)(1)(v)) must contact the health care 
professional associated with the care of the patient using active 
query to gather further medical perspective on the case and to 
acquire a full data set for the report. If the manufacturer 
(applicant for proposed Sec. Sec.  314.80(c)(1)(v) and 
600.80(c)(1)(v)) is unable to contact the health care professional, 
it must include in the report for the serious SADR: (A) The 
reason(s) for its inability to contact the health care professional 
and (B) a description of its efforts to contact the health care 
professional.

The agency believes that contact with a health care professional is 
warranted for serious SADRs because of the critical nature of these 
reactions. However, in those situations in which a manufacturer or 
applicant is unable to contact the health care professional (e.g., 
health care professional does not return phone calls, consumer does not 
permit manufacturer or applicant to contact its health care provider), 
it would include in its report to FDA the reason(s) for its inability 
to contact the health care professional and a description of its 
efforts to contact the health care professional.
    For nonserious SADRs with a minimum data set, proposed Sec. Sec.  
314.80(c)(1)(vi) and 600.80(c)(1)(vi) would require applicants to 
submit to FDA all safety information received or otherwise obtained. 
Applicants would not be required to acquire information in addition to 
the minimum data set, except that reports of nonserious SADRs resulting 
from a medication error would require a full data set. Thus, followup 
would not be required for reports of nonserious SADRs that contain a 
minimum data set and do not occur because of a medication error.
III.C.6. Spontaneous Reports and Reports From Clinical Trials
    Proposed Sec. Sec.  310.305(c)(1)(i)(B), 314.80(c)(1)(i)(B), and 
600.80(c)(1)(i)(B) would require that, for spontaneous reports, 
manufacturers and applicants must always assume, for safety reporting 
purposes only, that there is at least a reasonable possibility, in the 
opinion of the initial reporter, that the drug or

[[Page 12431]]

biological product caused the spontaneously reported event. Proposed 
Sec. Sec.  310.305(c)(1)(i)(C), 314.80(c)(1)(i)(C), and 
600.80(c)(1)(i)(C) state that, for a clinical trial, the possibility 
that the drug or biological product caused the SADR or that a 
medication error has occurred would be assumed if either the 
investigator or the applicant/manufacturer believes that such a 
reasonable possibility exists.
    These proposed changes would clarify that all spontaneous reports 
received by manufacturers and applicants that contain a minimum data 
set (minimum information for a report of a medication error that does 
not result in SADR) would be reported to FDA (i.e., as an individual 
case safety report and/or in a summary tabulation). These changes are 
consistent with the premarketing safety reporting requirements 
described in section III.B.2.b of this document (i.e., determination of 
the possibility of causality (attributability) of an SADR to the drug 
or biological product in a clinical investigation would be based on the 
opinion of either the applicant/sponsor or investigator). These 
proposed amendments are also consistent with the ICH E2A guidance (60 
FR 11284 at 11286):

    Causality assessment is required for clinical investigation 
cases. All cases judged by either the reporting health care 
professional or the sponsor as having a reasonable suspected causal 
relationship to the medicinal product qualify as ADR's. For purposes 
of reporting, adverse event reports associated with marketed drugs 
(spontaneous reports) usually imply causality.
III.C.7. Lack of Efficacy Reports
    With regard to reports of a lack of efficacy for an approved drug 
or biological product, the guidance of 1992 and guidance of 1993 advise 
applicants to submit all individual cases of such reports that occur in 
the United States in postmarketing periodic safety reports. In this 
proposed rule, FDA would not require submission of individual case 
safety reports for reports of a lack of efficacy. Instead, applicants 
would be required to submit to FDA expedited reports of information 
sufficient to consider a product administration change, based upon 
appropriate medical judgement, for any significant unanticipated safety 
finding or data in the aggregate from a study that suggests a 
significant human risk. For example, applicants would be required to 
submit information concerning reports of a lack of efficacy with a drug 
or biological product used in treating a life-threatening or serious 
disease (see section III.D.2 of this document). In addition, applicants 
would be required to include in postmarketing periodic safety reports 
(i.e., TPSRs, PSURs, IPSRs) an assessment of whether it is believed 
that the frequency of lack of efficacy reports is greater than would be 
predicted by the premarketing clinical trials for the drug or 
biological product (see sections III.E.1.c, III.E.2.k.vi, and III.E.3 
of this document). This assessment would be provided for reports of a 
lack of efficacy whether a serious SADR, nonserious SADR, or no SADR 
occurs. Applicants that submit PSURs and IPSRs to FDA would also 
include in these reports a discussion of medically relevant lack of 
efficacy reports (e.g., might represent a significant hazard to the 
treated population) for a product(s) used to treat serious or life-
threatening diseases (see sections III.E.2.h and III.E.3 of this 
document).

III.D. Postmarketing Expedited Reports

    Current postmarketing expedited safety reporting regulations at 
Sec. Sec.  310.305(c), 314.80(c), and 600.80(c) require submission of 
``15-day Alert reports'' to FDA. FDA is proposing to amend these 
regulations by removing the term ``15-day Alert report'' and replacing 
it with the term ``expedited report'' to be consistent with terminology 
used in the ICH E2A guidance. FDA is also proposing the following 
revisions to its postmarketing expedited safety reporting regulations.
III.D.1. Serious and Unexpected SADRs
    Under the existing postmarketing expedited safety reporting 
regulations at Sec.  310.305(c)(1)(i), persons subject to this 
requirement must report to FDA each adverse drug experience received or 
otherwise obtained that is both serious and unexpected as soon as 
possible, but in no case later than 15 calendar days of initial receipt 
of the information by the person. Under the existing postmarketing 
expedited safety reporting regulations at Sec. Sec.  314.80(c)(1)(i) 
and 600.80(c)(1)(i), persons subject to these requirements must report 
each adverse drug experience that is both serious and unexpected, 
whether foreign or domestic, as soon as possible, but in no case later 
than 15 calendar days of initial receipt of the information by the 
person.
    FDA is proposing minor revisions to these regulations for 
consistency. Proposed Sec.  310.305(c)(2)(i) would amend Sec.  
310.305(c)(1)(i) by adding the phrase ``whether foreign or domestic'' 
after the phrase ``that is both serious and unexpected.'' Proposed 
Sec. Sec.  314.80(c)(2)(i) and 600.80(c)(2)(i) would amend Sec. Sec.  
314.80(c)(1)(i) and 600.80(c)(1)(i) by adding the phrase ``to FDA'' 
after the word ``report'' and by adding the phrase ``received or 
otherwise obtained'' before the phrase ``that is both serious and 
unexpected.''
    Proposed Sec. Sec.  310.305(c)(2)(i), 314.80(c)(2)(i), and 
600.80(c)(2)(i) would amend Sec. Sec.  310.305(c)(1)(i), 
314.80(c)(1)(i), and 600.80(c)(1)(i) by removing the phrase ``of 
initial receipt of the information by the person whose name appears on 
the label (``by the applicant'' for Sec.  314.80(c)(1)(i), and ``by the 
licensed manufacturer'' for Sec.  600.80(c)(1)(i)) and replacing it 
with the phrase ``after receipt by the manufacturer (``applicant'' for 
proposed Sec. Sec.  314.80(c)(2)(i), and 600.80(c)(2)(i)) of the 
minimum data set for the serious, unexpected SADR.'' This proposed 
amendment is consistent with proposed revisions to the premarketing 
expedited safety reporting regulations at proposed Sec.  
312.32(c)(1)(i) (see section III.B.2.b of this document). The amendment 
would clarify that the 15 calendar day timeframe would begin as soon as 
manufacturers and applicants have knowledge of the minimum data set for 
an SADR that is serious and unexpected. Manufacturers and applicants 
must use due diligence to acquire this information. For this purpose, 
they would be required, as described in section III.C.5 of this 
document, to use active query to determine the outcome for the SADR 
(whether the SADR is serious or nonserious) and acquire at least the 
minimum data set for the individual case safety report if they are not 
able to immediately obtain this information. Manufacturers and 
applicants should include in postmarketing expedited safety reports a 
chronological history of their efforts to acquire a minimum data set 
and to determine the seriousness and expectedness of an SADR if there 
is a delay in obtaining such information.
    Proposed Sec. Sec.  310.305(c)(2)(i), 314.80(c)(2)(i) and 
600.80(c)(2)(i) state that if a full data set is not available for a 
serious and unexpected SADR report at the time of initial submission of 
the report to FDA, manufacturers and applicants must submit the 
information required under proposed Sec. Sec.  310.305(c)(1)(iv), 
314.80(c)(1)(iv) and 600.80(c)(1)(iv) as described in section III.C.5 
of this document and also submit a 30-day followup report as described 
in section III.D.6 of this document. FDA is proposing this action to 
clarify the importance of acquiring complete information for serious 
SADRs.

[[Page 12432]]

III.D.2. Information Sufficient To Consider Product Administration 
Changes
    Proposed Sec. Sec.  310.305(c)(2)(ii), 314.80(c)(2)(ii), and 
600.80(c)(2)(ii) would require that manufacturers and applicants submit 
to FDA information, received or otherwise obtained, whether foreign or 
domestic, that would be sufficient, based upon appropriate medical 
judgment, to consider changes in product administration. Manufacturers 
and applicants would be required to submit this information to the 
agency as soon as possible, but in no case later than 15 calendar days 
after the manufacturer or applicant determines that the information 
qualifies for expedited reporting. Examples of such information include 
any significant unanticipated safety finding or data in the aggregate 
from an in vitro, animal, epidemiological, or clinical study, whether 
or not conducted under an IND, that suggests a significant human risk, 
such as reports of mutagenicity, teratogenicity, or carcinogenicity, or 
reports of a lack of efficacy with a drug or biological product used in 
treating a life-threatening or serious disease. The proposed rule would 
require that manufacturers and applicants maintain records of their 
efforts to determine whether information that they have received or 
otherwise obtained would qualify for expedited reporting under this 
proposed requirement. This proposed requirement is consistent with the 
proposed revisions to the premarketing expedited safety reporting 
regulations at proposed Sec.  312.32(c)(1)(ii) (see section III.B.2.c 
of this document) and with the ICH E2A guidance (60 FR 11284 at 11286). 
The proposed amendment would further clarify some of the types of 
safety information that must be submitted to FDA in an expedited 
manner.

III.D.3. Unexpected SADRs With Unknown Outcome

    FDA expects that, in most cases, manufacturers and applicants will 
be able to determine the outcome for an SADR (whether the SADR is 
serious or nonserious). However, in those few cases where a 
determination may not be possible, FDA would require submission of 
unexpected SADRs with unknown outcome in an expedited manner (proposed 
Sec. Sec.  310.305(c)(2)(iii), 314.80(c)(2)(iii), and 
600.80(c)(2)(iii)). Expedited safety reports for unexpected SADRs with 
unknown outcome would be submitted to FDA within 45 calendar days after 
initial receipt by the manufacturer or applicant of the minimum data 
set for the unexpected SADR. FDA is proposing this action to expedite 
review of potentially serious SADRs.
    The proposed rule would require that manufacturers and applicants 
reporting an unexpected SADR with unknown outcome include in the 
expedited safety report the reason(s) for their inability to classify 
an SADR as either serious or nonserious (i.e., unknown outcome). For 
this purpose, manufacturers and applicants should include in the 
expedited report a chronological history of their efforts to determine 
the outcome of the SADR.
    Manufacturers and applicants reporting an unexpected SADR with 
unknown outcome must exercise due diligence to determine the 
expectedness for the SADR and to acquire at least the minimum data set 
for the individual case safety report. For this purpose, these persons 
would be required to use active query to acquire this information (see 
section III.C.5 of this document). These persons should include in 
postmarketing expedited safety reports a chronological history of their 
efforts to acquire this information if there is a delay in obtaining 
it.
III.D.4. Always Expedited Reports
    Proposed Sec. Sec.  310.305(c)(2)(iv), 314.80(c)(2)(iv), and 
600.80(c)(2)(iv) would require manufacturers and applicants to submit 
to FDA individual case safety reports for SADRs, received or otherwise 
obtained, whether foreign or domestic, that are the subject of an 
always expedited report. These always expedited reports would be 
submitted to the agency as soon as possible, but in no case later than 
15 calendar days after receipt by the manufacturer (``applicant'' for 
proposed Sec. Sec.  314.80(c)(2)(iv), and 600.80(c)(2)(iv)) of the 
minimum data set for the report. The following medically significant 
SADRs, which may jeopardize the patient or subject and/or require 
medical or surgical intervention to treat the patient or subject, would 
be subject to an always expedited report:
    [sbull] Congenital anomalies,
    [sbull] Acute respiratory failure,
    [sbull] Ventricular fibrillation,
    [sbull] Torsades de pointe,
    [sbull] Malignant hypertension,
    [sbull] Seizure,
    [sbull] Agranulocytosis,
    [sbull] Aplastic anemia,
    [sbull] Toxic epidermal necrolysis,
    [sbull] Liver necrosis,
    [sbull] Acute liver failure,
    [sbull] Anaphylaxis,
    [sbull] Acute renal failure,
    [sbull] Sclerosing syndromes,
    [sbull] Pulmonary hypertension,
    [sbull] Pulmonary fibrosis,
    [sbull] Confirmed or suspected transmission of an infectious agent 
by a marketed drug or biological product,
    [sbull] Confirmed or suspected endotoxin shock, and
    [sbull] Any other medically significant SADR that FDA determines to 
be the subject of an always expedited report (i.e., may jeopardize the 
patient or subject and/or require medical or surgical intervention to 
treat the patient or subject).

These SADRs would be submitted to the agency in an expedited manner 
whether unexpected or expected and whether or not the SADR leads to a 
serious outcome. The medical gravity of these SADRs requires expedited 
reporting.
    The agency is proposing that a confirmed or suspected transmission 
of an infectious agent by a marketed drug or biological product would 
be the subject of an always expedited report. Examples of such 
transmissions include human immunodeficiency virus (HIV) transmission 
by anti-hemophilic factor, hepatitis C transmission by intravenous 
immunoglobulin, bacterial contamination of albumin leading to sepsis, 
and parvovirus contamination of anti-hemophilic factor causing an SADR. 
These SADRs indicate a public health problem that requires expedited 
review by the agency.
    The proposal provides that the agency could make a new SADR the 
subject of an always expedited report. Such an SADR would only become 
the subject of these reports if FDA determines that the SADR is 
medically significant (i.e., may jeopardize the patient or subject and/
or require medical or surgical intervention to treat the patient or 
subject). New SADRs that become the subject of always expedited reports 
would be included in the agency's current guidance for industry on 
postmarketing safety reporting for human drugs and licensed biological 
products.
    Proposed Sec. Sec.  310.305(c)(2)(iv)(B), 314.80(c)(2)(iv)(B), and 
600.80(c)(2)(iv)(B) would require that if a full data set is not 
available for always expedited reports at the time of initial 
submission of the report to FDA, manufacturers and applicants would 
submit the information required under proposed Sec. Sec.  
310.305(c)(1)(iv), 314.80(c)(1)(iv) and 600.80(c)(1)(iv) as described 
in section III.C.5 of this document and also submit a 30-day followup 
report as described in section III.D.6 of this document. FDA is 
proposing this action to clarify the importance of acquiring complete 
information for medically significant SADRs that are the subject of 
always expedited reports.

[[Page 12433]]

III.D.5. Medication Errors
    Proposed Sec. Sec.  310.305(c)(2)(v)(A), 314.80(c)(2)(v)(A), and 
600.80(c)(2)(v)(A) would require that each domestic report of an actual 
medication error, received or otherwise obtained, be submitted to the 
agency as soon as possible, but in no case later than 15 calendar days 
after receipt by the manufacturer (``applicant'' for proposed 
Sec. Sec.  314.80(c)(2)(v)(A) and 600.80(c)(2)(v)(A)) of the minimum 
data set for a report of an SADR or, if an SADR does not occur, the 
minimum information for the report as described in section III.C.5 of 
this document (i.e., an identifiable patient, an identifiable reporter, 
and a suspect drug or biological product). For postmarketing safety 
reporting purposes, all reports of medication errors would be 
considered unexpected. FDA is proposing this new type of expedited 
report to protect public health.
    Proposed Sec. Sec.  310.305(c)(2)(v)(B), 314.80(c)(2)(v)(B), and 
600.80(c)(2)(v)(B) would require that reports of potential medication 
errors, received or otherwise obtained, be submitted to the agency as 
soon as possible, but in no case later than 15 calendar days after 
receipt by the manufacturer (``applicant'' for proposed Sec. Sec.  
314.80(c)(2)(v)(B) and 600.80(c)(2)(v)(B)) of the minimum information 
described in section III.C.5 of this document (i.e., an identifiable 
reporter and a suspect drug or biological product). FDA is proposing 
submission of this information to the agency in an expedited manner to 
attempt to prevent actual medication errors.
    Proposed Sec. Sec.  310.305(c)(2)(v)(C), 314.80(c)(2)(v)(C), and 
600.80(c)(2)(v)(C) state that if a full data set is not available for 
an actual or potential medication error report at the time of initial 
submission of the report to FDA, manufacturers and applicants would 
submit the information required under proposed Sec. Sec.  
310.305(c)(1)(iv), 314.80(c)(1)(iv) and 600.80(c)(1)(iv) as described 
in section III.C.5 of this document and also submit a 30-day followup 
report as described in section III.D.6 of this document. FDA is 
proposing this action to clarify the importance of acquiring complete 
information for reports of medication errors.
III.D.6. Followup Reports
    Current postmarketing expedited safety reporting regulations at 
Sec. Sec.  310.305(c)(2), 314.80(c)(1)(ii), and 600.80(c)(1)(ii) 
require persons subject to these regulations to promptly investigate 
all serious, unexpected adverse drug experiences that are the subject 
of expedited reports and to submit followup reports within 15 calendar 
days of receipt of new information or as requested by FDA. If 
additional information is not obtainable, records should be maintained 
of the unsuccessful steps taken to seek additional information. Thus, 
followup reports are currently only required to be submitted to FDA if 
requested by the agency or if new information is obtained or otherwise 
received by the manufacturer or applicant for an adverse drug 
experience previously reported to FDA.
    In this rulemaking, FDA continues to require submission of these 
followup reports. In addition, as described in the following paragraph, 
a 30-day followup report would be required to be submitted in certain 
cases (i.e., initial serious and unexpected SADR reports, always 
expedited reports and medication error reports that do not contain a 
full data set). If a 30-day followup report is required and no new 
information is available for the report, then the manufacturer or 
applicant would still be required to submit the 30-day followup report, 
indicate in the report that no new information was available and 
include a description of the reason(s) for its inability to acquire 
complete information and its efforts to obtain complete information. In 
all other cases, if there is no new information to report to FDA on a 
previously submitted SADR no followup report would be required to be 
submitted to the agency.
    Proposed Sec. Sec.  310.305(c)(2)(vi), 314.80(c)(2)(vi), and 
600.80(c)(2)(vi) would require manufacturers and applicants to use 
active query to obtain additional information for any serious and 
unexpected SADR submitted to FDA in an expedited report under proposed 
Sec. Sec.  310.305(c)(2)(i), 314.80(c)(2)(i), and 600.80(c)(2)(i) that 
does not contain a full data set. The proposed amendment would also 
require these persons to use active query to obtain additional 
information for any always expedited report under proposed Sec. Sec.  
310.305(c)(2)(iv), 314.80(c)(2)(iv), and 600.80(c)(2)(iv) or any 
medication error report under proposed Sec. Sec.  310.305(c)(2)(v), 
314.80(c)(2)(v), and 600.80(c)(2)(v) that does not contain a full data 
set. This information would be submitted to the agency in a followup 
report within 30 calendar days after initial submission of the 
expedited report to FDA by the manufacturer or applicant (30-day 
followup report). This proposed amendment would provide the agency with 
timely acquisition of more complete information for SADRs and 
medication errors that are the subject of these reports.
    Proposed Sec. Sec.  310.305(c)(2)(vi), 314.80(c)(2)(vi), and 
600.80(c)(2)(vi) would also state that:

    * * * If a full data set is still not obtainable, the 30-day 
followup report must contain the information required under 
paragraph (c)(1)(iv) of this section. Any new safety information in 
the 30-day followup report must be highlighted. Any new information, 
received or otherwise obtained, after submission of a 30-day 
followup report must be submitted to FDA as a 15-day followup report 
under paragraph (c)(2)(vii) of this section.

This proposed amendment would clarify the information that would be 
required in a 30-day followup report if a full data set is still not 
available for the report. It would also clarify that FDA would require 
a 15-day followup report, as described in the paragraphs that follow, 
for any new information obtained or otherwise received for the report 
after submission of the 30-day followup report. The proposed amendment 
would ensure that manufacturers and applicants would exercise due 
diligence to obtain complete information for SADRs that are the subject 
of 30-day followup reports.
    Proposed Sec. Sec.  310.305(c)(2)(vii), 314.80(c)(2)(vii), and 
600.80(c)(2)(vii) would amend Sec. Sec.  310.305(c)(2), 
314.80(c)(1)(ii), and 600.80(c)(1)(ii) to clarify that manufacturers 
and applicants must submit 15-day followup reports to FDA of any new 
information received or otherwise obtained for any expedited or 
followup report (except for initial expedited reports under proposed 
Sec. Sec.  310.305(c)(2)(i), (c)(2)(iv), and (c)(2)(v), 314.80 
(c)(2)(i), (c)(2)(iv), and (c)(2)(v), and 600.80(c)(2)(i), (c)(2)(iv), 
and (c)(2)(v) that do not contain a full data set) within 15 calendar 
days of initial receipt of new information by the manufacturer or 
applicant. Proposed Sec. Sec.  310.305(c)(2)(vii), 314.80(c)(2)(vii), 
and 600.80(c)(2)(vii) would also state that:

    * * * Expedited reports under paragraphs (c)(2)(i), (c)(2)(iv), 
and (c)(2)(v) of this section that do not contain a full data set at 
the time of initial submission of the report to FDA are subject to 
the 30-day followup reporting requirements under paragraph 
(c)(2)(vi) of this section rather than the 15-day followup reporting 
requirements under this paragraph.

Thus, 15-day followup reports would be submitted for the following 
types of expedited and followup reports:
    [sbull] Serious and unexpected SADR reports that contain a full 
data set,
    [sbull] Information sufficient to consider product administration 
changes,

[[Page 12434]]

    [sbull] Unexpected SADRs with unknown outcomes,
    [sbull] Always expedited reports that contain a full data set,
    [sbull] Actual and potential medication error reports that contain 
a full data set,
    [sbull] 30-day followup reports, and
    [sbull] 15-day followup reports.

These proposed revisions clarify the types of expedited reports that 
would be subject to the 15-day followup reporting requirements.
    FDA notes that a 15-day followup report, rather than a serious and 
unexpected SADR report, should be submitted to FDA for an SADR that is 
initially reported to the agency as serious and expected or nonserious 
and unexpected, but is subsequently determined to be serious and 
unexpected. In these cases, manufacturers and applicants should include 
in the 15-day followup report a chronological history describing the 
events that transpired which resulted in determination of the serious 
and unexpected character of the SADR.
    FDA is proposing to amend its postmarketing expedited safety 
reporting regulations at Sec. Sec.  310.305(c)(2), 314.80(c)(1)(ii), 
and 600.80(c)(1)(ii) by removing the second sentence in these 
paragraphs regarding maintaining records if additional information is 
not obtainable for a serious and unexpected adverse drug experience. 
The agency is proposing this amendment because postmarketing safety 
reporting requirements for serious and unexpected SADR reports that do 
not contain a full data set are now prescribed under proposed 
Sec. Sec.  310.305(c)(1)(iv) and (c)(2)(vi), 314.80(c)(1)(iv) and 
(c)(2)(vi), and 600.80(c)(1)(iv) and (c)(2)(vi).
III.D.7. Supporting Documentation
    Proposed Sec. Sec.  310.305(c)(2)(viii)(A), 314.80(c)(2)(viii)(A), 
and 600.80(c)(2)(viii)(A) would require that manufacturers and 
applicants submit to FDA, if available, a copy of the autopsy report if 
the patient dies. If an autopsy report is not available, the proposed 
rule would require that manufacturers and applicants submit a death 
certificate to FDA. If an autopsy report becomes available after the 
manufacturer or applicant has submitted a death certificate to the 
agency, the manufacturer or applicant must submit the autopsy report to 
FDA. If the patient was hospitalized, manufacturers and applicants 
would be required to submit to FDA, if available, a copy of the 
hospital discharge summary. If any of these documents is not in 
English, an English translation of the document would be required. FDA 
is proposing that manufacturers and applicants submit these documents 
to provide the agency with complete information for SADRs that result 
in a death or hospitalization.
    Proposed Sec. Sec.  310.305(c)(2)(viii)(A), 314.80(c)(2)(viii)(A), 
and 600.80(c)(2)(viii)(A) would require that manufacturers and 
applicants use active query to obtain the documents required to be 
submitted to FDA under this paragraph. These documents would be 
required to be submitted to FDA as 15-day followup reports (see section 
III.D.6 of this document) within 15 calendar days of initial receipt of 
the document by the manufacturer or applicant. In instances when a 
document is not submitted to FDA in a 15-day followup report within 3 
months after submission of the initial expedited report for the death 
or hospitalization, the agency would assume that active query by the 
manufacturer or applicant did not result in access to these documents. 
In this case, a record of the reason(s) for the lack of documentation 
and the effort that was made to obtain the documentation would be 
required to be maintained by the manufacturer and applicant.
    Proposed Sec. Sec.  310.305(c)(2)(viii)(B), 314.80(c)(2)(viii)(B), 
and 600.80(c)(2)(viii)(B) would require that each expedited report 
contain in the narrative a list of other relevant documents (e.g., 
medical records, laboratory results, data from studies) regarding the 
report that are maintained by manufacturers and applicants. FDA may 
require, when appropriate, that copies of one or more of these 
documents be submitted to the agency within 5 calendar days after 
receipt of the request. FDA would usually request such records in 
response to a suspected safety problem associated with the use of a 
drug or licensed biological product.
III.D.8. Scientific Literature
    Current postmarketing expedited safety reporting regulations at 
Sec. Sec.  314.80(d)(1) and 600.80(d)(1) require that expedited reports 
based on information from the scientific literature be accompanied by a 
copy of the published article. These regulations apply only to reports 
found in scientific and medical journals either as case reports or as 
the result of a formal clinical trial. Proposed Sec. Sec.  
314.80(c)(2)(ix) and 600.80(c)(2)(ix) would amend the current 
regulations by removing the phrase ``either as case reports or as the 
result of a formal clinical trial'' to clarify that all reports from 
the scientific literature, including case reports, and results of a 
formal clinical trial, epidemiological study, in vitro study, or animal 
study, that qualify for expedited reporting under proposed Sec. Sec.  
314.80(c)(2) and 600.80(c)(2) would be required to be submitted to FDA.
    The proposed rule would also remove Sec. Sec.  314.80(d)(2) and 
600.80(d)(2). These paragraphs provide that reports based on the 
scientific literature must be submitted on FDA Form 3500A or comparable 
format prescribed by the regulations and that, in cases where persons 
subject to the postmarketing safety reporting regulations believe that 
preparing the FDA Form 3500A constitutes an undue hardship, 
arrangements can be made with the agency for use of an acceptable 
alternative reporting format. FDA is proposing to remove these 
paragraphs because the reporting format for reports based on 
information in the scientific literature would be specified under 
proposed Sec. Sec.  314.80(c)(4) and 600.80(c)(4) (see section III.F of 
this document).
    For organizational purposes, FDA is proposing to move Sec. Sec.  
314.80(d) and 600.80(d), as revised by this proposed rule, to proposed 
Sec. Sec.  314.80(c)(2)(ix) and 600.80(c)(2)(ix). Proposed Sec.  
310.305(c)(2)(ix) would amend Sec.  310.305(c) by adding the paragraph:

    Scientific literature. An expedited report based on information 
from the scientific literature applies only to reports found in 
scientific and medical journals. These expedited reports must be 
accompanied by a copy of the published article.

This proposed amendment would clarify for prescription drug products 
marketed for human use without an approved application the types of 
safety information found in scientific literature that would qualify 
for expedited reporting. The proposed amendment would also require that 
these reports include a copy of the published article that is the 
subject of the expedited report. The proposed amendment would provide 
the agency with more complete information for review of safety 
information from the scientific literature and would also provide 
uniformity between FDA's postmarketing expedited safety reporting 
requirements for prescription drugs marketed for human use without an 
approved application and marketed drugs with an approved application.
III.D.9. Contractors and Shared Manufacturers
    Current regulations at Sec. Sec.  310.305(c)(1)(i) and (c)(3), 
314.80(c)(1)(iii), and 600.80(c)(1)(iii) require any person whose name 
appears on the label of a marketed drug product or licensed biological 
product as a packer or distributor to submit either

[[Page 12435]]

expedited reports of serious and unexpected adverse drug experiences 
directly to FDA or reports of all serious adverse drug experiences to 
the manufacturer (Sec.  310.305(c)(3) or applicant (Sec. Sec.  
314.80(c)(1)(iii) and 600.80(c)(1)(iii)) instead of FDA in 5 calendar 
days. This provision also applies to manufacturers for Sec. Sec.  
314.80(c)(1)(iii) and 600.80(c)(1)(iii) and to shared manufacturers, 
joint manufacturers, and any participants involved in divided 
manufacturing for Sec.  600.80(c)(1)(iii). Proposed Sec. Sec.  
310.305(c)(2)(xi)(A), 314.80(c)(2)(x)(A), and 600.80(c)(2)(x)(A) would 
amend these regulations to require contractors, as defined in proposed 
Sec. Sec.  310.305(a), 314.80(a) and 600.80(a) (see section III.A.4 of 
this document), to submit to the manufacturer (proposed Sec.  
310.305(c)(2)(xi)(A)) or applicant (proposed Sec. Sec.  
314.80(c)(2)(x)(A) and 600.80(c)(2)(x)(A)) safety reports of all SADRs 
(serious and nonserious) and medication errors for the manufacturer's 
(proposed Sec.  310.305(c)(2)(xi)) or applicant's (proposed Sec. Sec.  
314.80(c)(2)(x) and 600.80(c)(2)(x)) drug or biological product, 
obtained or otherwise received, within 5 calendar days of initial 
receipt of the report by the contractor. This provision would also 
apply to shared manufacturers of licensed biological products for 
proposed Sec.  600.80(c)(2)(x)(A) (i.e., all SARs and medication errors 
would be required to be submitted to the applicant within 5 calendar 
days). The contractor would be required to submit a report of an SADR 
to the manufacturer (proposed Sec.  310.305(c)(2)(xi)(A)) or applicant 
(proposed Sec. Sec.  314.80(c)(2)(x)(A) and 600.80(c)(2)(x)(A)) even if 
the report does not contain a minimum data set. Contractors and shared 
manufacturers would only be required to convey to manufacturers 
(proposed Sec.  310.305(c)(2)(xi)(A)) or applicants (proposed 
Sec. Sec.  314.80(c)(2)(x)(A) and 600.80(c)(2)(x)(A)) whatever safety 
information was obtained or otherwise received. They would not be 
required to use active query to acquire safety information, to conduct 
followup, or to submit postmarketing safety reports to FDA. Upon 
receipt of a safety report from a contractor or shared manufacturer, 
the manufacturer (proposed Sec.  310.305(c)(2)(xi)(A)) or applicant 
(proposed Sec. Sec.  314.80(c)(2)(x)(A) and 600.80(c)(2)(x)(A)) would 
be required to comply with the postmarketing safety reporting 
requirements under proposed Sec. Sec.  310.305, 314.80 and 600.80 
(e.g., use active query, if necessary, to acquire safety information, 
conduct followup, submit postmarketing safety reports to FDA). These 
proposed amendments would provide manufacturers and applicants with 
complete safety information regarding its products.
    Proposed Sec. Sec.  310.305(c)(2)(xi)(B), 314.80(c)(2)(x)(B), and 
600.80(c)(2)(x)(B) would require that contracts between manufacturers 
and contractors (Sec.  310.305(c)(2)(xi)(B)) and applicants and 
contractors (Sec. Sec.  314.80(c)(2)(x)(B) and 600.80(c)(2)(x)(B)) 
specify the postmarketing safety reporting responsibilities of the 
contractor. Although contractors and shared manufacturers have 
postmarketing safety reporting responsibilities, the manufacturer 
(proposed Sec.  310.305(c)(2)(xi)(B)) or applicant (proposed Sec. Sec.  
314.80(c)(2)(x)(B) and 600.80(c)(2)(x)(B)) would be responsible for 
ensuring that the contractors and shared manufacturers of its products 
comply with these postmarketing safety reporting responsibilities. FDA 
believes that, in general, this proposal represents a practice that is 
already customary and usual in the pharmaceutical industry because 
contractors are typically considered agents of the manufacturer or 
applicant.
    Proposed Sec. Sec.  310.305(c)(2)(xi)(C), 314.80(c)(2)(x)(C), and 
600.80(c)(2)(x)(C) would require that contractors and shared 
manufacturers maintain records of SADR reports and medication errors. 
This proposal is consistent with current postmarketing safety reporting 
requirements.
    Proposed Sec. Sec.  310.305(c)(2)(xi)(D), 314.80(c)(2)(x)(D), and 
600.80(c)(2)(x)(D) state that the recordkeeping, written procedures, 
and disclaimer provisions under proposed Sec. Sec.  310.305, 314.80 and 
600.80 would apply to contractors and shared manufacturers. This 
proposal clarifies for contractors and shared manufacturers which of 
the postmarketing safety reporting provisions would apply to them.
III.D.10. Prescription Drugs Marketed for Human Use Without an Approved 
Application
    Proposed Sec.  310.305(c)(2)(x) would amend Sec.  310.305(c)(1)(i) 
to require that expedited reports for prescription drugs marketed for 
human use without an approved application be accompanied by a list of 
the current addresses where all safety reports and other safety-related 
records for the drug product are maintained by manufacturers and 
contractors. In the October 1994 proposal, FDA proposed to include, 
under Sec. Sec.  314.80(c)(2) and 600.80(c)(2), a section in its 
postmarketing periodic safety reports on location of adverse drug 
experience records (59 FR 54046 at 54061). FDA is now reproposing this 
amendment for its postmarketing periodic safety reports (see sections 
III.E.1.g, III.E.2.k.x, and III.E.3 of this document). The agency is 
also proposing to require the list of addresses in expedited reports 
for drugs covered under Sec.  310.305 because manufacturers of these 
drugs are not required to submit postmarketing periodic safety reports 
to FDA. The list of addresses would provide rapid access to safety-
related records for FDA inspections and for requests by FDA for 
additional information concerning safety issues.
III.D.11. Class Action Lawsuits
    Manufacturers and applicants should not submit SADRs from class 
action lawsuits to FDA in an expedited report. The agency believes that 
SADRs from class action lawsuits would be submitted to FDA from other 
sources (e.g., spontaneous reports) prior to initiation of the class 
action lawsuit. Summary tabulations of SADRs from class action lawsuits 
would be required in postmarketing periodic safety reports (see 
sections III.E.1.e and III.E.2.k.v of this document).
III.D.12. Blood and Blood Component Safety Reports
    Current Sec.  606.170(a) requires a blood establishment to 
thoroughly investigate any complaint of an adverse reaction arising as 
a result of blood collection or transfusion and to prepare and maintain 
a written report of the investigation, including followup and 
conclusions, as part of the record for that lot or unit of final 
product. If appropriate, the report must be forwarded to the 
manufacturer of the blood or blood component or the collection 
facility. Under Sec.  606.170(b), a complication of a blood collection 
or blood transfusion resulting in a fatality must be reported to FDA as 
soon as possible by telephone or other rapid means of communication, 
and a written report of the investigation must be submitted to FDA 
within 7 days of the fatality. Each year, in accordance with Sec.  
606.170(b), FDA receives between 50 and 80 reports of fatalities.
    Current Sec.  606.171 requires licensed manufacturers of blood and 
blood components, unlicensed registered blood establishments and 
transfusion services to report biological product deviations. A 
biological product deviation is an event that represents either: (1) A 
deviation from current good manufacturing practices, applicable 
regulations, applicable standards, or established specifications that 
may affect the safety, purity, or potency of a product; or (2) an 
unexpected or

[[Page 12436]]

unforseeable event that may affect the safety, purity, or potency of a 
product. In some cases, a biological product deviation reportable under 
Sec.  606.171 may actually result in an adverse reaction in the 
transfusion recipient. In many other cases, the biological product 
deviation may be discovered before the affected products are 
administered or administration of the product may not result in an 
adverse reaction.
    Although manufacturers of blood and blood components are currently 
exempt from the safety reporting requirements under Sec.  600.80, FDA 
receives reports of fatal adverse reactions related to blood and blood 
components and may receive some additional information through 
biological product deviation reporting. However, the agency does not 
currently receive adequate information to monitor and assess safety-
related information concerning the collection and transfusion of blood 
and blood components. Such information is essential for evaluating the 
agency's scientific and regulatory policies and for monitoring industry 
practices and their implications on blood safety. For these purposes, 
FDA is proposing to amend Sec.  606.170 to require the reporting of all 
serious SARs, in addition to fatalities, that are related to the 
collection or transfusion of blood and blood components (e.g., red 
blood cells, plasma, platelets, and cryoprecipitate). For fatal SARs, 
proposed Sec.  606.170(c) would continue the current requirement that a 
fatal SAR be reported immediately by telephone, facsimile, express 
mail, or electronically transmitted mail and in a written report within 
7 calendar days of the fatality. Because blood establishments are 
already required to investigate all complaints of an adverse reaction 
related to the collection and transfusion of blood and blood components 
and many of these reactions are well recognized and understood by blood 
establishments and by FDA, the agency is not proposing to require the 
submission of postmarketing periodic safety reports (i.e., TPSRs, 
PSURs, IPSRs and individual case safety reports--semiannual 
submissions).
    Specifically, FDA is proposing to amend Sec.  606.170 by revising 
the title of the section to read ``Suspected adverse reaction 
investigation and reporting''; by making editorial changes to Sec.  
606.170(a), which prescribes requirements for the investigation and 
recording of any complaint of an SAR related to the collection or 
transfusion of blood or blood components; by adding a new requirement 
for reporting of serious SARs related to transfusion or collection 
procedures (proposed Sec.  606.170(b)); and by redesignating current 
Sec.  606.170(b) as Sec.  606.170(c) and revising the paragraph as 
discussed below. FDA is also proposing that the terms ``SAR'' and 
``serious SAR,'' as used in proposed Sec.  606.170, have the same 
meaning as defined in proposed Sec.  600.80(a)(see sections III.A.1 and 
III.A.3 of this document).
    In general, FDA believes that any SAR related to blood donation or 
transfusion that requires immediate medical intervention or followup 
medical attention should be reported. For the purpose of reporting 
serious SARs related to blood collection, FDA interprets the term to 
include:
    [sbull] Vasovagal reactions with syncope (hypotension and 
bradycardia) requiring medical intervention;
    [sbull] Citrate reactions requiring significant medical 
intervention;
    [sbull] Anaphylaxis or any major allergic reactions;
    [sbull] Seizure of any type or duration;
    [sbull] Cerebrovascular accidents;
    [sbull] Cardiac arrhythmia, angina of any duration, myocardial 
infarction, or cardiac arrest;
    [sbull] Clinically significant hypotension;
    [sbull] Bronchospasm, respiratory insufficiency;
    [sbull] Arterial puncture, air embolus;
    [sbull] Phlebotomy-related nerve damage; and,
    [sbull] Thrombophlebitis, phlebitis, or any procedure-related 
infection.

    For SARs related to donation, FDA interprets the term ``serious 
SAR'' not to include:
    [sbull] Self-limited vasovagal reactions (hemodynamically stable);
    [sbull] Self-limited citrate reactions;
    [sbull] Localized hematoma, uncomplicated; and,
    [sbull] Localized skin irritation, uncomplicated.
    For the purposes of reporting serious SARs related to receipt of a 
blood transfusion, FDA interprets the term to include:
    [sbull] Any complication from the use of an unsuitable unit, 
including infusion of hemolyzed blood;
    [sbull] Any complication from improper blood administration, 
including failure to use a standard blood filter (e.g., air embolism);
    [sbull] Induced hemolysis, acute or delayed;
    [sbull] Transmitted infections, including bacterial infections;
    [sbull] Associated graft versus host disease;
    [sbull] Related hypersensitivity with respiratory insufficiency 
and/or hypotension (e.g., anaphylaxis);
    [sbull] Transfusion-related acute lung injury (TRALI);
    [sbull] Induced alloimmunization which prevents effective 
transfusion therapy (e.g., posttransfusion purpura);
    [sbull] Induced congestive heart failure; and
    [sbull] Induced cardiac arrhythmias, including those resulting from 
metabolic imbalance.
    For SARs related to receipt of a blood transfusion, FDA interprets 
the term ``SAR'' not to include:
    [sbull] Febrile nonhemolytic transfusion reactions;
    [sbull] Related hypersensitivity without respiratory insufficiency 
nor hypotension;
    [sbull] Induced alloimmunization which does not prevent effective 
transfusion therapy;
    [sbull] Infections not clinically significant to the recipient, 
such as cytomegalovirus (CMV) infection in an immunocompetent adult; 
and,
    [sbull] Induced hemochromatosis.
    FDA is proposing to require that for a serious SAR related to blood 
collection, the establishment performing the blood collection be 
responsible for reporting the serious SAR to FDA, and for a serious SAR 
related to transfusion, the establishment responsible for the 
compatibility testing be responsible for reporting the serious SAR to 
FDA (proposed Sec.  606.170(b)). FDA is proposing to require that 
reports of serious SARs, including fatal SARs under proposed Sec.  
606.170(c), be reported to FDA using the reporting format described in 
proposed Sec.  600.80(c)(4). Thus the reporting facility would be 
required to submit a report for each individual patient on FDA Form 
3500A or a computer-generated facsimile of FDA Form 3500A using the 
appropriate ``preferred term'' in the latest version of MedDRA (see 
section III.F of this document).
    Current Sec.  606.171 requires reports of biological product 
deviations be submitted as soon as possible, but not to exceed 45 
calendar days. Because there will be instances when an SAR occurs and a 
biological product deviation may have contributed to an SAR, FDA is 
proposing to require reporting of serious SARs to the agency within 45 
calendar days (for fatal SARs, within 7 calendar days) of the 
determination that a serious SAR related to blood collection or 
transfusion has occurred. This will permit a blood establishment to 
investigate and report both a biological product deviation and an SAR 
related to the biological product deviation at the same time and will 
limit the reporting burden. In the case of a reported serious SAR that 
subsequently results in a fatality, FDA would not require two separate 
reports,

[[Page 12437]]

one reporting the serious SAR and the other reporting the fatality. 
However, if the fatality occurs after the report of the serious SAR is 
submitted to the agency, the blood establishment should update the 
initial report to report the fatality.

III.E. Postmarketing Periodic Safety Reporting

    The proposed rule would require all applicants to submit to FDA 
semiannually on an FDA Form 3500A (VAERS form for vaccines, CIOMS I 
Form, if desired, for foreign SADRs) certain spontaneously reported 
SADRs (see tables 7 and 9 and section III.E.4 of this document 
regarding individual case safety reports--semiannual submissions). 
Applicants would also be required to submit other postmarketing 
periodic safety reports (i.e., traditional periodic safety reports 
(TPSRs), periodic safety update reports (PSURs), or interim periodic 
safety reports (IPSRs)) to FDA with a frequency as described in section 
III.E.5.a of this document (see tables 7 and 9). PSURs, IPSRs, and 
TPSRs would provide FDA with an overview or summary of the safety 
profile of a drug or licensed biological product (excluding individual 
case safety reports). A TPSR would essentially contain the same format 
and content as the periodic safety report currently required by the 
agency's postmarketing periodic safety reporting regulations (see table 
10 and section III.E.1 of this document). A PSUR would essentially be 
consistent with the format and content of the periodic safety report 
described in the ICH E2C guidance (see section III.E.2 of this 
document), and an IPSR would represent an abbreviated form of a PSUR 
(see section III.E.3 of this document). Applicants with drugs and 
licensed biological products approved prior to January 1, 1998, would 
have the option to submit either a TPSR or PSUR to FDA, whereas 
applicants with products approved on or after January 1, 1998, would be 
required to submit a PSUR (see tables 7 and 9 and section III.E.5.a of 
this document). FDA is proposing to require submission of periodic 
safety reports in a PSUR format for products approved on or after 
January 1, 1998, to be consistent with the ICH E2C guidance. FDA is not 
proposing to require submission of PSURs for products approved prior to 
January 1, 1998, because the agency recognizes that the most 
significant new safety information on a product is usually acquired in 
the first few years after it has been on the market. It is not 
necessary for applicants to reformat periodic safety reports for 
products approved prior to January 1, 1998. In addition, in some cases, 
it will be sufficient for FDA to review an abbreviated form of the PSUR 
(i.e., at 7.5 and 12.5 years after U.S. approval of a product). For 
these cases, the agency is proposing to require submission of an IPSR 
instead of a PSUR (see tables 7 and 9 and sections III.E.3 and 
III.E.5.a of this document).
III.E.1. Traditional Periodic Safety Reports (TPSRs)
    Current regulations (Sec. Sec.  314.80(c)(2)(ii)(a) through 
(c)(2(ii)(c) and 600.80(c)(2)(ii)(A) through (c)(2)(ii)(C)) require the 
submission of postmarketing periodic adverse drug experience reports 
that contain:
    [sbull] A narrative summary and analysis of the information in the 
report and an analysis of the 15-day postmarketing Alert reports 
submitted during the reporting period (all 15-day Alert reports being 
appropriately referenced by the applicant's patient identification 
number, adverse reaction term(s), and date of submission to FDA);
    [sbull] An FDA Form 3500A describing each adverse drug experience 
not previously reported (with an index consisting of a line listing of 
the applicant's patient identification number and adverse reaction 
term(s)); and
    [sbull] A history of actions taken since the last periodic report.
    Proposed Sec. Sec.  314.80(c)(3)(i) and 600.80(c)(3)(i) would amend 
these regulations by replacing the term ``periodic adverse drug 
experience report'' with the term ``traditional periodic safety report 
(TPSR).'' FDA is proposing this revision to differentiate the existing 
postmarketing periodic safety report from the proposed new 
postmarketing periodic safety reports (i.e., PSURs and IPSRs, see 
sections III.E.2 and III.E.3 of this document).
    III.E.1.a. Narrative summary and analysis of individual case safety 
reports. Proposed Sec. Sec.  314.80(c)(3)(i)(A) and 600.80(c)(3)(i)(A) 
would amend Sec. Sec.  314.80(c)(2)(ii)(a) and 600.80(c)(2)(ii)(A) by 
providing paragraph headings and reorganizing and revising these 
paragraphs. Proposed Sec. Sec.  314.80(c)(3)(i)(A)(1) and 
600.80(c)(3)(i)(A)(1) would amend Sec. Sec.  314.80(c)(2)(ii)(a) and 
600.80(c)(2)(ii)(A) by replacing the phrase ``the information in the 
report'' with the following:

serious, expected SADRs and nonserious, unexpected SADRs occurring 
in the United States that were submitted to the applicant during the 
reporting period from all spontaneous sources (i.e., health care 
professionals and other individuals) (with an index consisting of a 
line listing of the applicant's manufacturer report number and SADR 
term(s)). The narrative summary and analysis would include 
spontaneous reports submitted to the applicant by health care 
professionals and other individuals (e.g., consumers).

    Proposed Sec. Sec.  314.80(c)(3)(i)(A)(2) and 600.80(c)(3)(i)(A)(2) 
would amend Sec. Sec.  314.80(c)(2)(ii)(a) and 600.80(c)(2)(ii)(A) by 
replacing the phrase ``an analysis of the 15-day Alert reports * * * 
date of submission to FDA)'' with the phrase:

    An analysis of the expedited reports submitted during the 
reporting period under paragraphs (c)(2)(i) through (c)(2)(vii) of 
this section (all expedited reports must be appropriately referenced 
by the applicant's manufacturer report number, SADR term(s), if 
appropriate, and date of submission to FDA),

    Current regulations at Sec. Sec.  314.80(c)(2)(iii) and 
600.80(c)(2)(iii) state that periodic reporting, except for information 
regarding 15-day Alert reports, does not apply to adverse drug 
experience information obtained from postmarketing studies (whether or 
not conducted under an IND), from reports in the scientific literature, 
and from foreign marketing experience. FDA is proposing to remove this 
statement because proposed Sec. Sec.  314.80(c)(3)(i)(A)(1) and 
600.80(c)(3)(i)(A)(1) specifies the type of information that FDA would 
require in a TPSR.
    III.E.1.b. Individual case safety reports. FDA is also proposing to 
remove Sec. Sec.  314.80(c)(2)(ii)(b) and 600.80(c)(2)(ii)(B) from 
these regulations. FDA is proposing this change because the requirement 
to submit individual case safety reports to FDA on FDA Form 3500A 
(VAERS form for vaccines) would be required in a separate submission on 
a semiannual basis (see section III.E.4 of this document).
    III.E.1.c. Increased frequency reports. Proposed Sec. Sec.  
314.80(c)(3)(i)(A)(3) and 600.80(c)(3)(i)(A)(3) would amend Sec. Sec.  
314.80(c)(2)(ii)(a) and 600.80(c)(2)(ii)(A) to require applicants to 
include in TPSRs a discussion of any increased reporting frequency of 
serious, expected SADRs, including comments on whether it is believed 
that the data reflect a meaningful change in SADR occurrence. Even 
though the agency has revoked the requirement to submit increased 
frequency reports in an expedited manner (62 FR 34166), FDA is 
interested in reviewing periodically information on increased 
frequencies of serious, expected SADRs and is proposing that this type 
of information be submitted to the agency in TPSRs.

[[Page 12438]]

    The proposed rule would also require that this section of the TPSR 
include an assessment of whether it is believed that the frequency of 
lack of efficacy reports, obtained or otherwise received during the 
reporting period, is greater than would be predicted by the 
premarketing clinical trials for the drug or biological product. This 
assessment would be provided whether a serious SADR, nonserious SADR, 
or no SADR occurs as a result of a lack of efficacy of the product.
    III.E.1.d. Safety-related actions to be taken. Proposed Sec. Sec.  
314.80(c)(3)(i)(A)(4) and 600.80(c)(3)(i)(A)(4) would require 
applicants to include in TPSRs the applicant's conclusion as to what, 
if any, safety-related actions should be taken based on the analysis of 
the safety data in the TPSR (e.g., labeling changes, studies 
initiated). FDA is proposing this amendment to highlight safety-related 
actions that may be necessary.
    III.E.1.e. Summary tabulations. Proposed Sec. Sec.  
314.80(c)(3)(i)(B), and 600.80(c)(3)(i)(B) would require that a new 
section of summary tabulations (i.e., lists of all SADR terms and 
counts of occurrences) be included in TPSRs for all serious, expected 
SADRs; nonserious, unexpected SADRs; nonserious, expected SADRs; and 
expected SADRs with unknown outcome occurring in the United States that 
are submitted to the applicant during the reporting period from all 
spontaneous sources (i.e., health care professionals and other 
individuals). These tabulations would include SADRs that were 
previously submitted to FDA in an expedited report (i.e., serious, 
unexpected SADRs, unexpected SADRs with unknown outcome, and always 
expedited reports) and reports of SADRs not previously submitted to FDA 
by applicants (e.g., reports submitted to applicants by FDA; reports 
obtained from FDA from freedom of information requests at the 
discretion of applicants; reports from class action lawsuits). The 
proposed rule would require that cumulative data be provided for SADRs 
that are determined to be both serious and unexpected (i.e., all cases 
reported to date). These summary tabulations would be presented by body 
system or standard organ system classification scheme (e.g., 
cardiovascular, central nervous system, endocrine, renal). The proposed 
rule would also require summary tabulations for all domestic reports of 
actual medication errors (i.e., serious SADRs, nonserious SADRs, no 
SADRs) and potential medication errors (i.e., number of reports for 
specific errors) that were previously submitted to the agency as an 
expedited report.
    In the guidance of 1992, FDA advises applicants to include in their 
postmarketing periodic safety reports a listing by body system of all 
adverse drug experience terms and counts of occurrences submitted 
during the reporting period. FDA is now proposing to clarify and codify 
this expectation.
    III.E.1.f. History of safety-related actions taken. Proposed 
Sec. Sec.  314.80(c)(3)(i)(C), and 600.80(c)(3)(i)(C) would amend 
Sec. Sec.  314.80(c)(2)(ii)(c) and 600.80(c)(2)(ii)(C) by adding the 
phrase ``safety-related'' before the word ``actions'' and by removing 
the phrase ``because of adverse drug experiences.'' FDA is proposing 
these changes because actions may be taken for safety-related reasons 
other than SADRs. The proposed rule would also amend these regulations 
by adding the phrase ``periodic safety'' before the word ``report'' for 
clarification.
    III.E.1.g. Location of safety records. Proposed Sec. Sec.  
314.80(c)(3)(i)(D) and 600.80(c)(3)(i)(D) would require another new 
section in TPSRs that would contain a list of the current address(es) 
where all safety reports and other safety-related records for the drug 
product or licensed biological product are maintained. FDA is proposing 
to require a list of these addresses to provide rapid access to safety-
related records for FDA inspections and for requests by FDA for 
additional information concerning safety issues.
    III.E.1.h. Contact person. Proposed Sec. Sec.  314.80(c)(3)(i)(E) 
and 600.80(c)(3)(i)(E) would require another new section in TPSRs that 
would contain the name and telephone number of the licensed physician 
or licensed physicians responsible for the content and medical 
interpretation of the data and information contained within the TPSR. 
The fax number and e-mail address for the licensed physician would also 
be included, if available. This proposal would provide the agency with 
someone to contact with any questions that may arise during review of a 
TPSR. FDA is proposing that the contact persons be licensed physicians 
because of their crucial knowledge of the medical significance of the 
information provided in a TPSR.
    Table 10 highlights the differences in content between the 
currently required postmarketing periodic adverse drug experience 
reports and proposed TPSRs.

 Table 10.--Differences Between the Current Requirement for the Content
    of Postmarketing Periodic Adverse Drug Experience Reports and the
                       Proposed Content of TPSRs.
------------------------------------------------------------------------
                                          Proposed revisions to content
    Content of periodic adverse drug         of periodic adverse drug
           experience report               experience report (proposed
                                                      TPSRs)
------------------------------------------------------------------------
Narrative summary and analysis of the    Excludes nonserious expected
 information contained in the report.     SADRs.
                                         Includes discussion of
                                          increased frequency of serious
                                          expected SADRs and lack of
                                          efficacy reports.
                                         Includes applicant's
                                          recommendations for safety-
                                          related actions to be taken.
Analysis of expedited reports submitted  Not revised.
 to FDA during the reporting interval.
FDA Form 3500A (VAERS form for           Revoked requirement. \1\
 vaccines) for each adverse drug
 experience not submitted to FDA as an
 expedited report.
Index consisting of a line listing of    Not revised.
 the applicant's patient identification
 number and adverse reaction term(s).
History of actions taken since the last  Not revised.
 report because of adverse drug
 experiences.
                                         Require submission summary
                                          tabulations.\2\
                                         New section added for location
                                          of safety records.
                                         New section added for contact
                                          information for licensed
                                          physician responsible for
                                          information in TPSR.
------------------------------------------------------------------------
\1\ Individual case safety reports would be submitted to FDA separately
  on a semiannual basis (see section III.E.4 of this document).
\2\ Summary tabulations are currently requested (see the guidance of
  1992) but not required for postmarketing periodic adverse drug
  experience reports.


[[Page 12439]]

III.E.2. Periodic Safety Update Reports (PSURs)
    Proposed Sec. Sec.  314.80(c)(3)(ii) and 600.80(c)(3)(ii) would 
amend FDA's postmarketing periodic safety reporting regulations by 
adding a new type of postmarketing periodic safety report. This new 
report would be identified as a ``periodic safety update report 
(PSUR).'' The proposed content and format for the PSUR, as described 
below, are consistent with the ICH E2C guidance (62 FR 27470) and would 
enable applicants to submit a single core document (PSUR excluding 
appendices) to regulatory authorities worldwide. All dosage forms, 
formulations, and indications for which applicants hold an approved 
application (i.e., NDA, ANDA, BLA) for a given drug substance or 
licensed biological product should usually be covered in one PSUR. The 
PSUR may include separate presentations of these data as well as other 
data (e.g., populations) if such presentations would facilitate review 
of the PSUR. FDA is proposing that a PSUR contain the following 
information:
    III.E.2.a. Title page, table of contents, and introduction. The 
title page would include, at a minimum, the following information:
    [sbull] Name and international birth date of the drug substance or 
licensed biological product that is the subject of the PSUR,
    [sbull] Various dosage forms and formulations of the drug substance 
or biological product covered by the PSUR,
    [sbull] Name and address of the applicant,
    [sbull] Reporting period covered by the PSUR, and
    [sbull] Date of the PSUR.

The introduction would provide a brief description of how this PSUR 
relates to previous reports and circumstances, would reference relevant 
drug products, drug substances, or biological products reported in 
other periodic safety reports (e.g., a combination product reported in 
a separate PSUR), and would indicate any data duplication with other 
PSURs. If two or more companies co-market the same drug substance or 
licensed biological product, the safety reporting responsibilities of 
each of the companies should be specified clearly in the introduction.
    III.E.2.b. Worldwide marketing status. This section of the PSUR 
would contain a table of the chronological history of the worldwide 
marketing status of the drug or biological product(s) covered by the 
PSUR from the date the product was first approved (i.e., the 
international birth date) through its current status (i.e., cumulative 
information). The table would include:
    [sbull] Dates of drug or biological product approval and renewal,
    [sbull] Safety-related restrictions on product use,
    [sbull] Indications for use and special populations covered by the 
drug or biological product approval,
    [sbull] Lack of approval of the drug substance or biological 
product in any dosage form or for any indication for use by any 
regulatory authority(ies),
    [sbull] Withdrawal of a pending drug or biological product 
marketing application by the applicant for safety-or efficacy-related 
reasons,
    [sbull] Dates of market launches, and
    [sbull] Trade name(s).

Drug or biological products that are approved in a country for a 
particular indication, population, or dosage form that may result in 
different types of patient exposure in that country should be 
identified, particularly if there are meaningful differences in the 
safety information reported in the PSUR due to the difference in 
patient exposures.
    III.E.2.c. Actions taken for safety reasons. This section of the 
PSUR would contain details on regulatory authority-initiated (e.g., 
FDA) and/or applicant-initiated actions related to safety that were 
taken during the period covered by the PSUR and between the data lock 
point and PSUR submission (i.e., ``late-breaking'' safety concerns) 
including:
    [sbull] Withdrawal or suspension of product approval or indication 
for use approval,
    [sbull] Failure to obtain a marketing authorization renewal or to 
obtain an approval for a new indication for use,
    [sbull] Restrictions on distribution (e.g., products recalled for 
safety reasons),
    [sbull] Clinical trial suspension,
    [sbull] Dosage modification,
    [sbull] Changes in target population or indications, and
    [sbull] Formulation changes.

    This section of the PSUR would also contain a narrative identifying 
the safety-related reasons that led to these actions with relevant 
documentation appended when appropriate. Any communication with health 
care professionals (e.g., Dear Healthcare Professional letters) 
resulting from such actions would also be described with copies 
appended.
    III.E.2.d. Changes to CCSI. This section of the PSUR would describe 
changes to the CCSI (e.g., new contraindications, precautions, 
warnings, SADRs, or interactions) made during the period covered by the 
PSUR. A copy of any modified section of the CCSI would be included. 
Applicants would use the CCSI in effect at the beginning of the 
reporting period for the PSUR. The revised CCSI would be used as the 
reference document for the next reporting period.
    III.E.2.e. Worldwide patient exposure. This section of the PSUR 
would include, for the reporting period, an estimate of the worldwide 
patient exposure to the drug or biological product(s) covered by the 
PSUR (i.e., number of patients, average or median dose received, and 
average or median length of treatment). In many cases, accurate patient 
exposure data for a reporting period may be difficult to obtain. 
However, applicants should exercise due diligence to obtain an estimate 
of this exposure. The method used to estimate patient exposure would 
always be described. If the patient exposure is impossible to estimate 
or is meaningless, an explanation of and justification for such 
conclusions would be provided. If patient exposure is impossible to 
estimate, other measures of exposure, such as patient-days, number of 
prescriptions, or number of dosage units, could be used. If these or 
other more precise measures are not available and an adequate 
explanation for the lack of such information is provided, bulk sales 
could be used with estimates of what such numbers may mean in terms of 
patient exposure.
    When possible, data broken down by gender and age (especially 
pediatric versus adult) would be provided. Data for the pediatric 
population would be reported, if possible, by age group (e.g., 
neonates, infants, children, adolescents). If these data are not 
available, an explanation for the lack of such information would be 
included. In addition, when a pattern of reports indicates a potential 
problem, details by country (with locally recommended dosage regimens) 
or other segmentation (e.g., indication, dosage form) would also be 
presented.
    Patient exposure for clinical studies should also be provided when 
SADR data from these types of studies are included in the PSUR. For 
ongoing or blinded clinical studies, an estimate of patient exposure 
should be provided.
    III.E.2.f. Individual case safety reports.
    III.E.2.f.i. Line listings. Individual line listings of various 
data points from individual case safety reports are included as part of 
the format for international PSURs agreed to by ICH (ICH E2C guidance, 
62 FR 27470 at 27473 and 27474). FDA will not require submission of 
such line listings in PSURs because, instead, the agency is proposing 
to require a separate

[[Page 12440]]

semiannual submission of certain individual case safety reports on FDA 
Form 3500A (VAERS form for vaccines, CIOMS I form, if desired, for 
foreign SADRs) (see section III.E.4 of this document). However, FDA is 
willing to accept line listings in PSURs as described in the ICH E2C 
guidance if applicants wish to include them. FDA believes that such an 
approach will help further the goal of harmonizing PSUR generation, 
formatting, and submission globally.
    III.E.2.f.ii. Summary tabulations. This section of the PSUR would 
consist of summary tabulations of individual case safety reports (e.g., 
serious unlisted SADRs, serious listed SADRs, nonserious unlisted 
SADRs, nonserious listed SADRs) for the following SADRs obtained or 
otherwise received during the reporting period:
    [sbull] All serious and nonserious SADRs from spontaneous sources 
that were submitted to applicants by a health care professional,
    [sbull] All serious SADRs from studies, individual patient INDs, 
or, in foreign countries, from named-patient ``compassionate'' use,
    [sbull] All serious SADRs and nonserious unlisted SADRs from the 
scientific literature,
    [sbull] All serious SADRs from regulatory authorities, and
    [sbull] Serious SADRs from other sources such as reports created by 
poison control centers and epidemiological data bases.

    These summary tabulations would be made up of lists by body system 
or standard organ system classification scheme (e.g., cardiovascular, 
central nervous system, endocrine, renal) of all SADR terms and counts 
of occurrences. For SADRs that are determined to be both serious and 
unlisted, cumulative data would also be provided (i.e., all cases 
reported to date). Applicants may provide information for this section 
of the PSUR in a narrative rather than a summary tabulation if the 
number of cases is small or the information is inadequate for any of 
the tabulations.
    As noted previously, FDA would consider ``study'' information to 
include the following: safety information from company-sponsored 
patient support programs, disease management programs, patient 
registries, including pregnancy registries, or any organized data 
collection scheme (see section III.A.7 of this document). FDA is 
proposing to include summary tabulations for serious listed SADRs from 
study information in PSURs to be consistent with the ICH E2C guidance 
(62 FR 27470 at 27474), even though the agency indicated in the 
clarification guidance of 1997 that only serious and unexpected adverse 
drug experiences for which there is a reasonable possibility that the 
drug or biological product caused the adverse drug experience should be 
reported to FDA from studies.
    This section of the PSUR would also contain a brief discussion of 
the individual case data in the summary tabulations (e.g., discussion 
of medical significance or mechanism). This section of the PSUR should 
be used to comment on specific cases rather than to provide an overall 
assessment of the cases.
    III.E.2.g. Safety studies. This section of the PSUR would contain a 
discussion (not just a listing of the studies) of nonclinical, 
clinical, and epidemiological studies concerning important safety 
information including:
    [sbull] All applicant-sponsored studies newly analyzed during the 
reporting period;
    [sbull] New studies specifically planned, initiated, or continuing 
during the reporting period that examine a safety issue, whether actual 
or hypothetical; and
    [sbull] Published safety studies in the scientific and medical 
literature, including relevant published abstracts from meetings 
(provide citations for all reports from the literature).

As noted previously, FDA would consider ``study'' information to 
include the following: safety information from company-sponsored 
patient support programs, disease management programs, patient 
registries, including pregnancy registries, or any organized data 
collection scheme (see section III.A.7 of this document).
    The study design and results of newly analyzed studies should be 
clearly and concisely presented with attention to the usual standards 
of data analysis and description that are applied to nonclinical and 
clinical study reports. Copies of full reports for these studies should 
be appended only if new safety issues are raised or confirmed. FDA may 
request copies of other studies, if necessary.
    For new or ongoing studies, the objective, starting date, projected 
completion date, number of subjects (planned and enrolled), and 
protocol abstract for each study should be provided. When possible and 
relevant, interim results of ongoing studies should be presented.
    III.E.2.h. Other information. This section of the PSUR would 
contain a discussion of medically relevant lack of efficacy reports 
(e.g., might represent a significant hazard to the treated population) 
for a product(s) used to treat serious or life-threatening diseases, or 
any important new information received after the data lock point (e.g., 
significant new cases).
    III.E.2.i. Overall safety evaluation. This section of the PSUR 
would contain a concise, yet comprehensive, analysis of all of the 
safety information provided in the PSUR, including new information 
provided under the section entitled ``Other Information.'' In addition, 
the section would include an assessment by applicants of the 
significance of the data collected during the reporting period, as well 
as from the perspective of cumulative experience. Applicants would 
highlight any new information on:
    [sbull] Serious, unlisted SADRs;
    [sbull] Increased reporting frequencies of listed SADRs, including 
comments on whether it is believed that the data reflect a meaningful 
change in SADR occurrence;
    [sbull] A change in characteristics of listed SADRs (e.g., 
severity, outcome, target population); and
    [sbull] Nonserious, unlisted SADRs.
    As part of the overall safety evaluation, applicants would also 
explicitly address any new safety issue including but not limited to 
the following:
    [sbull] Drug interactions;
    [sbull] Experience with overdose, whether deliberate or accidental, 
and its treatment;
    [sbull] Drug abuse or intentional misuse;
    [sbull] Positive or negative experiences during pregnancy or 
lactation;
    [sbull] Effects with long-term treatment; and
    [sbull] Experience in special patient groups (e.g., pediatric 
population evaluated, if possible, by age group; geriatric; organ 
impaired).

Applicants would note a lack of significant new information for any of 
these categories.
    III.E.2.j. Conclusion. This section of the PSUR would indicate new 
safety information that is not in accord with previous cumulative 
experience and with the CCSI in use at the beginning of the reporting 
period (e.g., new evidence that strengthens a possible causal 
relationship between the drug or biological product and an SADR, such 
as positive rechallenge, an epidemiological association, or new 
laboratory studies). This section of the PSUR would also specify and 
justify any action recommended or initiated, including changes in the 
CCSI.
    III.E.2.k. Appendices. This section of the PSUR would include the 
following information as appendices:

[[Page 12441]]

    III.E.2.k.i. Company core data sheet. A copy of the company core 
data sheet covered by the PSUR (i.e., in effect at the beginning of the 
period covered by the PSUR) would be provided. The company core data 
sheet would be numbered and dated and include the date of last 
revision. In addition, a copy of the company core data sheet for the 
next reporting period would be provided.
    III.E.2.k.ii. U.S. labeling. A copy of the current approved U.S. 
labeling would be provided. Any safety information that is included in 
the CCSI but not in the U.S. labeling would be identified and an 
explanation for the discrepancy provided. Any safety-related changes or 
proposed changes to the U.S. labeling made during the reporting period 
would be described, including the supplement numbers and dates of 
submission for the supplements. Any suggested change or changes in the 
U.S. labeling that should be considered based on the safety analysis in 
the PSUR would also be described. (If appropriate, a supplemental 
application would be filed with FDA concerning those changes as 
prescribed under Sec. Sec.  314.70 or 601.12.)
    III.E.2.k.iii. Spontaneous reports submitted to the applicant by an 
individual other than a health care professional. This appendix would 
contain summary tabulations (e.g., serious unlisted SADRs, serious 
listed SADRs, nonserious unlisted SADRs, nonserious listed SADRs) for 
all spontaneously reported serious SADRs, whether domestic or foreign, 
and all spontaneously reported nonserious SADRs occurring in the United 
States, obtained or otherwise received during the reporting period by 
the applicant from an individual other than a health care professional 
(e.g., SADR reports from consumers). These summary tabulations would 
consist of lists by body system or by standard organ system 
classification scheme (e.g., cardiovascular, central nervous system, 
endocrine, renal) of all SADR terms and counts of occurrences. For 
those SADRs that are determined to be both serious and unlisted, 
cumulative data (i.e., all cases reported to date by individuals other 
than a health care professional) would also be provided. The impact of 
these spontaneous reports on the overall safety evaluation would be 
discussed briefly. FDA may require applicants to submit to the agency, 
when appropriate, SADR reports (e.g., FDA Form 3500As), within 5 
calendar days after receipt of the request, for any or all of the SADRs 
contained within this appendix (see section III.H of this document).
    III.E.2.k.iv. SADRs with unknown outcome. This appendix would 
contain summary tabulations for unlisted and listed SADRs with unknown 
outcome from all spontaneous sources (i.e., health care professionals 
and other individuals), obtained or otherwise received by the applicant 
during the reporting period. These summary tabulations would consist of 
lists by body system or by standard organ system classification scheme 
of all SADR terms and counts of occurrences. The impact of these 
spontaneous reports on the overall safety evaluation would be discussed 
briefly. FDA may require applicants to submit to the agency, when 
appropriate, individual case safety reports (e.g., FDA Form 3500As), 
within 5 calendar days after receipt of the request, for any or all of 
the listed SADRs with unknown outcome contained within this appendix 
(see section III.H of this document).
    III.E.2.k.v. Class action lawsuits. This appendix would contain 
summary tabulations (e.g., serious unlisted SADRs, serious listed 
SADRs, nonserious unlisted SADRs, nonserious listed SADRs) for all 
SADRs obtained or otherwise received during the reporting period by the 
applicant from class action lawsuits. These summary tabulations would 
consist of lists by body system or by standard organ system 
classification scheme of all SADR terms and counts of occurrences. For 
SADRs that are both serious and unlisted, cumulative data would also be 
provided. The impact of these reports on the overall safety evaluation 
would be discussed briefly. FDA may require applicants to submit to the 
agency, when appropriate, individual case safety reports (e.g., FDA 
Form 3500As), within 5 calendar days after receipt of the request, for 
any or all of the SADRs contained within this appendix (see section 
III.H of this document).
    III.E.2.k.vi. Lack of efficacy reports. This appendix would contain 
an assessment of whether it is believed that the frequency of lack of 
efficacy reports, obtained or otherwise received during the reporting 
period, is greater than would be predicted by the premarketing clinical 
trials for the drug or biological product. This assessment would be 
provided whether a serious SADR, nonserious SADR, or no SADR results 
from a lack of efficacy of the product.
    III.E.2.k.vii. Information on resistance to antimicrobial drug 
products. This appendix would contain information, received or 
otherwise obtained by the applicant, on resistance to antimicrobial 
drug products intended to treat infectious diseases. Information would 
include:
    [sbull] Changes in U.S. microbial in vitro susceptibility,
    [sbull] The relationship of changes in U.S. microbial in vitro 
susceptibility and clinical outcomes,
    [sbull] Therapeutic failure that may possibly be due to resistance 
to the antimicrobial drug product, and
    [sbull] Whether the U.S. labeling should be revised because of the 
information on antimicrobial resistance learned during the period 
covered by the report.
    III.E.2.k.viii. Medication errors. This appendix would contain 
summary tabulations for all domestic reports of medication errors 
submitted during the reporting period as an expedited report. For 
actual medication errors, summary tabulations would be provided for 
serious SADRs, nonserious SADRs, and no SADRs. For serious SADRs, 
cumulative data (i.e., all cases reported to date) would also be 
provided. For potential medication errors, the number of reports for 
specific errors would be provided. If an SADR occurs, the summary 
tabulations would consist of lists by body system or by standard organ 
system classification scheme of all SADR terms and counts of 
occurrences. The impact of these reports on the overall safety 
evaluation would be discussed briefly.
    III.E.2.k.ix. U.S. patient exposure. This appendix would contain, 
for the reporting period, an estimate of the U.S. patient exposure to 
the drug product(s) or biological product(s) covered by the PSUR (i.e., 
number of patients, average or median dose received, and average or 
median length of treatment). The method used to estimate patient 
exposure would always be described. If the patient exposure is 
impossible to estimate or is meaningless, an explanation of and 
justification for such conclusions would be provided. If patient 
exposure is impossible to estimate, other measures of exposure, such as 
patient-days, number of prescriptions, or number of dosage units, may 
be used. If these or other more precise measures are not available and 
an adequate explanation for the lack of such information is provided, 
bulk sales may be used.
    III.E.2.k.x. Location of safety records. This appendix would 
contain a list of the current address(es) where all safety reports and 
other safety-related records for the drug product or licensed 
biological product are maintained. The list of addresses would provide 
rapid access to safety-related records for FDA inspections and for 
requests by FDA for additional information concerning safety issues.
    III.E.2.k.xi. Contact person. The name and telephone number of the 
licensed

[[Page 12442]]

physician or licensed physicians responsible for the content and 
medical interpretation of the data and information contained within the 
PSUR would be provided. The fax number and e-mail address of the 
licensed physician would also be included, if available. This proposal 
would provide the agency with someone to contact with any questions 
that may arise during review of a PSUR. FDA is proposing that the 
contact persons be licensed physicians because of their crucial 
knowledge of the medical significance of the information provided in a 
PSUR.
    The PSUR excluding appendices, as proposed in this rule, would 
represent a harmonized core document for worldwide postmarketing 
periodic safety reporting for marketed drugs and licensed biological 
products.
III.E.3. Interim Periodic Safety Reports (IPSRs)
    Proposed Sec. Sec.  314.80(c)(3)(iii) and 600.80(c)(3)(iii) would 
amend FDA's postmarketing periodic safety reporting regulations by 
adding another new type of postmarketing periodic safety report. FDA is 
proposing that this new report be identified as an ``interim periodic 
safety report (IPSR).'' An IPSR would contain the same information as a 
PSUR, except that the following information would not be provided:
    [sbull] Summary tabulations for individual case safety reports, 
obtained or otherwise received during the reporting period and brief 
discussion of the data concerning these reports (see section 
III.E.2.f.ii of this document),
    [sbull] Any important new information received after the data lock 
point (e.g., significant new cases) (see section III.E.2.h of this 
document),
    [sbull] Summary tabulations for spontaneous reports of SADRs 
submitted to the applicant by an individual other than a health care 
professional (see section III.E.2.k.iii of this document),
    [sbull] Summary tabulations for spontaneous reports of SADRs with 
unknown outcome submitted to the applicant by health care professionals 
and other individuals (see section III.E.2.k.iv of this document),
    [sbull] Summary tabulations for reports of SADRs from class action 
lawsuits (see section III.E.2.k.v of this document),
    [sbull] Summary tabulations of domestic reports of medication 
errors (see section III.E.2.k.viii of this document).

The IPSR would provide the agency with an overview of the safety 
profile of a drug product containing a drug substance or biological 
product without requiring summary information on individual case safety 
reports.
III.E.4. Semiannual Submission of Individual Case Safety Reports
    Currently, postmarketing periodic safety reporting regulations 
(Sec. Sec.  314.80(c)(2)(ii)(b) and 600.80(c)(2)(ii)(B)) require 
applicants to submit to FDA in periodic adverse drug experience reports 
an FDA Form 3500A (VAERS form for vaccines) for each spontaneously 
reported adverse drug experience occurring in the United States that 
has not been submitted to the agency as an expedited report (i.e., 
serious, expected adverse drug experiences and all nonserious adverse 
drug experiences, whether unexpected or expected). FDA is proposing to 
remove this requirement (see section III.E.1.b of this document). 
Instead, under proposed Sec. Sec.  314.80(c)(3)(v) and 600.80(c)(3)(v), 
the agency would require applicants to submit semiannually a separate 
report to FDA consisting of a compilation of FDA Form 3500As (VAERS 
forms for vaccines, CIOMS I forms, if desired, for foreign SADRs) for 
certain spontaneously reported individual case safety reports as 
described in the following explanation. This report would be identified 
as ``Individual Case Safety Reports--Semiannual Submission.''
    The semiannual submission from applicants that submit TPSRs for a 
drug or licensed biological product would include an individual case 
safety report for each serious, expected SADR, whether domestic or 
foreign, and each nonserious, unexpected SADR occurring in the United 
States that is submitted to the applicant during the reporting period 
from all spontaneous sources (i.e., health care professionals and other 
individuals). The semiannual submission for vaccines would also include 
an individual case safety report for each nonserious, expected SADR and 
each expected SADR with unknown outcome occurring in the United States 
that is submitted to the applicant during the reporting period from all 
spontaneous sources. For drugs and licensed biological products that 
are not vaccines, nonserious, expected SADRs and expected SADRs with an 
unknown outcome would not be submitted as individual case safety 
reports in a semiannual submission. Instead, they would be reported as 
part of a summary tabulation in a TPSR (see section III.E.1.e of this 
document).
    The semiannual submission from applicants that submit PSURs for a 
drug product containing a drug substance or licensed biological product 
would include an individual case safety report for each serious, listed 
SADR, whether domestic or foreign, and each nonserious, unlisted SADR 
occurring in the United States that is submitted to the applicant 
during the reporting period from all spontaneous sources. The 
semiannual submission for vaccines would also include an individual 
case safety report for each nonserious, listed SADR and each listed 
SADR with unknown outcome occurring in the United States that is 
submitted to the applicant during the reporting period from all 
spontaneous sources. For drugs and licensed biological products that 
are not vaccines, nonserious, listed SADRs and listed SADRs with an 
unknown outcome would not be submitted as individual case safety 
reports in a semiannual submission. Instead, they would be reported as 
part of a summary tabulation in a PSUR (see sections III.E.2.f.ii and 
III.E.2.k.iii of this document). The semiannual submission should not 
include individual case safety reports for serious, listed SADRs that 
were previously submitted to FDA as a serious, unexpected SADR in an 
expedited report (i.e., the agency does not want to receive duplicative 
reports for the same SADR).
    FDA needs to continue to receive information on serious, expected/
listed SADRs and nonserious SADRs, whether unexpected/unlisted or 
expected/listed, to monitor the safety profile of marketed products to 
determine if studies need to be undertaken to evaluate a particular 
issue and/or to take appropriate regulatory action (e.g., labeling 
change, distribution of Dear Healthcare Professional letter, 
restriction on distribution of product, withdrawal of product from the 
market). Reports of serious, expected/listed SADRs are used to monitor 
changes in the frequency of occurrence or severity of a serious, 
expected/listed SADR (e.g., frequency of serious, expected/listed SADR 
increases because product interacts with a new approved product that is 
frequently used concomitantly with the product). The agency's proposal 
to require submission of spontaneously reported serious, expected/
listed SADRs from foreign sources would provide FDA with important 
information that the agency currently does not receive (e.g., reports 
from foreign countries in which the product is approved for more 
indications than in the United States or the product results in 
exposure to certain populations that are limited in the United States).
    Reports of nonserious, unexpected/unlisted SADRs are used to 
identify new nonserious SADRs that are associated with the use of a 
product (e.g., sedation, sexual dysfunction, gastrointestinal 
distress). This information is valuable

[[Page 12443]]

for individuals taking the product because, if one of these SADRs 
occurs, the individual might suspect that it was due to the product and 
not due to the onset of a new disorder. These reports may also serve to 
signal the emergence of a serious, unexpected/unlisted SADR (e.g., an 
aggregate of reports of decreased white blood cell counts may be an 
early indicator of a serious condition such as bone marrow suppressive 
disorder).
    The reports (i.e., individual case safety reports for vaccines or 
summary tabulations for drugs and licensed biological products that are 
not vaccines) of nonserious, expected/listed SADRs are used to monitor 
changes in the frequency of occurrence or severity of a nonserious, 
expected/listed SADR. Such information could indicate a potential 
safety problem that is worthy of further investigation (e.g., a new 
drug or food interaction not previously associated with use of the 
product).
    Proposed changes to FDA's current reporting requirements for these 
types of SADRs include: (1) Different reporting frequencies for the 
SADRs, (2) receipt of spontaneously reported serious, expected/listed 
SADRs from foreign sources and (3) submission of nonserious, expected/
listed SADRs in a summary tabulation instead of as individual case 
safety reports for drugs and licensed biological products that are not 
vaccines. With regard to different reporting frequencies, some SADRs 
would be reported less frequently (e.g., semiannually rather than every 
3 months) and others would be reported more frequently (e.g., 
semiannually rather than annually). FDA seeks comment on these proposed 
changes.
    The current approved U.S. labeling would be used as the reference 
document to determine whether an SADR is unexpected or expected, and 
the CCSI would be used to determine whether an SADR is unlisted or 
listed.
    As described previously, a minimum data set would be required for 
all individual case safety reports of an SADR (see section III.C.5 of 
this document). In addition, a full data set would be required for 
reports of serious, expected SADRs and serious, listed SADRs. If a full 
data set is not available for these SADR reports, the information 
required under proposed Sec. Sec.  314.80(c)(1)(iv) and 
600.80(c)(1)(iv) would be provided. For nonserious SADRs with a minimum 
data set, the proposal would require that all safety information 
received or otherwise obtained be submitted. The proposal would not 
require that information in addition to the minimum data set be 
acquired. Thus, followup would not be required for nonserious SADRs 
that contain a minimum data set.
    Followup information on SADRs submitted in an individual case 
safety report--semiannual submission may be submitted in the next 
individual case safety report--semiannual submission, unless such 
information changes the classification of the SADR to a serious, 
unexpected SADR. In these cases, the followup information would be 
submitted to FDA as an expedited 15-day followup report (see section 
III.D.6 of this document).
    Applicants should not submit any reports of lack of efficacy in an 
individual case safety report--semiannual submission. As noted 
previously, applicants would be required to submit to FDA in an 
expedited manner information regarding certain lack of efficacy reports 
for the product (i.e., expedited reports of information sufficient to 
consider product administration changes) and also to provide in 
postmarketing periodic safety reports an assessment of all lack of 
efficacy reports for the product as compared to premarketing clinical 
trials for the product (see section III.C.7 of this document).
    Applicants should not submit SADRs from class action lawsuits to 
FDA in an individual case safety report--semiannual submission. The 
agency believes, as noted previously, that SADRs from class action 
lawsuits would be submitted to FDA from other sources (e.g., 
spontaneous report) prior to initiation of the class action lawsuit 
(see section III.D.11 of this document). Summary tabulations of these 
SADRs would be required to be included in postmarketing periodic safety 
reports (see sections III.E.1.e and III.E.2.k.v of this document).
    Applicants should not submit reports of medication errors in an 
individual case safety report--semiannual submission. These reports 
would be submitted, as previously noted, as an expedited report (see 
section III.D.5 of this document).
III.E.5. Reporting Requirements
    III.E.5.a. Reporting intervals. Current regulations (Sec. Sec.  
314.80(c)(2)(i) and 600.80(c)(2)(i)) require the submission of 
postmarketing periodic safety reports at quarterly intervals for 3 
years from the date of approval of the application in the United States 
and then annually thereafter. Quarterly safety reports must be 
submitted within 30 days of the close of the quarter (the first quarter 
beginning on the date of U.S. approval of the application); annual 
safety reports must be submitted within 60 days of the anniversary date 
of U.S. approval of the application. FDA is proposing revisions to 
these reporting requirements. The proposals are consistent with the 
recommendations of ICH (62 FR 27470 at 27472): ``Therefore, it is 
recommended that the preparation of PSUR's for all regulatory 
authorities should be based on data sets of 6 months or multiples 
thereof.''
    Products approved before January 1, 1998. Proposed Sec. Sec.  
314.80(c)(3)(i) and 600.80(c)(3)(i) would require applicants holding an 
NDA, ANDA, or BLA that was approved for initial marketing of a drug 
product containing a drug substance or licensed biological product 
before January 1, 1998, to submit either a TPSR or a PSUR every 5 years 
after U.S. approval of the application. The proposed rule would also 
require these applicants to submit a TPSR or an IPSR 7.5 years and 12.5 
years after U.S. approval of the application. Under proposed Sec. Sec.  
314.80(c)(3)(iii) and 600.80(c)(3)(iii), the reporting period for an 
IPSR would cover the period between the last PSUR or TPSR and the data 
lock point for the IPSR (e.g., between years 5 and 7.5 for an IPSR with 
a data lock point at 7.5 years after U.S. approval of the application).
    Products approved on or after January 1, 1998. Under proposed 
Sec. Sec.  314.80(c)(3)(ii) and 600.80(c)(3)(ii), applicants holding an 
NDA, ANDA, or BLA that was approved for initial marketing of a drug 
product containing a drug substance or licensed biological product on 
or after January 1, 1998, would be required to submit a PSUR to FDA 
with the following schedule:
    [sbull] Semiannually (i.e., every 6 months) for 2 years after U.S. 
approval of the application,
    [sbull] Annually for the next 3 years, and then
    [sbull] Every 5 years thereafter.

The proposed rule would also require applicants to submit an IPSR 7.5 
years and 12.5 years after U.S. approval of the application.
    Products with approved pediatric use supplements. Proposed 
Sec. Sec.  314.80(c)(3)(iv) and 600.80(c)(3)(iv) would require 
applicants holding an approved pediatric use supplement to an approved 
application (i.e., a supplement for use of the human drug or biological 
product in the pediatric population) to submit a PSUR to FDA with the 
following schedule:
    [sbull] Semiannually (i.e., every 6 months) for 2 years after U.S. 
approval of the supplement,
    [sbull] Annually for the next 3 years, and
    [sbull] Then every 5 years thereafter.

The proposed rule would also require these applicants to submit an IPSR 
7.5

[[Page 12444]]

years and 12.5 years after U.S. approval of the supplement. These 
applicants would be required to submit PSURs and IPSRs to FDA even if 
the pediatric use supplement or original application was approved prior 
to January 1, 1998. FDA is proposing this action to harmonize 
acquisition of new safety information regarding pediatric populations 
for timely review by the agency.
    All products. Under proposed Sec. Sec.  314.80(c)(3)(v) and 
600.80(c)(3)(v), applicants holding an NDA, ANDA, or BLA would be 
required to submit an individual case safety reports--semiannual 
submission to FDA every 6 months after U.S. approval of an application. 
The 6-month interval for these reports would coincide with the 
reporting interval (6-month or multiples of 6 months) for TPSRs, PSURs 
or IPSRs.
    Alternative reporting frequency. Proposed Sec. Sec.  314.80(c) and 
600.80(c) would provide that, when appropriate, FDA may require in 
writing that applicants submit postmarketing periodic safety reports at 
time intervals other than prescribed by the regulations (see section 
III.C.4 of this document). Usually such variations would occur if new 
safety concerns arose requiring more timely reporting (e.g., approval 
of a new indication or dosage form for the product, approval for use of 
the product in a new population, new safety issues in individual case 
safety reports submitted to FDA for the product). When anticipated, FDA 
would state the revised reporting interval in the approval letter for 
the new indication, new population, or new dosage form. In other cases, 
such revisions to the reporting interval would be conveyed to 
applicants in a written letter from the director of the responsible 
review division in FDA with an explanation of why such a new reporting 
time interval is required.
    III.E.5.b. Submission date. Proposed Sec. Sec.  314.80(c)(3) and 
600.80(c)(3) would require that the data lock point for postmarketing 
periodic safety reports be the month and day of the international birth 
date of the drug product (proposed Sec. Sec.  314.80(c)(3)(i) and 
314.80(c)(3)(v)), drug substance (proposed Sec. Sec.  314.80(c)(3)(ii), 
314.80(c)(3)(iii), and 314.80(c)(3)(iv)) or licensed biological product 
(proposed Sec. Sec.  600.80(c)(3)(i) through 600.80(c)(3)(v)) or any 
other month and day agreed on by the applicant and FDA. For example, 
applicants that are submitting PSURs on an every 5 year basis may, in 
agreement with FDA, change the data lock point to facilitate 
international reporting so long as there is never a time period of 
greater than 5 years in which FDA has not received a PSUR. Or, the 
applicant and FDA may agree to change the data lock point to the month 
and day of U.S. approval of the application if this date would result 
in better use of the applicant's resources.
    Proposed Sec. Sec.  314.80(c)(3) and 600.80(c)(3) would require 
that all postmarketing periodic safety reports be submitted to FDA 
within 60 calendar days after the data lock point for the report. As 
noted previously, the data lock point (i.e., month and day) for 
postmarketing periodic safety reports would be based on the month and 
day of the international birth date for the product and the frequency 
for submission of these reports would be based on the product's date 
(i.e., year) of U.S. approval (see section III.A.10 of this document).
    III.E.5.c. Cover letter. Proposed Sec. Sec.  314.80(c)(3) and 
600.80(c)(3) would require that applicants include a cover letter with 
all postmarketing periodic safety reports (i.e., TPSRs, PSURs, IPSRs, 
individual case safety reports--semiannual submissions). This cover 
letter would contain a list of the NDA and/or ANDA numbers for the 
human drug products or BLA numbers for the human biological products 
covered by the report.
    III.E.5.d. International birth date for combination products. 
Proposed Sec. Sec.  314.80(c)(3) and 600.80(c)(3) would also state that 
the international birth date for combination products would be the 
international birth date of the human drug product containing the drug 
substance or licensed biological product that was most recently 
approved for marketing. For combination products that are also marketed 
individually, applicants may submit either a separate PSUR for the 
combination product or include information for the combination product 
as a separate presentation in the PSUR for one of the individual 
components.

III.F. Reporting Format

    Current postmarketing safety reporting regulations at Sec. Sec.  
310.305(d)(1), 314.80(f)(1), and 600.80(f)(1) require persons subject 
to these requirements to submit an FDA Form 3500A (VAERS form for 
vaccines) for each report of an adverse drug experience. Foreign SADRs, 
including those associated with the use of vaccines, may be submitted 
on an FDA Form 3500A or, if preferred, on a CIOMS I form.
III.F.1. Forms Versus Narrative Format
    Proposed Sec. Sec.  310.305(d)(1), 314.80(c)(4)(i), and 
600.80(c)(4)(i) would amend the current postmarketing safety reporting 
format regulations by reorganizing these regulations and by adding new 
information. Proposed Sec. Sec.  310.305(d)(1)(i) would prescribe, 
except as provided in the regulations, that:

    * * * the manufacturer must complete an FDA Form 3500A for each 
individual case safety report of an SADR. Reports based on 
information about individual cases or case series in the scientific 
literature must be submitted on an FDA Form 3500A(s).

Proposed Sec. Sec.  314.80(c)(4)(i)(A) and 600.80(c)(4)(i)(A) would 
prescribe the same requirements for submission of postmarketing 
individual case safety reports by applicants. Proposed Sec.  
600.80(c)(4)(i)(A) would also describe requirements for use of the 
VAERS form for vaccines. Proposed Sec. Sec.  310.305(d)(1)(ii), 
314.80(c)(4)(i)(B) and 600.80(c)(4)(i)(B) would prescribe that:

    Foreign SADRs may be submitted either on an FDA Form 3500A or, 
if preferred, on a CIOMS I form (foreign SARs for vaccines, may be 
submitted either on a VAERS form, or, if preferred, on a CIOMS I 
form, for proposed Sec.  600.80(c)(4)(i)(B)).

Proposed Sec. Sec.  310.305(d)(1)(iii), 314.80(c)(4)(i)(C) and 
600.80(c)(4)(i)(C) would prescribe that:

    Each domestic report of an actual or potential medication error 
must be submitted on an FDA Form 3500A (or, for vaccines, on a VAERS 
form for proposed Sec.  600.80(c)(4)(i)(C)).

Proposed Sec. Sec.  310.305(d)(1)(iv), 314.80(c)(4)(i)(D) and 
600.80(c)(4)(i)(D) would prescribe that:

    Reports of overall findings or data in the aggregate from 
published and unpublished in vitro, animal, epidemiological, or 
clinical studies must be submitted in a narrative format.

These proposed amendments would clarify the reporting format that would 
be required for individual case safety reports or other safety 
information (i.e., overall findings or data in the aggregate). Reports 
of actual and potential medication errors would be required to be 
submitted on an FDA Form 3500A (or VAERS form, as appropriate) because 
these reports describe an individual case even if an SADR does not 
occur or a patient is not identifiable. Reports of overall findings or 
data in the aggregate would be submitted in a narrative format rather 
than on FDA Form 3500A because FDA Form 3500A has been designed for 
reporting of data from an individual case.
III.F.2. Medical Dictionary for Regulatory Activities (MedDRA)
    ICH has developed an international medical terminology, MedDRA (the

[[Page 12445]]

medical dictionary for regulatory activities), to support the 
computerization and transmission of information related to many aspects 
of the regulation of medical products (ICH M1). Use of a single medical 
terminology internationally would facilitate global communication of 
safety information for human drug and biological products (see section 
II.B.1 of this document).
    Proposed Sec. Sec.  310.305(d)(2), 314.80(c)(4)(ii), and 
600.80(c)(4)(ii) would require that each SADR in an individual case 
safety report be coded on the FDA Form 3500A, CIOMS I Form, or VAERS 
Form using the appropriate ``preferred term'' in the latest version of 
MedDRA in use at the time the manufacturer or applicant becomes aware 
of the individual case safety report. FDA is proposing to require use 
of MedDRA to be consistent with ICH M1.
    Proposed Sec. Sec.  310.305(d)(2), 314.80(c)(4)(ii), and 
600.80(c)(4)(ii) would also require that each individual case safety 
report of a medication error be coded both as a medication error and, 
if applicable, with the preferred term for any SADRs associated with 
the medication error. The proposal clarifies how actual and potential 
medication errors would be coded.
    MedDRA must be licensed for a fee from an international MSSO. TRW 
was selected as the MSSO by ICH and the International Federation of 
Pharmaceutical Manufacturers Associations (IFPMA) through a contract 
process that involved bids from companies globally. FDA was involved in 
this process. The costs that would be imposed on industry to license 
MedDRA was a consideration in the selection of the MSSO.
    Companies may license the latest version of MedDRA 5.1 by 
contacting TRW in Reston, VA, toll free number 877-258-8280 (703-345-
7799 in Washington, DC area), FAX 703-345-7755, e-mail 
[email protected], Internet at www.meddramsso.com. Updated 
versions of MedDRA will be provided to subscribers as part of the 
annual licensing fee.
    MedDRA is a hierarchical system composed of various levels of 
terminology (i.e., system organ class, high level group term, high 
level term, preferred term, lower level term). The agency is proposing 
to require use of the preferred term for reporting to FDA because each 
preferred term represents a unique medical concept accepted 
internationally, which will aid in the transmission and translation of 
reports from various parts of the world. The preferred term provides 
medically validated representations of colloquial terms, which will 
result in fewer misrepresentations and misunderstandings of colloquial 
reports from various parts of the world. The preferred term also 
provides medically validated representations of noncurrent terms in 
other previously widely used coding terminologies such as COSTART and 
WHOART.
    FDA believes that use of MedDRA, a standardized medical 
terminology, will be welcomed by most of industry. However, for some 
manufacturers and applicants, use of MedDRA may result in a significant 
economic hardship. Applicants may request, under Sec. Sec.  314.90 or 
600.90, that FDA waive the requirement that each SADR in an individual 
case safety report be coded using MedDRA. If FDA finds that this 
requirement is economically burdensome for a small company, the agency 
intends to grant the company a waiver. A large company may also be 
granted a waiver if, for instance, it only markets a single product 
that generates a few safety reports a year. FDA intends to grant all 
reasonable waiver requests. This determination will be made on a case-
by-case basis.
III.F.3. Single Form for Each Identifiable Patient
    Current postmarketing safety reporting regulations, at Sec. Sec.  
310.305(d)(2), 314.80(f)(2), and 600.80(f)(2), state that each 
completed FDA Form 3500A, VAERS Form, or CIOMS I Form should refer only 
to an individual patient or a single attached publication. Under 
proposed Sec. Sec.  310.305(d)(3), 314.80(c)(4)(iii), and 
600.80(c)(4)(iii) FDA would remove the phrase ``or a single attached 
publication'' and replace the word ``patient'' with the word ``case.'' 
This proposed amendment would clarify that an FDA Form 3500A should be 
completed for each identifiable patient described in a scientific 
article (e.g., six FDA Form 3500As should be completed for an article 
describing six patients experiencing a particular SADR). This would 
also clarify that an FDA Form 3500A would be used to describe a 
potential medication error that does not involve a patient.
III.F.4. Contact Person
    Proposed Sec. Sec.  310.305(d)(4), 314.80(c)(4)(iv), and 
600.80(c)(4)(iv) would state:

    Each completed FDA Form 3500A (VAERS Form for proposed Sec.  
600.80(c)(4)(iv)) or CIOMS I Form must include the name and 
telephone number (and fax number and e-mail address, if available) 
for the licensed physician responsible for the content and medical 
interpretation of the data contained within the form (i.e., contact 
person for the company).

This information should be provided on FDA Form 3500A under the 
``contact office'' box (box G1 on FDA Form 3500A). This proposed 
revision would provide FDA with a person to contact with any questions 
that may arise during review of an individual case safety report. The 
agency believes that the potential medical significance of these safety 
reports warrants oversight by a licensed physician.
III.F.5. Computer-Generated Facsimile of FDA Form 3500A or Vaccine 
Adverse Event Reporting System (VAERS) Form
    Current Sec. Sec.  310.305(d)(3), 314.80(f)(3), and 600.80(f)(3) 
state that instead of using an FDA Form 3500A, manufacturers and 
applicants may use a computer-generated FDA Form 3500A or other 
alternative format provided that the content of the alternative format 
is equivalent in all elements to those specified in FDA Form 3500A and 
the format is agreed to in advance by MedWatch: The FDA Medical 
Products Reporting Program. Alternative formats to the Center for 
Biologics Evaluation and Research's VAERS Form must be approved by the 
Division of Biostatistics and Epidemiology (Sec.  600.80(f)(3)).
    Proposed Sec. Sec.  310.305(d)(5), 314.80(c)(4)(v), and 
600.80(c)(4)(v) would remove the use of alternative formats to FDA Form 
3500A and the requirement to obtain preapproval by MedWatch for use of 
a computer-generated FDA Form 3500A. Proposed Sec.  600.80(c)(4)(v) 
would also remove the use of alternative formats to the VAERS Form and 
the requirement to obtain preapproval by the Division of Biostatistics 
and Epidemiology for use of a computer-generated VAERS Form. Instead, 
the proposed rule would permit manufacturers and applicants to use a 
computer-generated facsimile of FDA Form 3500A (or VAERS Form for 
vaccines) provided that it is readable, includes appropriate 
identifying information and contains all the elements (i.e., format, 
sections, blocks, titles, descriptors within blocks, text for 
disclaimer) of FDA Form 3500A (or the VAERS Form for vaccines) in the 
identical enumerated sequence of the form. The proposed rule would also 
permit use of a one-page FDA Form 3500A for individual case safety 
reports in which no suspect medical device is involved. For one-page 
reports, the box, Section D. Suspect Medical Device, on the front page 
of FDA Form 3500A would be replaced with the box, Section

[[Page 12446]]

G. All Manufacturers, located on the back page of the form.
    To be considered ``readable'' by FDA, the computer-generated 
facsimile should be formatted as follows.
    [sbull] The facsimile should have at least a \1/4\ inch margin 
around the entire form so that information is not lost during scanning, 
copying, or faxing of the document. The left-hand margin may be 
increased up to \1/2\ inch to permit binding (e.g., hole-punching) of 
the form; all other margins should continue to be at least \1/4\ inch.
    [sbull] The data and text that is contained within the boxes should 
be in a font size of not less than 10 point.
    [sbull] The data and text that is contained within the boxes should 
be in a font type that is easy to read (e.g., CG Times, Arial) and not 
condensed, because the form may be copied or faxed multiple times. For 
visual contrast, the font type that is used for the data and text 
should, if possible, be different than the font type used to create the 
FDA Form 3500A or VAERS Form.
    [sbull] All data and text should be contained within each of the 
boxes, e.g., an ``x'' mark should be centered within the box, and 
narratives should include margins so that letters of the text are not 
obscured or made ambiguous by lines defining a box.
    FDA would consider ``appropriate identifying information'' to 
include:
    [sbull] The name of the company centered on the top of the front 
page;
    [sbull] In the lower left hand corner of the front page, the phrase 
``3500A Facsimile'' instead of the phrase ``FDA Form 3500A (date of 
form [e.g., 6/93])'' or the phrase ``VAERS facsimile'' instead of the 
phrase ``Form VAERS-1'';
    [sbull] The phrase ``continued'' at the end of each field that has 
additional information continued onto another page; and
    [sbull] On each continuation page containing additional 
information, the page number identified as Page----of----, the 
manufacturer report number in the upper right corner, the name of the 
company in the upper right corner, and the section and block number 
(e.g., Block B5) for each narrative entry.

This information is included in the draft guidance of 2001. Any 
revisions to these parameters would be included in updated versions of 
the guidance.
III.F.6. Other Revisions
    The proposed rule would remove Sec. Sec.  310.305(d)(4), 
314.80(f)(4), and 600.80(f)(4). These paragraphs provide manufacturers 
and applicants with addresses for obtaining copies of FDA Form 3500A 
and instructions for completing the form. FDA is proposing to remove 
these paragraphs because the addresses are provided in the draft 
guidance of 2001.
    The proposed rule would also remove Sec. Sec.  314.80(e)(2) and 
600.80(e)(2). These paragraphs state that persons subject to the 
postmarketing safety reporting regulations must separate and clearly 
mark reports of adverse drug experiences that occur during a 
postmarketing study as being distinct from those experiences that are 
being reported spontaneously to the person. FDA is proposing this 
revision because this information would be submitted to the agency in a 
completed FDA Form 3500A under the box for ``Report source'' (box G3 on 
FDA Form 3500A).

III.G. Patient Privacy

    Current postmarketing safety reporting regulations at Sec. Sec.  
310.305(e), 314.80(h), and 600.80(h) state that persons subject to 
these requirements should not include the names and addresses of 
individual patients in reports and, instead, should assign a unique 
code number to each report, preferably not more than eight characters 
in length. Proposed Sec. Sec.  310.305(e), 314.80(e), and 600.80(e) 
would amend these regulations by removing the word ``number.'' This 
proposed amendment would clarify that the code selected to identify a 
patient need not be limited to numbers (i.e., it could contain letters 
or a mixture of letters and numbers).

III.H. Recordkeeping

    Current postmarketing safety recordkeeping regulations at Sec.  
314.80(i) require applicants to maintain for a period of 10 years 
records of all adverse drug experiences known to the applicant, 
including raw data and any correspondence relating to the adverse drug 
experiences. Under proposed Sec.  314.80(f), FDA would amend these 
regulations to read:

    The applicant must maintain for a period of 10 years records of 
all safety information pertaining to its drug product, received or 
otherwise obtained, including raw data, any correspondence relating 
to the safety information, and any reports of SADRs or medication 
errors not submitted to FDA or only provided to FDA in a summary 
tabulation. The applicant must also retain for a period of 10 years 
any records required to be maintained under this section. When 
appropriate, FDA may require an applicant to submit any or all of 
these records to the agency within 5 calendar days after receipt of 
the request.

This proposed revision clarifies the type of safety records that 
applicants would be required to maintain for its drug products. With 
regard to a request for these records by FDA, the agency would usually 
make such a request either in response to a suspected safety problem 
associated with the use of a drug or to determine a company's 
compliance with the postmarketing safety reporting requirements. Under 
proposed Sec.  600.80(f), the agency is proposing similar revisions to 
the recordkeeping requirements for licensed biological products at 
Sec.  600.80(i). FDA is proposing these revisions to clarify what types 
of postmarketing safety reporting records must be maintained.
    Current Sec.  310.305(f)(1) requires manufacturers, packers, and 
distributors to maintain for a period of 10 years records of all 
adverse drug experiences required under Sec.  310.305, including raw 
data, any correspondence relating to adverse drug experiences, and the 
records required to be maintained under Sec.  310.305. FDA is proposing 
to amend these regulations to be consistent with the postmarketing 
safety recordkeeping regulations at proposed Sec. Sec.  314.80(f) and 
600.80(f).

III.I. Abbreviated New Drug Application (ANDA) Products

    Current Sec.  314.98 requires applicants holding an approved ANDA 
to comply with the postmarketing safety reporting requirements under 
Sec.  314.80. The proposed amendments to Sec.  314.80 in this rule 
would apply to applicants holding an approved ANDA. For postmarketing 
periodic safety reporting purposes, proposed Sec.  314.98(a) would 
require applicants holding an approved ANDA to determine the data lock 
point (i.e., month and day of the international birth date or any other 
month and day agreed by the applicant and FDA) for their periodic 
safety reports based on the data lock point of postmarketing periodic 
safety reports for other drug products containing the same drug 
substance (i.e., innovator NDA product that is the same drug product as 
the ANDA product or other ANDA products with the same drug substance if 
the innovator NDA product is no longer on the market). Thus, 
postmarketing periodic safety reports from different applicants for 
drug products containing the same drug substance would be submitted to 
FDA at the same time. Applicants holding an approved ANDA may contact 
FDA, if necessary, for assistance in determining the data lock point 
for postmarketing periodic safety reports.
    Proposed Sec.  314.98(a) would also state that applicants holding 
an approved ANDA would determine the type of postmarketing periodic 
safety report that would be required to be submitted to FDA (i.e., 
TPSR, PSUR, or IPSR)

[[Page 12447]]

based on the U.S. approval date of the application for the innovator 
NDA product. If the innovator NDA product (even if no longer on the 
market) was approved for marketing before January 1, 1998, applicants 
holding an approved ANDA for the drug product would have the option of 
submitting either TPSRs or PSURs and IPSRs to FDA. In these cases, an 
applicant holding an approved ANDA may choose to submit TPSRs to FDA 
even though other applicants with approved applications for the drug 
product submit PSURs and IPSRs. If the innovator NDA product was 
approved for marketing on or after January 1, 1998, applicants holding 
an approved ANDA for the drug product would be required to submit PSURs 
and IPSRs to FDA.
    Proposed Sec.  314.98(a) also provides that applicants holding an 
approved ANDA would determine the frequency of submission for 
postmarketing periodic safety reports based on the U.S. approval date 
of the application for the innovator NDA product. For example, if the 
innovator NDA product is the first human drug product containing the 
drug substance approved in the world and the application is approved 
for marketing on June 15, 1980, applicants of the innovator NDA product 
and all ANDA products with the same drug product would either submit a 
TPSR or PSUR to FDA every 5 years based on the U.S. approval date of 
the innovator NDA product (e.g., data lock point of June 15, 2000, June 
15, 2005). In this case, an applicant with an ANDA approved on January 
1, 1999, would have a data lock point of June 15, 2000, even though the 
reporting period for the drug product is less than 5 years; the next 
reporting period for the drug product would cover a 5-year period 
(i.e., June 16, 2000 through June 15, 2005). If the first human drug 
product containing the drug substance was approved for marketing in 
Europe on February 1, 1980, and the same drug product was approved in 
the United States on June 15, 1980, applicants of this drug product and 
all ANDA products with the same drug product would either submit a TPSR 
or PSUR to FDA with a 5-year frequency based on the U.S. approval date 
and with a date lock point based on the European approval date (e.g., 
February 1, 2000, February 1, 2005).
    All applicants holding an approved NDA or ANDA would be required to 
submit postmarketing individual case safety reports--semiannual 
submissions to FDA every 6 months (see section III.E.4 in this 
document). Thus, even though the agency would not be receiving TPSRs, 
PSURs, and IPSRs for drug products with approved ANDAs frequently after 
approval of the product, FDA would receive in a timely manner 
individual case safety reports for the product (i.e., expedited 
reports, individual case safety reports--semiannual submission) that 
would identify any potential problems associated with the formulation 
of the product. It is not necessary to receive TPSRs, PSURs, or IPSRs 
for drugs with approved ANDAs more frequently because the innovator NDA 
product has been evaluated for a number of years.

III.J. Postmarketing Approved New Drug Application (NDA) and Biologics 
License Application (BLA) Annual Reports

    Current Sec.  314.81(b)(2) requires applicants of marketed drug 
products subject to an NDA to submit an annual report to FDA within 60 
days of the anniversary date of U.S. approval of the application. This 
annual report must contain a brief summary of significant new 
information from the previous year that might affect the safety, 
effectiveness, or labeling of the drug product and a description of 
actions the applicant has taken or intends to take as a result of new 
information, such as submitting a labeling supplement, adding a warning 
to the labeling, or initiating a new study (Sec.  314.81(b)(2)(i)). 
This summary section must also contain, in accordance with the 1998 
pediatric final rule, a statement of whether labeling supplements for 
pediatric use were submitted and whether new studies in the pediatric 
population to support appropriate labeling for the pediatric population 
were initiated. The 1998 pediatric final rule also requires that the 
summary section include, where possible, an estimate of the patient 
exposure to the drug product, with special reference to the pediatric 
population (neonates, infants, children, and adolescents), including 
dosage form. The annual report also must contain a section on 
nonclinical laboratory studies that includes copies of unpublished 
reports and summaries of published reports of new toxicological 
findings in animal studies and in vitro studies (e.g., mutagenicity) 
conducted by, or otherwise obtained by, the applicant concerning the 
ingredients in the drug product (Sec.  314.81(b)(2)(v)). The applicant 
must submit a copy of a published report if requested by FDA. The 
annual report also must contain a section on clinical data that 
includes, among other data, published clinical trials on safety of the 
drug (or abstracts of them) and reports of clinical experience 
pertinent to safety (for example, epidemiological studies or analyses 
of experience in a monitored series of patients) conducted by or 
otherwise obtained by the applicant (Sec.  314.81(b)(2)(vi)). The 
clinical data section also must contain, in accordance with the 1998 
pediatric final rule, an analysis of available safety and efficacy data 
in the pediatric population, changes proposed in the labeling based on 
this information, and an assessment of data needed to ensure 
appropriate labeling for the pediatric population.
    Current Sec.  601.28 requires applicants of licensed biological 
products to submit an annual report to FDA within 60 days of the 
anniversary date of U.S. approval of the application. This annual 
report must contain, among other information, a brief summary stating 
whether labeling supplements for pediatric use were submitted and 
whether new studies in the pediatric population to support appropriate 
labeling for the pediatric population were initiated (Sec.  601.28(a)). 
This summary section also must contain, where possible, an estimate of 
the patient exposure to the product, with special reference to the 
pediatric population (neonates, infants, children, and adolescents), 
including dosage form. The annual report also must contain a section on 
clinical data that includes an analysis of available safety and 
efficacy data in the pediatric population and changes proposed in the 
labeling based on this information (Sec.  601.28(b)). This clinical 
data section also must contain an assessment of data needed to ensure 
appropriate labeling for the pediatric population.
    As noted in section I of this document, FDA received comments on 
the October 1994 proposal that noted that the proposed amendments to 
the agency's postmarketing safety reporting requirements would 
duplicate certain information required in postmarketing approved NDA 
annual reports. In light of these comments, FDA is proposing to revoke 
the requirement for safety-related information in postmarketing 
approved NDA and BLA annual reports to eliminate duplicative reporting.
    FDA is proposing to remove the requirement in Sec.  314.81(b)(2)(i) 
to report safety information or safety-related labeling changes in the 
summary section of approved NDA annual reports. FDA is also proposing 
to remove the requirement in Sec. Sec.  314.81(b)(2)(i) and 601.28(a) 
to submit an estimate of patient exposure to the drug product with 
special reference to the pediatric population. FDA is also proposing to 
remove the requirement in Sec.  314.81(b)(2)(v) to include the section 
on nonclinical laboratory studies in approved NDA annual reports. FDA 
is

[[Page 12448]]

also proposing to remove the requirement in Sec. Sec.  314.81(b)(2)(vi) 
and 601.28(b) to submit safety-related information in the clinical data 
section of approved NDA and BLA annual reports. FDA is proposing these 
changes because this safety-related information for a drug or licensed 
biological product would be provided to the agency in postmarketing 
safety reports (i.e., expedited reports, TPSRs, PSURs, IPSRs, 
individual case safety reports--semiannual submissions). For example, 
proposed Sec. Sec.  314.80(c)(2)(ii) and 600.80(c)(2)(ii) would require 
postmarketing expedited reports for certain information that would be 
sufficient, based on appropriate medical judgment, to consider changes 
in product administration (e.g., any significant unanticipated safety 
finding or data in the aggregate from an in vitro, animal, 
epidemiological, or clinical study, whether or not conducted under an 
IND, that suggests a significant human risk such as reports of 
mutagenicity, teratogenicity, or carcinogenicity, or reports of a lack 
of efficacy with a drug or biological product used in treating a life-
threatening or serious disease). Under proposed Sec. Sec.  
314.80(c)(3)(ii)(E), 314.80(c)(3)(iii)(E), 600.80(c)(3)(ii)(E), and 
600.80(c)(3)(iii)(E), PSURs and IPSRs would contain a section on 
worldwide patient exposure that includes, when possible, data broken 
down by gender and age (especially pediatric versus adult). Under 
proposed Sec. Sec.  314.80(c)(3)(ii)(G), 314.80(c)(3)(iii)(F), 
600.80(c)(3)(ii)(G) and 600.80(c)(3)(iii)(F), PSURs and IPSRs would 
include a section on safety studies that would contain a discussion of 
nonclinical, clinical, and epidemiological studies that contain 
important safety information. This safety studies section would include 
all applicant-sponsored studies newly analyzed during the reporting 
period; new studies specifically planned, initiated, or continuing 
during the reporting period; and published safety studies in the 
scientific and medical literature.

III.K. Safety Reporting for In Vivo Bioavailability and Bioequivalence 
Studies

    FDA's existing in vivo bioavailability and bioequivalence study 
regulations, under Sec.  320.31(a), require submission of an IND, as 
prescribed under part 312, for certain studies in humans (i.e., studies 
that involve a new chemical entity, a radioactively labeled drug 
product, or a cytotoxic drug product). Section 320.31(b) requires an 
IND for certain studies in humans using a drug product that contains an 
already approved, non-new chemical entity (i.e., a single-dose study 
where either the maximum single or total daily dose exceeds that 
specified in the approved labeling for the drug product, a multiple-
dose study where either the single or total daily dose exceeds that 
specified in the approved labeling of the drug product, a multiple-dose 
study on a controlled release product on which no single-dose study has 
been completed). Section 320.31(d) exempts all other in vivo 
bioavailability and bioequivalence studies in humans from the 
requirements of part 312 if certain conditions are satisfied (i.e., 
samples of any test article and reference standard are reserved by the 
person conducting the study and released to FDA upon request, studies 
are conducted in compliance with the requirements for institutional 
review set forth in 21 CFR part 56 and informed consent set forth in 21 
CFR part 50).
    FDA believes that drug products that are being investigated in 
human bioavailability and bioequivalence studies that are not subject 
to an IND are, in general, safe. However, as noted in section II.B.4 of 
this document, FDA receives some safety information periodically 
regarding drugs in these studies, thus making the agency uncertain 
whether it is receiving all necessary safety information regarding the 
specificity and severity of SADRs related to these drugs or any new 
SADRs that may be related to them. FDA has determined that a more 
comprehensive and orderly system for collecting safety information for 
these studies is needed. For this purpose, the agency is proposing to 
require persons conducting human bioavailability and bioequivalence 
studies that are not subject to an IND to submit expedited safety 
reports to FDA to alert the agency to potential safety problems 
quickly. The proposed rule would not require these persons to submit an 
IND to FDA for the studies.
    FDA believes that this new proposed safety reporting requirement 
will result in submission of minimal reports to the agency ([sim] 200/
year; see table 13 for estimate). FDA seeks comment on the 
reasonableness of this estimate and requests that comments provide 
information to support any alternative estimates.
    The act provides authority to FDA to require safety reports for 
human bioavailability and bioequivalence studies that are not subject 
to an IND. Section 505(i) of the act provides broad authority for FDA 
to issue regulations governing the clinical investigation of new drugs 
to protect the rights, safety, and welfare of human subjects and 
otherwise to protect the public health. In addition, section 701 of the 
act (21 U.S.C. 371) provides that the agency has authority to issue 
regulations for the efficient enforcement of the act.
    FDA is proposing to amend its regulations at Sec.  320.31(d) to 
require persons conducting human bioequivalence and bioavailability 
studies that are not subject to an IND to submit safety reports to FDA 
as prescribed under Sec.  312.32 for drug products subject to an IND. 
Under proposed Sec.  312.32(c)(1), a written safety report must be 
submitted within 15 calendar days to FDA and all participating 
investigators for any SADR that, based on the opinion of the 
investigator or sponsor, is both serious and unexpected and for 
information that, based upon appropriate medical judgment, might 
materially influence the benefit-risk assessment of an investigational 
drug, or that would be sufficient to consider changes in either product 
administration or in the overall conduct of a clinical investigation. 
Examples of reportable information would include any significant 
unanticipated safety finding or data in the aggregate from an in vitro, 
animal, epidemiological, or clinical study, whether or not conducted 
under an IND, that suggests a significant human risk, such as reports 
of mutagenicity, teratogenicity, or carcinogenicity, or reports of a 
lack of efficacy with a drug or biological product used in treating a 
life-threatening or serious disease. In addition, under proposed Sec.  
312.32(c)(2), a telephone or facsimile transmission safety report must 
be submitted within 7 calendar days to FDA for any unexpected fatal or 
life-threatening SADR.
    Proposed Sec.  320.31(d)(3) would require that these safety reports 
be transmitted to all participating investigators and the appropriate 
FDA division in the Center for Drug Evaluation and Research. Thus, 
safety reports for the reference listed drug would be sent to the new 
drug review division responsible for that drug; safety reports for the 
investigational drug product would be sent to the Director, Division of 
Bioequivalence, Office of Generic Drugs. The proposed rule would also 
require that each written notification bear prominent identification of 
its contents, i.e., ``Bioavailability/Bioequivalence Safety Report.'' 
Each report should clearly identify the sponsor of the bioavailability 
or bioequivalence study and the contract research organization, if 
applicable. In each written Bioavailability/Bioequivalence Safety 
Report, the sponsor would be required

[[Page 12449]]

to identify all safety reports previously filed for the bioavailability 
or bioequivalence study concerning a similar SADR and to analyze the 
SADR in light of previous similar reports, as required under proposed 
Sec.  312.32(c)(1)(i) for IND safety reports.
    An unexpected adverse drug experience is currently defined, under 
Sec.  312.32(a), as:

    Any adverse drug experience, the specificity or severity of 
which is not consistent with the current investigator brochure; or, 
if an investigator brochure is not required or available, the 
specificity or severity of which is not consistent with the risk 
information described in the general investigational plan or 
elsewhere in the current application, as amended. * * *

    For reporting purposes under proposed Sec.  320.31(d), an 
unexpected SADR would be any SADR, the specificity or severity of which 
is not consistent with the U.S. labeling for the reference listed drug. 
FDA is proposing use of the U.S. labeling for the reference listed drug 
for this purpose because studies that are not subject to an IND are 
unlikely to have an investigator brochure for use as a reference 
document.
    Under proposed Sec.  312.32(c)(4), a sponsor of a clinical study 
under an IND for a drug marketed in the United States is only required 
to submit IND safety reports to FDA (review division that has 
responsibility for the IND) for SADRs that occur during the clinical 
study itself, whether from domestic or foreign study sites of the IND. 
Proposed Sec.  312.32(c)(4) would apply to human bioavailability and 
bioequivalence studies that are the subject of proposed Sec.  
320.31(d). In these cases, the reference listed drug would be the 
marketed drug and persons conducting human bioequivalence and 
bioavailability studies that are not subject to an IND would only be 
required to submit safety reports to FDA from their studies.

III.L. Proposed Implementation Scheme

    FDA proposes that any final rule that may be issued regarding the 
proposal to require that SADRs in individual case safety reports be 
coded using MedDRA become effective 1 year after its date of 
publication in the Federal Register. FDA proposes that any final rule 
that may be issued based on all other proposals become effective 180 
days after its date of publication in the Federal Register.

IV. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

V. Analysis of Impacts

V.A. Background and Summary

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule has a significant impact on a substantial 
number of small entities, an agency must analyze regulatory options 
that would minimize any significant impact of the rule on small 
entities. Title II of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written assessment of anticipated costs and 
benefits before proposing any rule that may result in an expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100 million in any one year (adjusted annually for 
inflation). Section 205 of the Unfunded Mandates Reform Act also 
requires that the agency identify and consider a reasonable number of 
regulatory alternatives and from those alternatives select the least 
costly, most cost-effective, or least burdensome alternative that 
achieves the objective of the rule.
    The following analysis, in conjunction with the remainder of this 
document, demonstrates that this proposed rule is consistent with the 
regulatory philosophy and principles identified in Executive Order 
12866 and in the other two statutes. The proposed rule would amend 
current safety reporting requirements for human drug and biological 
products. Based on the analysis below, as summarized in table 11, FDA 
projects that the annual benefits would exceed the costs if this 
proposed rule resulted in a 2 percent reduction in hospital-related 
SADRs. The agency believes that a reduction in hospital related SADRs 
of at least 2 percent is a reasonable and likely outcome of this rule. 
The agency has determined that the proposed rule is an economically 
significant rule as described in the Executive Order. As required by 
the Regulatory Flexibility Act, the agency's Initial Regulatory 
Flexibility Analysis is included in this section. Because the rule may 
impose a mandate on the private sector that will result in a 1-year 
expenditure of $110 million or more (the current inflation adjusted 
threshold), FDA has conducted a cost-benefit analysis according to the 
Unfunded Mandates Reform Act. The relationship of this proposed rule 
with other agency rulemaking is described in the background section 
(e.g., reproposal of postmarketing periodic safety reporting 
requirements) (see section I of this document).
    The proposed rule covers a small part of a broader based set of 
international initiatives (ICH and CIOMS) that, taken collectively, 
have the potential to generate substantial benefits, savings, and 
efficiencies for consumers, manufacturers, and regulators. The full 
benefits of this proposed rule will accrue when international 
regulatory inconsistencies are addressed, safety reporting submission 
requirements are harmonized internationally, and electronic information 
exchange is uniform and compatible for the major participants involved 
in monitoring drug safety. A primary objective of the proposed rule is 
the harmonization of FDA's safety reporting requirements with 
international initiatives. The proposed rule would also improve the 
quality of information contained in postmarketing individual case 
safety reports for human drug and biological products. By providing 
more complete information for individual case safety reports, the 
revised reports would enhance the ability of the drug and biologics 
manufacturers and the agency to identify, monitor, and communicate the 
risks and benefits of marketed drug and biological products. Monitoring 
these risks and benefits is especially critical for newly approved 
products introduced to large and diverse patient populations.
    Specifically, the proposed rule would clarify and codify the 
agency's expectations for timely acquisition, evaluation, and 
submission of relevant safety information for marketed human drug and 
biological products. The proposed rule would expand postmarketing 
expedited safety reporting to include unexpected SADRs that cannot be 
classified as either serious or nonserious, information that is 
sufficient to consider changes in product administration, certain 
medically significant SADRs, and actual and potential medication errors 
as specified in the proposal. The proposed rule would require that each 
SADR in postmarketing individual case safety reports be coded using a 
single medical

[[Page 12450]]

dictionary, MedDRA. The proposed rule would also require applicants to 
conduct a more thorough review and analysis of the safety profile of 
marketed drug and biological products. Finally, the proposed rule would 
codify current best practices in postmarketing safety reporting.
    The proposed rule would also amend FDA's regulation on 
postmarketing annual reports for human drugs and licensed biological 
products to revoke the requirement for submission of safety-related 
information. The agency would also require the submission of expedited 
safety reports for certain bioavailability and bioequivalence studies 
that are exempt from submission of an IND.
    The summary of the costs and benefits of this proposed rule are 
presented in table 11. The total one-time costs of $144.2 million are 
primarily for adopting MedDRA and include planning for implementation 
of the MedDRA requirements, purchasing materials, and converting 
existing systems to the new dictionary. Firms would also incur annual 
operating costs of about $106.6 million for complying with the revised 
safety reporting and recordkeeping requirements and $28.5 million for 
maintaining the new MedDRA system. Total annualized costs are $155.6 
million (assuming a 10-year regulatory period and a 7 percent discount 
rate). A 10-year regulatory period for annualizing the costs and 
benefits of this proposed rule was selected as a reasonable time frame 
to adjust for investments, returns and savings given the potential for 
unforseen advances in both medical and information technology. In 
addition, by the fourth year savings and costs remain constant.
    The expected health benefits of the rule would result from the 
improved timeliness and quality of the safety reports and analyses. 
Submission of more complete safety information would reduce the number 
and duration of hospitalizations due to SADRs. If the proposed rule 
reduced the incidence of SADR-related hospitalizations by 2 percent, 
these annual savings could be $368.5 million (see table 11). A 1 
percent reduction in hospital related events would save $184 million 
annually; a 3 percent reduction would save $553 million annually. In 
addition, industry will experience economic benefits due to the more 
efficient allocation of resources permitted by the international 
harmonization of the safety reporting requirements. The annualized 
present value of these savings is $28.5 million assuming a 7 percent 
discount over 10 years (see table 11). The agency believes this 
represents only a partial estimate of future industry savings.

              Table 11.--Summary of the Costs and Benefits
                               [$ million]
------------------------------------------------------------------------
   Benefits assuming a 2 percent reduction in
             hospital related SADRs                       Annual
------------------------------------------------------------------------
Reducing hospital costs........................                    368.5
More efficient use of resources................                 \1\ 28.5
                                                ------------------------
      Total benefits...........................                   397.0
\1\ This is the annualized present value of the estimated savings
  assuming a 7 percent discount over 10 years.


------------------------------------------------------------------------
              Costs                  One-Time      Annual     Annualized
------------------------------------------------------------------------
Safety Reporting and
 Recordkeeping:
    Expedited reports (Except      ...........         29.0         29.0
     medication errors)..........
    Expedited reports--medication  ...........         68.0         68.0
     errors......................
    Periodic/other reports.......  ...........          9.6          9.6
Implementing MedDRA..............        144.2         28.5         49.0
                                  --------------
        Total....................        144.2        135.1        155.6
------------------------------------------------------------------------

V.B. Market Failure

    The host of international requirements and procedures that 
currently govern safety reporting for drugs and biologics creates 
substantial economic inefficiencies for firms. Manufacturers of drug 
and biological products operating in global markets must meet the 
regulatory safety reporting requirements of each country in which the 
product is marketed. In many cases, these safety reporting 
requirements, in particular submission timeframes for SADR reports, 
vary substantially among countries. Thus, drug and biologics 
manufacturers must devote considerable resources to reformatting the 
data and information pertaining to each SADR according to specific 
national requirements. Also, because the timing of report submissions 
is typically determined by product approval dates for each country, 
manufacturers must submit reports to different countries at different 
intervals. Such activities impose substantial costs on both industry 
and regulatory authorities. Moreover, product safety can be compromised 
due to the difficulty of analyzing SADR reports based on the 
inconsistent use of terms derived from multiple dictionaries.
    Despite the general recognition that manufacturers could realize 
substantial gains if safety reporting and terminologies were 
standardized globally, companies currently have limited incentives to 
invest capital and resources in standardized reporting systems (e.g., 
MedDRA) unless the standards are required by regulation. This shortfall 
in industry incentives occurs because the economic gains of 
harmonization cannot be attained by individual firms acting alone. 
Although most regulatory authorities have agreed in principal to 
implement international standardized reporting procedures, formal 
procedures have not yet been established. A few companies have 
voluntarily invested in the standardized process, but in the absence of 
global standards, these firms are uncertain of potential gains. FDA 
believes that the proposed rule is a necessary step toward achieving 
the desired international standardization and its corresponding 
economic and health benefits.
    Industry would benefit from FDA action to reduce uncertainties 
associated with investments in harmonization and from the ability to 
more efficiently allocate resources associated with safety reporting. 
Society would benefit from the improved quality of adverse event 
information that is a critical component to reducing health care costs 
associated with avoidable SADRs. More timely and

[[Page 12451]]

improved information on SADRs is needed to ensure the safe use of 
products and to monitor early warnings and unexpected risks associated 
with drugs, drug-drug interactions, drug-food interactions, and risks 
to certain patient populations.

V.C. Benefits

    The benefits of the proposed rule would result both from the public 
health gains attributable to the improved scope, uniformity, and 
quality of information and analyses submitted in safety reports and the 
economic savings attributable to the more efficient use of industry and 
regulatory resources.
    This proposed rule would require improved factual and analytic data 
underlying safety reporting and analysis, provide for more timely 
safety information for certain serious SADRs, and would require a 
common medical dictionary, MedDRA.
    The timely identification of SADRs is critical to managing risk 
information and to the safe prescribing and use of new drugs. Accurate 
and timely risk information is especially significant in the early 
months after product launch to develop appropriate prescribing and use 
behaviors as health care practitioners and consumers are learning about 
the product safety and use. Newly approved product use can quickly grow 
from a few thousand patients (the population in clinical trials) to 
many thousands or millions. Rare but serious SADRs are detected only 
after exposure to very large patient populations. Forty percent of SADR 
reports are for drugs approved within the last 3 years. Compounding 
this need for timely serious SADR information, U.S. patients are 
increasingly the first in the world to have access to new medications 
(49 percent of new drugs were first approved in the United States 
between 1996 and 1998, compared with 31 percent in 1991-1995).
    More timely and improved factual information would also enhance the 
identification of other important factors associated with the risks of 
SADRs. These factors include subpopulations that may differ from 
clinical trial participants, patients taking multiple medications or 
medications that require therapeutic monitoring, and patients with 
concurrent comorbidities.
    This rule would require affected entities to complete either a 
minimum or full set of data in safety reports, reflecting levels of 
risk. That is, more detail is required for higher risk events and 
reduced reporting for lower risk events. This rule would also require 
the use of MedDRA, a medical dictionary developed by the ICH, in coding 
SADR terms. MedDRA will provide a uniform, consistent and specific 
presentation of medical terms. By eliminating the use of multiple 
dictionaries, MedDRA would facilitate the retrieval, presentation, and 
summarization of SADR data and enhance the global communication and 
acceptance of safety information and reports. The use of a single 
dictionary will substantially upgrade the quality of safety analysis by 
incorporating uniformity of terms. MedDRA will aid in more expeditious 
and broader international drug use comparisons within a class, and 
prescribing and use decisions. Providing more complete information and 
more timely safety assessments would enhance the ability of the 
manufacturers to more quickly identify, monitor, and communicate the 
potential risks and benefits of marketed drugs and biologics.
    It is well recognized that drug safety information is a critical 
element in the risk management of marketed drugs and biologics. In 
addition, the medical literature provides substantial documentation of 
avoidable hospitalizations associated with SADRs. Improving the quality 
and timeliness of safety information and accelerating the communication 
of risk information will enable health care practitioners and consumers 
to take appropriate corrective actions (in the case of medication 
errors) and to make more informed decisions about treatments. Moreover, 
the management of risk information is an essential component of risk-
based decisions that determine the continued marketing or withdrawal of 
effective products with newly identified serious SADRs. We discuss 
benefits more fully below and show that a small reduction in the number 
of hospitalizations due to SADRs (as low as 0.85 percent), due to 
improved prescribing and use decisions, would result in the annual 
benefits outweighing the total costs.
V.C.1. Expanded Safety Information
    New drug approval decisions are based on safety and testing 
information derived from clinical trials that typically include several 
thousands of patients. However, the number of individuals tested in 
preapproval trials is not sufficiently large to reliably detect rare, 
serious SADRs. Patient exposure can quickly grow from thousands to 
millions after product launch. Thus, especially in the first few years 
after product launch, postmarketing surveillance is a critical 
component of the overall continuing review and assessment of drug 
safety (Ref. 1). Recent studies have identified common factors 
associated with increased risks of SADRs. These factors include 
subpopulations who differ from the clinical trial participants, e.g., 
the elderly, patients taking multiple medications or medications that 
require therapeutic monitoring, and patients with concurrent 
comorbidities (Refs. 2 through 5). The proposed rule would require 
companies to collect proactively more complete safety information, 
improving the factual and analytical data underlying the safety 
analyses. This expanded risk information would enable health care 
practitioners and consumers to take appropriate corrective actions (in 
cases of avoidable medication errors) and to make more informed 
decisions about treatments.
V.C.2. Improved Uniformity and Quality of Safety Information
    For years, numerous health care organizations, teaching hospitals, 
health care professionals, and educators have recognized the importance 
to public health of monitoring SADRs. Substantial evidence demonstrates 
that effective monitoring and analyzing of SADRs facilitate the 
identification of trends and warning signals that result in improved 
medication use and patient care (Refs. 6 through 10). Yet, the current 
drug and biologics safety reporting system, encompassing raw material 
suppliers, manufacturers, health care providers, and consumers, is 
fragmented with respect to its oversight and lacks common reporting 
procedures and tools for evaluating SADRs. For example, FDA oversees 
mandatory safety reporting by manufacturers of drug and biological 
products and voluntary reporting from health care providers and 
consumers. Health care facilities, on the other hand, may be subject to 
safety reporting oversight by individual state regulatory programs, 
although not all states have oversight systems. The Joint Commission on 
Accreditation of Health Care Organizations (JCAHO), which accredits 
health care facilities, has had standards for establishing SADR 
reporting systems for hospitalized patients for many years. Hospitals 
may establish their own systems independently and almost all conform to 
the JCAHO standards (Ref. 11). Despite growing evidence that avoidable 
SADRs and serious SADRs are important public health problems and 
widespread acknowledgment that monitoring SADRs provides public health 
benefits, FDA continues to receive reports of only a small percentage 
of the serious and avoidable SADRs that occur in health care facilities 
(Ref. 12). This proposed rule would improve safety reporting by drug

[[Page 12452]]

and biologics manufacturers, which may serve to provide a national 
framework for improved data collection and analysis of safety reports 
from a variety of sources.
    The proposed rule would also require the use of MedDRA, a single, 
medical terminology developed by ICH that can be used for the coding of 
SADR terms. MedDRA is a broad-based dictionary, developed for 
international use, that combines both SADR and morbidity terminology to 
provide a uniform, consistent, and specific presentation of medical 
terms. By eliminating the use of multiple dictionaries, MedDRA would 
facilitate the retrieval, presentation, and summarization of SADR data 
and enhance the global communication and acceptance of safety 
information and reports. In addition, the use of a single comprehensive 
medical dictionary by drug safety reporters and reviewers would 
substantially upgrade the quality of safety analysis by incorporating 
uniformity of terms. Standardizing the terms and improving the quality 
of the roughly 250,000 safety reports submitted annually to FDA would 
lead to better and more timely safety assessments and to improved 
communication of risk information. The widespread use and acceptance of 
standardized SADR information by regulators would ultimately enhance 
drug comparisons within a class and drug prescribing and use decisions.
V.C.3. Potential Savings From Reduced SADR-Related Hospitalizations
    Improved timeliness and analysis of SADR data would lead to a 
better understanding and a more rapid communication of the risks of 
SADRs. By providing such improvements, the proposed rule would reduce 
the incidence of SADRs. An agency estimate of the potential economic 
benefits of the rule is presented below and reflects the value of the 
expected hospital cost savings and the avoided lost wages that might 
result from reduced numbers of SADRs.
    V.C.3.a. Reduced rate of SADR-related hospitalizations. Numerous 
studies have documented drug-related hospitalizations (60 FR 44182 at 
44232, August 24, 1995). A comprehensive review of 36 articles focused 
specifically on SADRs as the primary cause of hospitalization. This 
study counted the number of reactions attributed to unintended 
consequences of drug therapy, excluding admissions due to overdose, 
intentional poisoning, attempted suicides, drug abuse, or intoxication. 
The percentage of hospitalizations due to SADRs ranged from 0.2 to 22 
percent, with a mean of 5.5 percent. FDA adjusted this figure to 5 
percent to remove over-the-counter drugs (Ref. 13). Based on 27.8 
million hospital admissions reported in 1997, excluding obstetrical 
admissions (Ref. 14), the agency estimates the annual number of SADR-
related hospitalizations at about 1.4 million (5 percent x 27.8 
million). Absent available data, the agency assumes the costs 
associated with SADR-related hospitalizations are similar to the 
average cost of a hospital stay, but requests comments and supporting 
data on this assumption. Therefore, applying an estimated cost of 
$9,177 for an average hospital stay (Ref. 15) implies total annual 
SADR-related hospital admission costs of about $12 billion ($9,177 x 
1.4 million).
    If the improved reporting and analyses of SADRs led to the 
avoidance of only 2 percent of these hospitalizations, the economic 
savings would amount to $252.2 million annually.
    V.C.3.b. Reduced rate of in-hospital SADRs. Bates et al. conducted 
a random sample of nonobstetrical admissions to two large tertiary care 
hospitals in Massachusetts over a 6-month period (Ref. 16). His 
prospective investigation of SADRs included interviews with medical 
staff and daily reviews of all medical charts. He estimated the 
incidence of all SADRs, including medical errors, at 6.5 percent with 
an average increase in hospital costs of $2,595 per case. Extrapolating 
these findings, FDA estimated the annual number of in-hospital SADRs at 
1.8 million and the total additional hospital cost at $4.7 billion 
annually. If this proposed rule led to a 2 percent reduction, the 
economic benefits would be $93.6 million annually.
    In a comprehensive review of studies that estimated the incidence 
of SADRs and/or the magnitude of hospital costs due to SADRs, the U.S. 
General Accounting Office cited substantial variation in estimates 
(Ref. 17). These differences may be due to inconsistent definitions of 
SADRs, different study methodologies (active prospective investigation 
versus retrospective review of patient records), representativeness of 
the samples, and particular methods used to extrapolate study findings 
to a national level. For example, Lazarou et al. and Classen et al. 
estimated the incidence of serious SADRs using the WHO definition of 
SADR and excluding other factors such as poisonings, intentional 
overdoses, and therapeutic failure (Refs. 18 and 19). These two studies 
had findings similar to Bates et al. On the other hand, Thomas et al. 
reviewed randomly selected hospital discharge records in two states and 
found a lower incidence of ``drug injury''. However, he used a 
particularly restrictive definition of SADR, one that resulted in 
prolonged hospitalization or disability at discharge (Ref. 20). Despite 
the uncertainties of estimating the incidence and cost of hospital 
related SADRs, FDA believes that the $4.7 billion estimate for in-
hospital SADRs derived above provides a plausible estimate.
    V.C.3.c. Indirect benefits of reducing the hospital costs of SADRs. 
The indirect benefits of reduced drug-related illnesses are derived 
from estimates of the costs of missed work or reduced productivity. 
Several studies on SADR-related hospital admissions stratified findings 
by patient age. Roughly 58 percent of SADR admissions were for patients 
aged 20 to 59. The remaining 42 percent were for patients under 20 
years (less than 10 percent) and over 59 years old (Refs. 21 through 
23). To calculate productivity losses, the agency assumed 56 hours per 
admission for patients aged 20 to 59 years (40 hours of lost work per 
hospitalization plus 16 additional hours for recovery and followup 
doctor visits) \2\ and 14 hours for the remaining groups (to account 
for lost volunteer time or for time away from work for the care givers 
of dependent patients). The wage rates used are the average hourly 
production workers earnings of $15.96 for patients aged 20 to 59 
($12.28 plus 30 percent for benefits), and $12.28 for the remaining 
patients or their care givers (Ref. 14). The estimated value of this 
lost productivity is $812 million.
---------------------------------------------------------------------------

    \2\ The agency used 40 hours to estimate work productivity 
losses. This estimate is consistent with current hospital discharge 
data and with the length of stay for drug-related hospitalizations 
(Ref. 21).
---------------------------------------------------------------------------

    To estimate similar indirect benefits for in-hospital SADRs, the 
agency assumed the same distribution of patient ages. Related 
productivity losses are assumed to be 16 and 6 additional hours 
respectively, for patients aged 20 to 59, and for the remaining groups. 
The estimated value of this lost productivity is $323 million.
    A 2 percent reduction in costs of SADR-related hospitalizations and 
prolonged hospitalizations would yield indirect benefit savings of 
$22.7 million. These estimates may somewhat overstate the value of lost 
productivity for the 20 to 59 age group because all patients are 
assumed to be employed. On the other hand, indirect benefits for the 
remaining age groups are understated because many of these patients are 
in the workforce and for those who are not, data are inadequate to 
measure their contribution to society.

[[Page 12453]]

    V.C.3.d. Sum of SADR-related costs. Summing these estimates, the 
total annual direct and indirect benefits of reducing avoidable SADR-
related hospitalizations and longer hospital stays by 2 percent would 
lead to economic benefits of $368.5 million per year. Varying the 
assumption of a 2 percent reduction in hospital costs with a 1, 3, and 
5 percent reduction, would yield annual benefits of $184 million, $553 
million, and $921 million, respectively. A reduction of only 0.85 
percent in the hospital costs associated with SADRs would be needed to 
outweigh the annualized industry costs of $155 million. Furthermore, 
under any of these scenarios, the total SADR-related hospital savings 
would outweigh the costs of this rule. With a 2 percent or greater 
reduction, the annual benefits would outweigh the costs beginning in 
the first year. Nonetheless, the agency seeks comment on our estimates 
of expected reductions in hospital-related costs, including the 
potential for reducing the incidence and length of stay of hospital-
related SADRs.
    In contrast to focusing only on hospital costs of SADRs, one study 
estimated the direct costs of drug-related morbidity and mortality for 
the ambulatory population at $76.6 billion annually, with the largest 
component $47.4 billion for drug-related hospitalizations (Ref. 24). 
The remaining cost components included: $14.4 billion for long-term 
care, $7.5 billion for physician visits, $5.3 billion for emergency 
department visits, and $1.9 billion for additional prescriptions. 
Again, assuming a 2 percent reduction, savings are approximately $948 
million annually.
V.C.4. Cost Savings and More Efficient Use of Resources
    The proposed rule is intended to complement and formalize 
international efforts by industry representatives and major 
international regulatory bodies to achieve a more uniform and global 
approach to safety reporting. The content, analyses, and timing of SADR 
report submissions would closely align with international initiatives 
and recommendations. To the extent that U.S. requirements become 
harmonized within a global context, companies that compete 
internationally would benefit from this proposed rule. Multiple 
international due dates for safety report submissions and reformatting 
of the same information to meet different regulatory requirements 
represent opportunity costs that could be allocated elsewhere. 
Companies would accrue savings through a substantial reduction or 
elimination of the reformatting of postmarketing periodic safety report 
information to meet varying international requirements and by 
synchronizing report frequencies and due dates internationally. Thus, 
as the international community harmonizes, companies would achieve 
efficiencies, eliminate duplicative processes, and reallocate those 
resources more efficiently.
    The agency contracted with the Eastern Research Group, Inc. (ERG), 
an economics consulting firm, to estimate the potential benefits that 
would accrue to drug and biologics companies in the long run, as 
international harmonization efforts align and generate cost savings. 
These savings include more efficient regulatory safety reporting, more 
efficient sharing of safety information, and a common medical 
terminology. ERG estimated the following specific categories of 
benefits: More efficient management of drug safety data, more efficient 
intercompany agreements, and international harmonization of the 
postmarketing periodic safety report format (i.e., use of PSUR format). 
ERG applied estimates of savings by category and firm size to the 
number of affected firms within each affected industry. The 
methodologies and procedures for deriving these estimates are fully 
presented in ERG's final report (Ref. 25).
    V.C.4.a. Savings related to maintaining and building data bases of 
SADRs and intercompany transfers of drug safety data.
    Drug and biologics companies maintain safety data bases of all 
domestic and foreign SADRs involving their products. The management of 
these data bases can be quite complex depending on the individual 
circumstances of manufacturing and marketing. Companies may have 
foreign subsidiaries, domestic and foreign manufacturing sites, and 
varied licensing agreements with other companies for marketing 
products. Foreign subsidiaries and licensees generally submit SADR 
reports to U.S. companies by fax. U.S. companies then reenter the 
reports into their own databases. Use of standardized safety report 
formats and content internationally will lend itself to electronic 
transmission of safety information. In these cases, intercompany and 
intracompany sharing of safety information will be substantially 
facilitated. ERG estimated these benefits at $3.1 million annually.
    V.C.4.b. Savings related to greater ease in entering into 
intercompany agreements. As requirements for drug and biologics safety 
reporting become harmonized, drug and biologics companies will find it 
easier to coordinate safety reporting efforts when entering into 
various agreements with other manufacturers or sales organizations. In 
the current organizational structure of the industry, companies are 
frequently negotiating licensing agreements, mergers, joint ventures, 
and other contractual matters with other companies. For these 
arrangements, companies must develop, share, and merge drug safety 
reports from around the world. At present, negotiation of drug safety 
data sharing is often complicated by reporting formats and requirements 
that differ between regions. ERG estimated the potential savings that 
would accrue from simplified negotiation of licensing agreements due to 
standardized reporting formats and requirements at $4.2 million 
annually.
    V.C.4.c. Savings related to eventual international harmonization to 
the PSUR format. ERG estimated the potential savings to industry of 
preparing a single PSUR that would be accepted by regulatory 
authorities internationally on the same date. Currently, companies are 
faced with many inconsistent requirements and must meet the individual 
requirements and timeframes of each country. ERG estimated these 
savings at $24.3 million annually.
    V.C.4.d. Potential savings in clinical trial management. Some 
companies noted that they would convert medical terms from clinical 
trials to MedDRA whether or not it was required by FDA. Assuming that 
this transition will gradually apply to future clinical trials, a 
single medical terminology, internationally developed, accepted, and 
applied, would allow companies to more easily transmit, integrate, and 
analyze clinical trial data from global sites. Subsequent reductions in 
time and resources would contribute to reduced costs during drug 
development. Based on input from industry, ERG developed a narrow focus 
of savings associated with clinical trial data management valued at 
$7.2 million annually.
    V.C.4.e. Leveraging specialized knowledge. This proposed rule also 
provides the groundwork for establishing focused centers of technical 
information on drug safety. Global companies and regulatory agencies 
will have the opportunity to create economies of expertise by 
concentrating specialized knowledge of global drug use and product 
risks and benefits in centralized locations. To the extent that safety 
information is better managed, understood, and shared with interested 
parties, substantial benefits will accrue. Neither ERG nor FDA could 
quantify these benefits.

[[Page 12454]]

    V.C.4.f. Total benefits. ERG estimated the total industry savings 
from more efficient use of resources to be $38.8 million annually. This 
estimate, however, accounts for only a modest portion of the potential 
benefits of the broader set of initiatives that enhance electronic 
submissions and global harmonization of safety reporting. Table 12 
summarizes the estimated annual benefits of this proposed rule. The 
agency recognizes, however, that the industry savings component will 
not be fully realized until safety reporting requirements are 
harmonized internationally. The agency believes that these benefits 
could be achieved in a relatively short period after this rule becomes 
final. The agency is ready to accept PSUR formats and the use of MedDRA 
for coding of individual case safety reports at the present time (see 
draft guidance of 2001). In addition, the European Union and Japan 
currently accept PSUR formats and the use of MedDRA.

                Table 12.--Summary of the Annual Benefits
------------------------------------------------------------------------
                                                             $ Million
                    Savings category                        (annually)
------------------------------------------------------------------------
Public health benefits for a 2 percent reduction in SADR-
 related hospital costs:
    Reduced SADR-related hospital admissions............           252.2
    Reduced in-hospital SADRs...........................            93.6
    Indirect benefits from reduced hospitalizations.....            22.7
                                                         ---------------
        Total hospital-related savings..................           368.5
Expanded safety information on product approvals........           (\2\)
Improved risk communication and product selection.......           (\2\)
Future Industry Savings:
    Efficiencies in database maintenance................             3.1
    Facilitation of PSUR submissions....................            24.3
    Facilitation of intercompany negotiations...........             4.2
    Clinical trial management...........................             7.2
                                                         ---------------
        Total Industry Savings..........................        \1\ 38.8
Economies of Managing Drug Expertise....................          (\2\)
------------------------------------------------------------------------
\1\ Assuming \1/3\ of these savings begin in year 2 ($11.6 million), \2/
  3\ in year 3 ($23.3 million), and $38.8 million in years 4 through 10,
  the annualized present value is $28.5 million, discounted at 7 percent
  over 10 years. The 10-year time horizon allows a reasonable projection
  of current information given the unforseen progress and impacts of
  medical and computer technology.
\2\ Not estimated.

V.D. Costs of Compliance

    This section presents the estimated compliance costs of the 
proposed requirements. As explained in the following paragraphs, the 
proposed rule clarifies and expands existing requirements for 
submitting premarketing expedited reports, postmarketing expedited 
initial and followup reports, and postmarketing periodic safety reports 
to FDA. Drug and biologics manufacturers would be required to use 
direct verbal contact to collect information sufficient to determine 
the nature, severity, and outcome of SADRs and to evaluate and describe 
the safety profile or changes in the safety profile of marketed drugs. 
The proposed regulation also specifies criteria for reporting 
individual case safety reports and designates data elements that must 
be completed as a condition for initial and followup reporting. Each 
SADR in a postmarketing individual case safety report for human drugs 
and biologics must be coded using the appropriate ``preferred term'' in 
the latest version of MedDRA. The proposal also requires a physician to 
review the postmarketing expedited and periodic safety reports. The 
proposed rule would codify the data elements, analyses, and report 
format of the required postmarketing periodic safety report submissions 
and harmonize many of these requirements with ICH initiatives. 
Applicants holding an approved marketing application would be required 
to submit semiannual individual case safety reports and more detailed 
postmarketing periodic safety reports that contain cumulative and 
comprehensive data, analyses, tabulations, summaries, and other 
information. The proposed rule also includes revisions to IND safety 
reporting requirements and bioavailability and bioequivalence study 
requirements.
V.D.1. Costs of New Recordkeeping and Reporting Requirements
    V.D.1.a. Number of reports. In 1998, manufacturers and applicants 
of human drug and biological products submitted approximately 230,000 
individual case safety reports of SADRs to FDA. Data from about 130,000 
of these individual case safety reports in the agency's Adverse Event 
Reporting System (AERS) were analyzed to estimate the annual number of 
future SADR reports expected to be included as revised expedited and 
new semiannual submissions. However, not enough data exists to predict 
the number of new expedited reports the agency may expect each year. 
For this analysis, estimates of new expedited reports for human drugs 
and biological products were based on counts of similar reports 
received by the agency during 1998. The estimated number of expedited 
reports for blood products is derived from published studies (Refs. 26 
and 27).
    The agency does not know how many TPSRs, and PSURs and IPSRs would 
be submitted annually, because applicants with pre-1998 drug approvals 
can submit either format. In addition, applicants with ANDAs approved 
on or after January 1, 1998, may choose to submit a TPSR rather than a 
PSUR or IPSR if the innovator NDA was approved before January 1, 1998. 
Despite this uncertainty, this analysis estimates the number of new 
filings of postmarketing periodic safety reports based on average 
counts of pre- and post-1998 drug approvals.
    The number of affected reports for prescription drugs marketed for 
human use without an approved application, IND safety reports, 
bioavailability/bioequivalence safety reports, and other reports were 
projected from counts of similar reports received by FDA. Estimates for 
the total number of reports affected by the proposed rule are shown in 
table 13.

[[Page 12455]]



                                               Table 13.--Number of Affected Reports by Regulatory Status
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                 Drugs
                                                               marketed                                                      Bioavailability
                      Type of report                          without an      NDA/AND    Biologics      Blood       IND            and           Total
                                                               approved                               products                bioequivalence
                                                              application
--------------------------------------------------------------------------------------------------------------------------------------------------------
Expedited:
    Serious and unexpected SADRs..........................             350      50,000        3,000           0          0                  0     53,350
    Always expedited report...............................              50       1,500          100           0          0                  0      1,650
    Unexpected SADR with unknown outcome..................              46         912           25           0          0                  0        983
    Information sufficient to consider product                           5         300            4           0          0                  0        309
     administration changes...............................
    Medication errors.....................................           1,000     100,000       10,000           0          0                  0    111,000
    30-day followup.......................................             340      43,000        3,000           0          0                  0     46,340
    Serious SARs--blood products..........................               0           0            0       7,000          0                  0      7,000
IND Safety
    Information sufficient to consider product                           0           0            0           0        600                  0        600
     administration changes...............................
    Bioavailability/bioequivalence safety report..........               0           0            0           0          0                200        200
Periodic:
    TPSR..................................................               0       1,400           35           0          0                  0      1,435
    PSUR..................................................               0       2,500           35           0          0                  0      2,535
    ISUR..................................................               0         350            3           0          0                  0        353
    Individual case safety reports--semiannual submission.               0       4,726          480           0          0                  0      5,206
Other:
    Reports to manufacturer or applicant..................               4       4,548          100           0          0                  0      4,652
    Submit safety records to FDA upon request.............               2          15            4           0          0                  0         21
    Annual reports........................................               0       2,363           69           0          0                  0      2,432
--------------------------------------------------------------------------------------------------------------------------------------------------------

    V.D.1.b. New time burden. The proposed rule requires manufacturers 
and applicants to use active query to acquire the outcome (i.e., 
whether an SADR is serious or nonserious) and required data set for any 
spontaneously reported individual case safety report that they receive 
pertaining to their marketed human drug or biological product. 
Furthermore, the proposed rule requires that every individual case 
safety report submitted to the agency be assigned an appropriate MedDRA 
code. Although individual case safety reports are currently submitted 
for most SADRs, depending on the type of SADR, the proposed rule may 
impose an additional burden on health professional personnel if active 
query is not already used routinely by a manufacturer or applicant. 
Regulatory affairs personnel working with the health professional may 
spend additional time assigning the MedDRA code and documenting the 
active query. The agency seeks comment on the reasonableness of the 
estimates of the time burden and the type of employee anticipated to 
fulfill the new requirements detailed in the following paragraphs.
    V.D.1.b.i. Expedited reports. The nature of the SADR (i.e., whether 
the SADR is expected or unexpected) and whether the outcome is known 
(i.e., SADR is serious or nonserious) will determine the data needed 
and when and if an individual case safety report should be submitted to 
FDA. At present, individual case safety reports of SADRs that are both 
serious and unexpected are submitted as 15-day alert reports.
    The proposed rule adds conditions for determining expedited reports 
(e.g., minimum data set required). In addition, it specifies that an 
expedited report for an individual case safety report must contain a 
full data set, including MedDRA codes, and that supporting 
documentation such as hospital discharge records, autopsy reports, or 
death certificates must be submitted, if available. This aspect of the 
proposal may impose a new burden estimated at 1 hour each for health 
professionals and regulatory affairs personnel (see table 14).
    The proposal defines new criteria for determining when expedited 
reports should be submitted. Certain medically significant SADRs as 
listed in the proposal, whether unexpected or expected, and all 
domestic reports of actual and potential medication errors would be 
required to be submitted to FDA in an expedited manner. Furthermore, 
when the outcome of a spontaneous, unexpected SADR cannot be 
determined, an expedited report must be submitted to the agency. In 
these circumstances, manufacturers and applicants are assumed to 
allocate from 16 to 24 hours more time for health professionals and 
regulatory affairs and clerical personnel to prepare and submit these 
new reports. Table 14 lists the additional hours each type of employee 
may spend complying with these new requirements.
    In addition to individual case safety reports, manufacturers and 
applicants may receive safety information from domestic or foreign 
studies that is judged to be sufficient to consider a change in product 
administration. In this case, the proposed rule requires that a 
narrative report of these findings be submitted to the agency as an 
expedited report. Preparing and submitting this new report may take up 
to 8 hours of time from health professionals and regulatory affairs and 
clerical personnel as shown in table 14.
    V.D.1.b.ii. Followup reports. The proposed rule establishes 
timeframes and data elements required for submission of expedited 
individual case safety reports. If required data elements were not 
submitted with the initial filing of an expedited report of a serious 
SADR or a medication error report, then the applicant must continue to 
use active query to obtain the additional information. This information 
must be submitted to FDA in a followup report

[[Page 12456]]

within 30 calendar days of the previous filing. If the full data set is 
still not obtainable, the 30-day followup report must include all 
safety information obtained, highlighting new information and stating 
the reasons for the inability to obtain complete information. The 
agency estimates that 8 additional hours, as shown in table 14, are 
needed for these followup reports.
    Applicants must also submit any new safety information to FDA for 
any other expedited or followup report within 15 days of receipt of the 
new information. This provision is currently required; therefore, no 
additional hours are allocated to this provision.
    V.D.1.b.iii. Blood products. Collection and transfusing facilities 
are currently required to investigate, prepare, and maintain written 
reports of complaints of SARs arising as a result of blood collection 
or transfusion. Furthermore, if a fatality occurs as a complication of 
blood collection or transfusion, facilities must notify FDA as soon as 
possible and follow up with a written report within 7 calendar days 
after the fatality occurs. The proposed rule will require that all 
written reports submitted to the agency use the individual case safety 
report format. This change in reporting format is not expected to 
increase the time needed to prepare and submit reports of fatalities. 
In addition, the proposed rule will require that any serious nonfatal 
SAR related to collection or transfusion of blood and blood components 
be submitted as a expedited report within 45 calendar days. As shown in 
table 14, blood facilities may spend up to 16 hours more preparing and 
submitting each of these expedited reports.
    V.D.1.b.iv. IND and bioavailability/bioequivalence safety reports. 
Sponsors of an IND are currently required to submit written and 
telephone safety reports. The proposed rule will add some conditions 
for reporting and require that reportable SADRs include the minimum 
data set. Sponsors of INDs will be required to submit written safety 
reports to FDA and all participating investigators of: (1) Any SADR 
that, based on the opinion of either the sponsor or investigator, is 
both serious and unexpected and (2) any information that might 
materially influence the benefit-risk assessment of an investigational 
drug or that would be sufficient to consider a change in either product 
administration or in the overall conduct of a clinical investigation. 
The agency is also expanding the current requirement for telephone and 
facsimile transmission of safety reports of unexpected death or life-
threatening SADRs to include those that meet these criteria based on 
the opinion of either the sponsor or investigator. In addition, the 
agency is making minor changes to align current IND safety reporting 
requirements with the proposed changes to postmarketing safety 
reporting.
    The agency anticipates that very few investigator-initiated reports 
would be submitted under the proposed rule. Because the number of new 
reports (i.e., approximately 10 per year) would represent less than 0.2 
percent of all individual IND safety reports submitted to the agency in 
a year, no additional burden is estimated. However, up to 4 hours may 
be needed for sponsors to accommodate the new requirements for written 
safety reports for information sufficient to consider a change in 
product administration (see table 14).
    In addition, the agency would require submission of expedited 
safety reports for certain bioavailability and bioequivalence studies 
that are exempt from submission of an IND. The agency estimates 14 
hours per report are needed to comply (see table 14).
    V.D.1.b.v. Semiannual submissions of postmarketing individual case 
safety reports. The current regulations require that postmarketing 
individual case safety reports from domestic marketing experience for 
serious expected adverse drug experiences, nonserious unexpected 
adverse drug experiences, and nonserious expected adverse drug 
experiences be submitted to the agency in postmarketing periodic safety 
reports. Under the proposed rule, most individual case safety reports 
not submitted to FDA as an expedited report would be submitted as a 
separate report twice a year. All reports of actual or potential 
medication errors, whether or not an SADR occurs, would be submitted as 
expedited reports and not submitted semiannually. Individual case 
safety reports of nonserious SADRs that are expected or listed would no 
longer be submitted to the agency. Exceptions, for vaccines, would be 
reports of nonserious, expected SARs and expected SARs with an unknown 
outcome, which would be submitted semiannually. Nevertheless, 
applicants would be expected to maintain these reports and include them 
in tabular summaries provided in the postmarketing periodic safety 
reports (e.g., PSURs).
    Whereas the current postmarketing periodic safety reporting 
regulations do not apply to foreign reports of SADRs, the proposed rule 
would require that foreign individual case safety reports of serious 
and expected or listed SADRS be submitted semiannually. The agency is 
unable to predict how many foreign reports may be submitted. For the 
purpose of this analysis, therefore, the number of nonserious and 
expected or listed individual case safety reports is assumed to be 
equal to the number of serious and expected or listed foreign reports, 
and the overall number of individual case safety reports submitted in a 
year would remain unchanged.
    Although the number of individual case safety reports submitted 
annually as a postmarketing periodic safety report is expected to 
remain stable, the timing of these submissions may change. Reports will 
be submitted less frequently (semiannually rather than quarterly) for 
products that have been on the market for less than 3 years and more 
frequently (semiannually rather than annually) for products that have 
been on the market for more than 3 years. Furthermore, additional time 
may be needed for an active query to obtain a full data set for reports 
of serious and expected or listed SADRs and a minimum data set for all 
SADRs. Based on reports to AERS in 1998, the agency estimates that, on 
average, approximately 35 individual case safety reports may be 
submitted semiannually for each drug product. Regulatory affairs 
personnel and health professionals might spend up to 10 additional 
hours each to obtain and process information for each semiannual 
submission (see table 14).

                      Table 14.--Estimated New Burden for Expedited and Semiannual Reports
----------------------------------------------------------------------------------------------------------------
                                                                           New burden (hours)
                                                       ---------------------------------------------------------
          Type of report              New or revised        Health        Regulatory
                                                         professional       affairs       Clerical      Total
----------------------------------------------------------------------------------------------------------------
Expedited:
    Serious and unexpected SADR..  Revised............               1               1            0            2
    Always expedited report......  New................               2              12            2           16
    Unexpected SADR with unknown   New................               3              18            3           24
     outcome.

[[Page 12457]]

 
    Information sufficient to      New................               3               3            2            8
     consider product
     administration changes.
    Medication errors............  New................               2              12            2           16
    30-day followup..............  New................               3               4            1            8
    Serious SARs--blood products.  Revised............               2              12            2           16
IND Safety:
    Information sufficient to      Revised............               1               2            1            4
     consider product
     administration changes.
    Bioavailability/               New................               1              11            2           14
     bioequivalence safety report.
    Individual case safety         Revised............              10              10            0           20
     reports--semiannual
     submission.
----------------------------------------------------------------------------------------------------------------

    V.D.1.b.vi. Postmarketing periodic safety reports (TPSR, PSUR, and 
IPSR). Current agency regulations require applicants to submit 
postmarketing periodic safety reports at specified intervals. Each 
periodic safety report must contain a narrative summary and analysis of 
adverse drug experiences received since the last periodic report. The 
proposed regulation would require applicants to provide more thorough 
review and analysis of the safety profile for certain drugs.
    For all applications approved on or after January 1, 1998, these 
reports would be in the PSUR format (with some variation) that is 
currently accepted by other regulatory authorities. These applications 
would be submitted semiannually for 2 years after the U.S. approval 
date, annually for the next 3 years, and every 5 years thereafter. In 
contrast to current regulations, postmarketing periodic safety reports 
would have to contain a more comprehensive analysis of the product's 
safety record. Specifically, applicants would be required to submit, as 
described in chart 1, summary tabulations of SADRs (i.e., all SADR 
terms and counts of occurrences) received since the last periodic 
report categorized by body system or standard organ system 
classification scheme.

        Chart 1.--Required Summary Tabulations of SADRs for PSURs
------------------------------------------------------------------------
             Source                              Outcome
------------------------------------------------------------------------
Spontaneous submissions from     All serious and nonserious.
 health care professionals.
Studies or individual patient    All serious.
 INDs.
Scientific literature..........  All serious; all nonserious unlisted.
Regulatory authorities.........  All serious.
Other (e.g. poison control       All serious.
 centers, epidemiological data
 bases).
------------------------------------------------------------------------

    In addition, applicants would have to submit cumulative summary 
tabulations for SADRs that are both serious and unlisted. Applicants 
would be required to include a discussion of these data including the 
medical significance or mechanism.
    Applicants would be required to submit a discussion of safety 
information from applicant-sponsored studies (either planned or 
initiated) and published safety studies and abstracts. Furthermore, 
applicants would be required to include a discussion of certain lack of 
efficacy reports and important new information received after the data 
lock point. In addition to analysis of individual case safety reports 
and studies, applicants would be required to submit a comprehensive 
analysis of other safety information specified in the proposal, such as 
increased frequencies of listed SADRs, specific populations, and drug 
interactions.
    Applicants would also be required to provide other relevant safety 
and baseline information as specified in the proposal. This information 
would include worldwide marketing status, changes to the CCSI, actions 
taken for safety reasons, and worldwide patient exposure. Appendices 
would include additional safety information as specified in the 
proposal including information related to the current (or proposed 
changes) in the U.S. labeling and safe use of the product, summary 
tabulations of spontaneous individual case safety reports from 
individuals other than a health care professional, summary tabulations 
of individual case safety reports of SADRs with unknown outcome and 
medication errors, summary tabulations of SADRs from class action 
lawsuits, U.S. patient exposure, assessments of lack of efficacy 
reports and new information on resistance to antimicrobial drug 
products. In addition, the name and telephone number of the licensed 
physicians responsible for the content and medical interpretation of 
the information in the PSUR and the addresses where all safety reports 
and other safety related records are maintained would be included.
    The proposal also requires IPSRs for approvals on or after January 
1, 1998. While following a similar format as the PSUR, the IPSR is less 
comprehensive than the PSUR (i.e., does not require submission of 
summary tabulation information). This report would be submitted 7.5 and 
12.5 years after the U.S. approval date.
    Under the proposed regulation, TPSRs would be required for 
applications approved before January 1, 1998. Although less 
comprehensive than the PSUR, the TPSR would have to contain product 
safety information, including summary tabulations and a narrative 
summary and analysis of individual case safety reports, and a history 
of safety-related actions taken during the

[[Page 12458]]

reporting period. The timing for these report submissions would be at 
5, 7.5, 10, 12.5, and 15 years after U.S. approval of the product and 
then every 5 years thereafter. Applicants would have the option to file 
using the PSUR and IPSR formats.
    The additional times required to complete the proposed changes to 
postmarketing periodic safety report submissions are shown in table 15. 
The agency estimates that the new burdens would be 16 hours for TPSRs, 
40 hours for PSURs, and 30 hours for IPSRs. These times represent 
estimates of the average time per report, recognizing that preparation 
times for each postmarketing periodic safety reports may take as little 
as a day for products with few or no SADRs or as much as several months 
for other products that are more complex or associated with many SADRs. 
Based on reports received by the agency, a few products account for the 
majority of the reports of SADRs. For example, 1998 AERS data showed 
that approximately 75 percent of the postmarketing periodic safety 
reports for drug products included 10 or fewer individual case safety 
reports, accounting for only about 5 percent of all of those reports 
submitted with postmarketing periodic safety reports. The other 25 
percent of postmarketing periodic safety reports included the remaining 
95 percent of individual case safety reports submitted in 1998.

                  Table 15.--Estimated New Burden for Periodic Safety Reports and Other Reports
----------------------------------------------------------------------------------------------------------------
                                                                           New burden (hours)
                                                       ---------------------------------------------------------
          Type of report              New or revised        Health        Regulatory
                                                         professional       affairs       Clerical      Total
----------------------------------------------------------------------------------------------------------------
Periodic:
    TPSR--application approved     Revised............               3               9            4           16
     before 1/1/95.
    PSUR--application approved on  New................               8              24            8           40
     or after 1/1/95.
    IPSR--application approved on  New................               6              18            6           30
     or after 1/1/95.
Other:
    Reports of nonserious SADRs    New................               0               1            0            1
     and certain medication
     errors to manufacturer or
     applicant.
    Submit safety records to FDA   New................               0               4            4            8
     upon request.
    Annual reports...............  Revised............         \1\ (3)           (7.5)          (3)        (14)
----------------------------------------------------------------------------------------------------------------
\1\ Values in parentheses represent an estimate of the decrease in burden.

    V.D.1.b.vii. Other reports. Currently, persons submitting 
postmarketing safety reports may elect to submit reports of serious 
adverse drug experiences to the manufacturer or applicant rather than 
submitting serious unexpected adverse drug experiences directly to FDA. 
The proposed rule would require submission of all safety reports (i.e., 
serious and nonserious SADRs and medication errors) to the manufacturer 
or applicant within 5 calendar days of initial receipt of the 
information. Contractors may need to allocate up to 1 additional hour 
to prepare and submit each report of a nonserious SADR or medication 
error that does not result in an SADR (see table 15).
    Persons maintaining records of SADRs may be asked to submit any or 
all records to FDA within 5 calendar days. The agency estimates that 21 
such requests for SADR records would be made in a given year. This new 
reporting requirement may take regulatory affairs and clerical 
personnel up to 4 hours each to fulfill each request (see table 15).
    FDA will no longer require that applicants subject to an NDA or BLA 
submit certain safety related information with annual reports. This 
reduction in reporting requirements will decrease the burden on these 
applicants. To prepare and submit each annual report, applicants may 
save an estimated 13.5 hours annually (see table 15).
    V.D.1.c. Annual cost of the reporting and recordkeeping provisions. 
Hourly compensation estimates for personnel implicated in the proposed 
changes to safety reports are shown in table 16. The additional cost of 
the proposed changes for each type of affected report and the total 
annual cost of the proposed rule are summarized in table 17. However, 
because the annual costs depend on the actual number and type of 
reports submitted to FDA, these costs are uncertain and may fluctuate 
from year to year. For example, if there are 50 percent fewer reports 
than estimated, annual costs would be approximately $52.2 million 
instead of $106.6 million. If the number of reports submitted is 50 
percent more than shown in table 17, the annual costs would be about 
$159.9 million. The agency seeks comments on the reasonableness of its 
estimates of number of reports, burden hours, and costs.

                     Table 16.--Hourly Compensation
------------------------------------------------------------------------
                          Regulatory Affairs\2\
 Health Practitioner\1\            \3\                 Clerical \2\
------------------------------------------------------------------------
              $67.31                   $36.92                 $17.39
------------------------------------------------------------------------
\1\ Hourly compensation derived from the annual salary range for
  clinical research physicians in the pharmaceutical industry from http://careers.yahoo.com. Hourly compensation includes benefits equal to 40
  percent of hourly wage.
\2\ U.S. Department of Labor, BLS, ``Employer Costs for Employee
  Compensation, Table 12,'' March 1999.
\3\ Includes biostatisticians.


[[Page 12459]]


                              Table 17.--Total Annual Cost of New Reporting Burden
----------------------------------------------------------------------------------------------------------------
                                                                     Number of      Per report
                         Type of report                              affected       cost of new     Annual cost
                                                                      reports         burden          ($ mil)
----------------------------------------------------------------------------------------------------------------
Expedited:
    Serious and unexpected SADRs................................          53,350        $104.23            $5.6
Always expedited reports........................................           1,650         612.44             1.0
    Unexpected SADR with unknown outcome........................             983         918.65             0.9
    Information sufficient to consider product administration                309        $347.46             0.1
     changes....................................................
    Medication errors...........................................         111,000         612.44            68.0
    30-day followup.............................................          46,340         366.99            17.0
    Serious SARs--blood products................................           7,000         612.44             4.3
IND Safety:
    Information sufficient to consider product administration                600         158.54             0.1
     changes....................................................
    Bioavailability/bioequivalence safety report................             200         508.21             0.1
Periodic:
    TPSR........................................................           1,435         603.76             0.9
    PSUR........................................................           2,535       1,563.66             4.0
    IPSR........................................................             353       1,172.75             0.4
    Individual case safety reports--semiannual submission.......           5,206       1,042.28             5.4
Other:
    Reports of nonserious SADRs and certain medication errors to           4,652          36.92             0.2
     manufacturer or applicant..................................
    Submit safety records to FDA upon request...................              21         217.24             0.0
    Annual reports..............................................           2,432    \1\ (530.99)           (1.3)
                                                                 -----------------
        Total Annual Cost of New Reporting Burden...............  ..............  ..............         $106.60 
----------------------------------------------------------------------------------------------------------------
\1\ Values in parentheses represent an estimate of cost savings.

V.D.2. Costs of MedDRA
    FDA contracted with ERG to estimate the industry cost of using 
MedDRA terms to code individual case safety reports. In the fall of 
1999, ERG and FDA staff visited three drug companies and conducted 
telephone interviews with several more companies and industry 
consultants. The purpose of the interviews was to collect information 
to assist in estimating the major cost components of implementing 
MedDRA. ERG's complete report is on file with the hearing clerk (Ref. 
25).
    Companies were asked to describe costs incurred or projected based 
on company experiences. Companies identified major cost elements that 
include one-time implementation costs such as planning and coordination 
of the conversion, converting existing data and information systems, 
and training. Recurring costs include MedDRA subscription and 
maintenance costs.
    ERG applied estimates of cost by category and firm size to the 
number of affected firms within each industry. Estimates of affected 
drug and biologic product manufacturers are derived by applying data 
from 1998 FDA Adverse Drug Event Reports and Vaccine Adverse Event 
Reports to aggregate firm data from the Small Business Administration, 
Census of Manufactures and the National Science Foundation. Estimates 
of affected blood facilities are derived from the FDA Center for 
Biologics Evaluation and Research database of licensed and/or 
registered establishments, the National Blood Data Research Center and 
the Census Bureau.
    Limitations on ERG cost estimation include the complexities 
associated with firms' abilities to separate incremental costs from 
factors that substantially influence expenditures, such as integrating 
operations of one or more newly merged corporations, isolating U.S. 
corporate policies and operations from global corporate policies and 
operations, and reaching consensus on the extent and timing of the 
conversion of historical SADRs and data.
V.D.2.a. One-time costs
    V.D.2.a.i. Planning and coordination. Companies will need to 
allocate time to plan and coordinate the conversion of MedDRA across 
their affected operations. Planning costs are affected by the extent of 
decentralization of coding and pharmacovigilance work within the 
corporate structure. Managers for drug and biologics firms are expected 
to spend from 240 hours for very small firms to 1,400 hours for very 
large firms (greater than 750 or 500 employees respectively for drug 
and biologics firms) for planning and coordination. Costs per company 
ranged from $10,800 to $64,500 for drug and biologics firms. In 
contrast to drug and biologics firms, blood facilities have a limited 
range of products, do not need to convert legacy data, and typically 
operate only in the United States. Therefore, ERG judged that 
compliance costs for blood facilities would be 4 to 5 percent of 
equivalent-sized drug and biologics firms. Estimated costs per firm 
range from $450 to $2,260 for very small and very large firms, 
respectively.
    V.D.2.a.ii. Development of information technology support 
structure. Companies reported that information technology (IT) 
personnel will need to modify existing database systems to:
    [sbull] Accommodate adding a new medical dictionary,
    [sbull] Allow for MedDRA's complex hierarchical structure and wider 
field widths,
    [sbull] Reconcile the comparability of existing dictionaries with 
MedDRA (in the short term),
    [sbull] Integrate a Web browser, and
    [sbull] Install or modify an autoencoder system.

IT personnel are estimated to need from 720 hours for very small firms 
to 1,920 hours for very large firms to develop and validate computer 
data systems that will accommodate MedDRA. Costs are estimated to range 
from $25,850 to $68,900 for drug and biologics firms. No costs were 
forecast for blood facilities.
    V.D.2.a.iii. Purchase or development of an autoencoder. Companies 
reported that they currently use an existing database such as COSTART 
or WHOART and supplement these dictionaries with their own medical 
vocabulary. Autoencoders assist with the automated conversion of 
existing medical terms to MedDRA. Companies

[[Page 12460]]

may purchase autoencoders, adapt existing in-house versions, or use 
outside contractors. Converting existing terms to MedDRA is estimated 
to cost from $20,000 to $100,000 for drug and biologics firms. Costs 
are not applicable to blood facilities.
    V.D.2.a.iv. Conversion of legacy safety data. Some companies 
reported that they would convert virtually all of their legacy data 
into MedDRA terms even though it is not required by this proposed rule. 
Some companies maintain that this conversion includes information from 
clinical trials. Nonetheless, some companies may not convert their 
legacy drug safety data into MedDRA or may convert only some of their 
products, based on criteria associated with experience and history of 
the drug. ERG estimated that 75 percent of companies would incur 
conversion costs to allow for the range of company responses. The 
number of terms that are converted automatically (with autoencoders) or 
manually will affect conversion costs. Estimated costs per company for 
converting existing legacy data range from about $16,500 (for 
converting 15,000 terms) for very small firms to $275,000 (for 
converting roughly 250,000 terms) for very large drug firms. Costs for 
biologics firms of corresponding size range from $3,300 (for 3,000 
terms) to $55,000 (for about 50,000 terms). Costs are not applicable to 
blood facilities.
    V.D.2.a.v. Training of personnel. Companies reported that staff 
most likely to receive MedDRA training include medical coders, 
biostatisticians, and pharmacovigilance, IT, and regulatory affairs 
personnel. In addition to formal training, medical data coders will 
require several months of experience before they become proficient with 
coding in MedDRA. Training costs are dependent on the number of 
employees that must be trained in MedDRA and the level of training 
needed for their relevant duties. Training costs were estimated to 
range from $9,300 to $330,300 for very small to very large drug 
manufacturers and from $9,300 to $90,600 for biologics firms of 
corresponding size. ERG estimated training costs from $1,300 to $4,300 
for very small to very large blood facilities.
    V.D.2.a.vi. Revision of standard operating procedures (SOPs). 
Companies will revise a substantial group of SOPs in implementing 
MedDRA. Affected procedures include dictionary/coding, IT, and drug 
safety/pharmacovigilance. Drug and biologics firms are expected to need 
from 130 to 1,300 hours for very small to very large firms to revise 
their SOPs for MedDRA, with costs ranging from $5,900 to $59,200. ERG 
allocated 8 to 50 hours for developing or revising SOPs for blood 
facilities. Per firm costs for SOPs are estimated to range from $370 to 
$2,260 for very small to very large blood facilities.
V.D.2.b. Recurring costs
    V.D.2.b.i. MedDRA core subscription. Companies must pay 
subscription costs on an annual basis to the MedDRA MSSO. Core 
subscription costs vary with the size of the company and with the level 
of services. Estimates of costs range from $5,000 to $40,000 for drug 
and biologics firms. ERG judged that blood facilities would incur only 
modest annual costs associated with MedDRA subscription and updates 
because of the limited range of terminology describing medical 
outcomes. ERG assumed that blood facilities would either work through 
industry associations to negotiate lower per firm subscription costs 
or, alternatively, contract with contract research organizations to 
obtain the necessary MedDRA codes.
    V.D.2.b.ii. MedDRA versions and quarterly updates. Currently the 
MSSO intends to provide quarterly updates as well as periodic new 
versions of MedDRA. Companies did not have a sufficient history with 
incorporating MedDRA changes to estimate the costs of updates. Cost 
components would include senior level reviews of each update, 
communicating the changes to affected personnel, and IT support to 
upload and reconcile new versions. Costs are estimated to range from 
$5,700 to $43,000 for drug and biologics firms. No costs were assigned 
to blood facilities.
    V.D.2.b.iii. Maintenance of existing dictionaries. Companies 
reported that they may need to maintain their existing dictionaries for 
an indeterminate time. Conditions that could influence whether and for 
how long a company would need to maintain its existing dictionaries 
are: (1) The company uses different dictionaries for its postmarketing 
safety and clinical study data bases; (2) the company has products in 
late-stage clinical trials; and (3) the company has marketed products 
near the end of their useful life. ERG estimates the maintenance costs 
for existing dictionaries are expected to range from $4,300 to $136,400 
annually for drug manufacturers and from $4,300 to $43,400 annually for 
biologics manufacturers. No costs were assigned to blood facilities.
    Table 18 presents the estimated costs to industry of implementing 
MedDRA for each cost category.

      Table 18.--Total Compliance Costs of MedDRA by Cost Category
------------------------------------------------------------------------
                                          Total cost \1\    Percent of
           Drugs and biologics              ($ million)      total \1\
------------------------------------------------------------------------
First-Time Costs:
    Planning and coordination...........            16.3               9
    Purchase or development of auto-                20.5              12
     encoder............................
    Personnel training..................            46.0              27
    Development of IT structure.........            14.7               9
    Legacy safety data conversion.......            31.9              18
    Revision of SOPs....................            14.8               9
        Total First-time................           144.2              83
                                         -----------------
Recurring Costs:
    Annual MedDRA core subscription.....             6.6               4
    MedDRA versioning...................             6.9               4
    Maintenance of additional medical               15.0               9
     dictionary.........................
                                         -----------------
        Total recurring.................            28.5              16
                                         -----------------
        Total first year costs (First-             172.8            100
         time + recurring)..............
------------------------------------------------------------------------
\1\ Totals may not add due to rounding.


[[Page 12461]]

V.E. Small Business Analysis

    The following analysis along with other sections of this preamble 
constitute the agency's regulatory flexibility analysis as required 
under the Regulatory Flexibility Act.
V.E.1. Need for and Objectives of the Rule
    A primary objective of this proposed rule is the harmonization of 
FDA's safety reporting requirements with international initiatives. The 
proposed rule would also improve the quality of information contained 
in postmarketing safety reports for marketed human drug and biological 
products. By providing more complete information for individual case 
safety reports, the revised reports would enhance the ability of 
manufacturers, applicants, and the agency to identify, monitor, and 
communicate the risks and benefits of marketed drug and biological 
products. Monitoring these risks and benefits is especially critical 
for recently approved products introduced to large and diverse patient 
populations following market approval.
V.E.2. Description and Estimate of Small Entities
    The proposed rule applies to manufacturers, applicants, and 
contractors of drug and biological products, and persons involved in 
blood collection and transfusion. The Small Business Administration 
(SBA) defines a small business in Standard Industrial Classification 
(SIC) 2834 (or North American Industry Classification System (NAICS) 
code 325412) as one employing fewer than 750 employees and in SIC 2836 
(or NAICS code 325414) as one employing fewer than 500 employees. 
According to 1996 U.S. Bureau of the Census statistics, almost 90 
percent of the firms under these SIC codes are considered small 
businesses. A review of 1998 AERS data, which contain postmarketing 15-
day and periodic safety reports from manufacturers and applicants of 
marketed drug and biological products, found that about 200 firms 
submitted at least one individual case safety report for a trade name 
product and that the majority of these firms were considered large 
under the SBA definitions. However, the number of firms submitting 
reports vary from year to year. Therefore, using the 1998 AERS data, 
estimates of the percentages of reporting firms by size were 
distributed to the number of firms in each SIC, suggesting that about 
230 drug and 72 biologics firms would be affected by the proposed rule, 
of which 190, or about 60 percent, would be considered small.
    FDA estimates that about 3,200 blood facilities would be affected 
by the proposed regulation. Approximately 3,000 are hospitals with 
blood collection and/or compatibility testing operations, classified in 
SIC 8062 (or NAICS code 62211), and 200 are blood banks or non-hospital 
blood and plasmapheresis centers, classified in SIC 8099 (or NAICS code 
621991). The SBA defines businesses in SIC 8062 and 8099 with annual 
revenues of $25 million and $7.5 million or less, respectively, as 
small. ERG estimated the number of small businesses affected in SIC's 
8062 and 8099 at 1,786 and 188, respectively. This is approximately 60 
and 94 percent of the blood facilities in SICs 8062 and 8099, 
respectively, that will be implementing the MedDRA requirements.
V.E.3. Projected Reporting, Recordkeeping, and Other Compliance 
Requirements
    V.E.3.a. Reporting and recordkeeping requirements. The proposed 
rule may impose an additional burden on manufacturers of human drug 
products for which SADRs are reported. In any year, SADRs may be 
reported for about half of the products marketed in the United States. 
AERS data from 1998 suggest that small firms manufactured less than 12 
percent of the products for which SADRs were reported. Moreover, during 
this same year, only about 2 percent of the postmarketing 15-day alert 
reports submitted to the agency were from small firms. Nevertheless, 
the proposed changes to the postmarketing safety reporting requirements 
may impose a substantial burden on a significant number of small firms, 
especially small startup firms with only one product on the market. The 
extent of the impact will depend on the time that has elapsed since the 
drug was approved and the number and types of individual case safety 
reports received in a reporting period.
    To illustrate the impact of the safety reporting and recordkeeping 
requirements of the proposed rule, table 19 shows the hypothetical 
first-year burden for a drug approved 6 months prior to the effective 
date of the final rule. Under this scenario, the first-year burden 
incurred for a newly approved product might be as much as $19,600, 
assuming 26 expedited and 6 followup reports, two semiannual reports, 
and two PSURs had been submitted.

                          Table 19.--Hypothetical First-Year Reporting and Recordkeeping Burden for Newly Approved Drug Product
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                       Expedited                                      Individual
                                       Expedited       Expedited      (unexpected       Always                        case safety
                                       (serious,      (medication      SADR with       expedited    30-day follow-   report--semi-     PSUR      Total
                                      unexpected        errors)         unknown         report            up            annual
                                         SADR)                         outcome)                                       submission
--------------------------------------------------------------------------------------------------------------------------------------------------------
Per report new burden \1\.........            $104            $612            $919            $612            $367          $1,042     $1,564
Number of reports.................               8              16               1               1               6               2          2         36
Totals \2\........................            $834          $9,799            $919            $612          $2,202          $2,084     $3,128   $19,578
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Only whole dollar values are shown.
\2\ Values rounded to the nearest whole number.

    V.E.3.b. Implementing MedDRA. Implementing MedDRA would impose 
additional significant one-time and recurring costs on drug and 
biological product manufacturers. Costs would vary among individual 
firms depending on circumstances, including the number of products 
manufactured, the frequency of SADRs, and the extent of legacy data 
converted. Table 20 displays ERG's estimates per firm of revenues, 
annualized compliance costs and costs as a percent of revenues. Costs 
for small entities are 0.15 percent and 0.28 percent of revenues for 
drug and biological product manufacturers, respectively. Similarly, 
average compliance costs for small entities are

[[Page 12462]]

0.01 percent and 0.03 percent of revenue for SICs 8062 and 8099, 
respectively.

                Table 20.--Compliance Costs as a Percent of Estimated Revenues for Small Entities
----------------------------------------------------------------------------------------------------------------
                                                                                                    Compliance
                                                     Number of       Per firm        Per firm        cost as a
     Industry classification         Number of       affected        estimated      annualized      percent of
                                     employees         firms         revenues       compliance       estimated
                                                                      ($000)       costs  ($000)     revenues
----------------------------------------------------------------------------------------------------------------
SIC 2834 Pharmaceutical                    < 750             146          44,265            66.9            0.15
 preparations...................
SIC 2836 Biological products....           < 500              44          15,752            44.4            0.28
SIC 8062 General medical and               < 500           1,786          13,366             0.6            0.01
 surgical hospitals.............
SIC 8099 Blood banks (Health and           < 500             188           1,320             0.3            0.03
 allied services, NEC)..........
----------------------------------------------------------------------------------------------------------------

    The reporting, coding, and analysis of SADRs are standard 
procedures that manufacturers routinely conduct under current 
regulations. No additional professional skills would be necessary to 
comply with this rule. However, current safety reviewers, analysts, and 
IT personnel would need training to implement MedDRA.
V.E.4. Alternatives and Steps To Minimize the Impact on Small Entities
    The major objectives of this proposed rule are to harmonize FDA's 
safety reporting requirements with international initiatives and to 
improve the quality of safety reports. With these objectives in mind, 
the agency considered alternatives to this proposed rule.
    V.E.4.a. Do nothing. The agency considered but rejected the option 
of not proposing this rule. The proposed rule would align FDA's safety 
report terms, formats and requirements for human drugs and biological 
products with the recommendations of ICH. With regard to use of a 
medical dictionary for safety reporting purposes, at the present time, 
major problems exist with comparing safety data globally because 
multiple medical dictionaries are being used internationally for coding 
of SADRs (see section III.F.2 of this document). In this rule, the 
agency proposes to require the use of MedDRA, the medical dictionary 
developed by ICH. FDA believes that ``to do nothing'' would be 
inconsistent with the agency's efforts to harmonize safety reporting 
with international initiatives.
    Another objective of this proposed rule is to improve the quality 
of safety reports. In this preamble, the agency cited a substantial 
number of studies that estimate the number of SADRs that have resulted 
in a hospitalization or that occur in a hospital and the hospital costs 
related to SADRs. Safety reports that are complete are critical and 
necessary to reduce SADRs, medication errors, and hospital costs. This 
proposed rule would improve the agency's ability to monitor the safety 
of human drugs and biological products. In light of this information, 
``to do nothing'' would be inconsistent with the agency's mission of 
protecting public health.
    V.E.4.b. Do not require a medical dictionary. The agency considered 
but rejected the alternative of not requiring the use of MedDRA terms 
in individual case safety reports. MedDRA is an integral part of the 
postmarket safety reporting system that was developed jointly with 
international stakeholders. Requiring MedDRA terms in safety reports 
will enhance the analysis of drug safety information. Moreover, MedDRA 
is a medical dictionary designed to translate terms in multiple 
languages, thus aiding in more expeditious and broader international 
drug use comparisons and analysis. Not requiring MedDRA would 
compromise the agency objective of improving drug safety reporting and 
analysis. In addition, continued use of multiple medical dictionaries 
to code SADRs will perpetuate the major problems with comparing safety 
data globally that currently exist.
    V.E.4.c. Do not require medication errors as expedited reports. The 
agency considered but rejected the alternative of not requiring 
medication errors as expedited reports. Requiring expedited reports of 
medication errors would allow the agency to review critical information 
and take appropriate and more timely action on SADRs that are 
preventable. Not requiring expedited reports of medication errors would 
ignore a key step in reducing medical errors.
    V.E.4.d. Do not require blood establishments to submit reports for 
all serious SADRs associated with blood collection and transfusion. The 
agency considered but rejected the alternative of not requiring blood 
establishments to submit reports for all serious SADRs associated with 
blood collection and transfusion, in addition to the current 
requirement to submit reports of fatalities. Because these 
establishments are currently required to conduct investigations and 
prepare and maintain reports of serious SADRs, this proposal would 
impose minimal costs. However, only some serious SADRs must be reported 
in a timely manner. The agency believes it is critical that we receive 
all such reports. This would improve the agency's ability to take 
appropriate action to protect the blood supply more consistently, to 
enhance donor safety and to ensure the safety, purity and potency of 
blood and blood components for administration to patients.
    V.E.4.e. Do not require certain bioavailability and bioequivalence 
reports as expedited reports. The agency considered but rejected the 
alternative of not requiring expedited reports of SADRs for 
bioavailability and bioequivalence studies not subject to an IND. This 
requirement would allow the agency quicker access to information and 
would facilitate appropriate action to protect those enrolled in 
clinical trials.
    V.E.4.f. Waivers for economic hardship. The agency recognizes that 
requiring individual case safety reports to be coded using MedDRA will 
likely impose significant costs on some small firms (see section 
III.F.2 of this document). One alternative would be to consider the 
option of allowing companies to request a waiver from MedDRA coding, 
based on economic hardship. The agency is seeking comment on ways to 
reduce economic hardships of implementing MedDRA while maintaining 
adequate procedures to monitor and assess the safety of products.
    V.E.4.g Small business outreach, training, and assistance. The 
agency has received both written and verbal input from interested 
parties, including small businesses, on the recommendations of ICH 
regarding safety reporting for human drugs and biological products 
(e.g., the ICH E2A guidance, the ICH E2C guidance, and ICH M1). These 
public comments addressed published draft versions of the ICH guidances 
as well as numerous agency presentations

[[Page 12463]]

at public workshops and forums (e.g., sponsored by the Drug Information 
Association (DIA) or the Pharmaceutical Education and Research 
Institute (PERI)). The agency has considered these comments in 
development of this proposed rule.
    Once this proposed rule is finalized, the agency will provide the 
public with an overview of the provisions in the rule at workshops and 
forums (e.g., DIA meetings, PERI workshops). All firms, including small 
firms, would have an opportunity to attend these presentations.
    Firms can access AERS-related information on the Internet at http://www.fda.gov/cder/aers/index.htm. The AERS site includes a ``Reporting 
Regulations and Guidances'' page that provides a summary of the 
rulemaking (proposed rules, final rules) and guidances regarding the 
agency's safety reporting requirements for human drugs and biological 
products. This site is updated as changes to the safety reporting 
requirements are made.

V.F. Unfunded Mandates Reform Act of 1995

    On the basis of the preceding discussion, under the Unfunded 
Mandates Reform Act, FDA concludes that if only .85 percent of the 
estimated SADRs are prevented, then the benefits of this proposed rule 
will exceed the annualized compliance costs that it imposes on the U.S. 
economy. In addition, the agency has considered other alternatives as 
discussed in section V.E.4 of this document and determined that the 
proposed rule is the best alternative that would meet the objectives of 
this rule.

V.G. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.

1. Friedman, Michael A. et al., ``The Safety of Newly Approved 
Medicines: Do Recent Market Removals Mean There Is a Problem?'' 
Journal of the American Medical Association, 281:1728-1734, 1999.
2. Murphy, Barbara M., and Lawrence C. Frigo, ``Development, 
Implementation, and Results of a Successful Multidisciplinary 
Adverse Drug Reaction Reporting Program in a University Teaching 
Hospital,'' Hospital Pharmacy, 28:1199-1204, 1993.
3. Beyth, Rebecca J., and Ron Shorr, ``Epidemiology of Adverse Drug 
Reactions in the Elderly by Drug Class,'' Drugs & Aging, 14:231-239, 
1999.
4. Cooper, James W., ``Adverse Drug Reaction-Related 
Hospitalizations of Nursing Facility Patients: A 4-Year Study,'' 
Southern Medical Journal, 92:485-490, 1999.
5. Gaines, Ann R., and Frederick Varricchio, ``Interferon Beta-1b 
Injection Site Reactions and Necroses,'' Multiple Sclerosis, 4:70-
73, 1998.
6. Schumock, Glen T. et al., ``Control Charts to Monitor Rates of 
Adverse Drug Reactions,'' Hospital Pharmacy, 30:1088-1096, 1995.
7. Johnston, Philip E., Jason D. Morrow, and R. A. Branch, ``Use of 
a Database Computer Program to Identify Trends in Reporting of 
Adverse Drug Reactions,'' American Journal of Hospital Pharmacy, 
47:1321-1327, 1990.
8. Kennedy, Diane L. et al., ``National Adverse Drug Event 
Reporting,'' American Journal of Hospital Pharmacy, 50:1913-1914, 
1993.
9. Pierce, L. Ross et al., ``Hemolysis and Renal Failure Associated 
With the Use of Sterile Water for Injection to Dilute 25% Human 
Albumin Solution,'' American Journal of Health Systems Pharmacy, 
55:1057-1070, 1998.
10. Institute of Medicine, edited by Linda T. Kohn et al., ``To Err 
is Human: Building a Safer Health System,'' National Academy Press, 
1999.
11. Tyler, Linda S., and Nancy A. Nickman, ``Hospital Pharmacy 
Compliance with JCAHO Standards and ASHP Guidelines for Reporting 
Adverse Drug Reactions,'' American Journal of Hospital Pharmacy, 
49:845-850, 1992.
12. U.S. Department of Health and Human Services, Office of the 
Inspector General, ``Review of the Food and Drug Administration's 
Handling of Adverse Drug Reaction Reports,'' Report No. A-15-98-
50001, 1999.
13. Einarson, Thomas R., ``Drug-Related Hospital Admissions,'' The 
Annals of Pharmacotherapy, 27:832-840, 1993.
14. U.S. Department of Commerce, ``Statistical Abstract of the 
United States,'' 1999.
15. Agency for Health Care Policy and Research, ``National Medical 
Expenditure Survey: Annual Expenses and Sources of Payment for 
Health Care Services Research Findings 14,'' p. 7, 1995.
16. Bates, David W. et al., ``The Costs of Adverse Drug Events in 
Hospitalized Patients,'' Journal of the American Medical 
Association, 277:307-311, 1997.
17. The U.S. General Accounting Office, ``Adverse Drug Events The 
Magnitude of Health Risk Is Uncertain Because of Limited Incidence 
Data,'' GAO/HEHS-00-21, January, 2000.
18. Lazarou, Jason et al., ``Incidence of Adverse Drug Reactions in 
Hospitalized Patients, A Meta-Analysis of Prospective Studies,'' 
Journal of the American Medical Association, 279:1200-1205, 1998.
19. Classen, David C. et al., ``Adverse Drug Events in Hospitalized 
Patients Excess Length of Stay, Extra Costs and Attributable 
Mortality,'' Journal of the American Medical Association, 277:301-
306, 1997.
    20. Thomas, Eric J. et al., ``Costs of Medical Injuries in Utah 
and Colorado,'' Inquiry, 36:255-264.
    21. Ives, Timothy J. et al., ``Drug-Related Admissions to a 
Family Medicine Inpatient Service'', Archives of Internal Medicine, 
147: 1117-1120, 1987.
    22. McKinney, James M., and W. L. Harrison, ``Drug-Related 
Hospital Admissions,'' American Journal of Hospital Pharmacy, 
33:792-795, 1976.
    23. Caranasos, George J. et al., ``Drug-Induced Illness Leading 
to Hospitalization,'' Journal of the American Medical Association, 
228:713-717, 1974.
    24. Johnson, Jeffrey A., and J. Lyle Bootman, ``Drug-Related 
Morbidity and Mortality, A Cost of Illness Model,'' Archives of 
Internal Medicine, 155:1949-1956, 1995.
    25. Eastern Research Group, Inc., ``Cost of Implementing MedDRA 
Terminology for Pharmaceutical and Biologics Companies,'' 2000.
    26. Goodnough, Lawrence T. et al., ``Transfusion Medicine,'' The 
New England Journal of Medicine, 340:438-447, 1999.
    27. Newman, B.H., ``Donor Reactions and Injuries From Whole 
Blood Donation,'' Transfusion Medicine Reviews, 11:64-75, 1997.
    28. ``International Reporting of Periodic Drug Safety Update 
Summaries,'' Final Report of the CIOMS Working Group II, 1992.
    29. ``Current Challenges in Pharmacovigilance: Pragmatic 
Approaches,'' Final Report of the CIOMS Working Group V, 2001.

VI. Paperwork Reduction Act of 1995

    This proposed rule contains collections of information which are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). ``Collection 
of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR 1320.3(c) 
and includes agency requests or requirements that members of the public 
obtain, maintain, retain, or report information to the agency, or 
disclose information to a third party or to the public. The title, 
description, and respondent description of the information collection 
are shown below with an estimate of the annual reporting burden. 
Included in the estimate is the time for reviewing instructions, 
gathering and maintaining the data needed, and completing and reviewing 
the collection of information.
    FDA invites comments on: (1) Whether the proposed collection of 
information is necessary for proper performance of FDA's functions, 
including whether the information will have practical utility; (2) the 
accuracy of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information

[[Page 12464]]

on respondents, including through the use of automated collection 
techniques, when appropriate, and other forms of information 
technology.
    Title: Safety Reporting Requirements for Human Drug and Biological 
Products
    Description: The proposed rule would amend FDA's safety reporting 
regulations for human drug and biological products to implement 
definitions, and reporting formats and standards as recommended by the 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) and by the World 
Health Organization's Council for International Organizations of 
Medical Sciences (CIOMS); codify the agency's expectations for timely 
acquisition, evaluation, and submission of relevant safety information 
for marketed drugs and licensed biological products; require that 
certain information, such as domestic reports of medication errors, be 
submitted to the agency in an expedited manner; clarify certain safety 
reporting requirements; and make other minor revisions. The proposed 
rule would also amend FDA's postmarketing annual reports regulations 
for human drugs and licensed biological products by revising the 
content for these reports. These changes would further worldwide 
consistency in the collection of safety information and submission of 
safety reports, increase the quality of safety reports, expedite FDA's 
review of critical safety information, and enable the agency to protect 
and promote public health. The estimates provided in this section are 
not only attributed to the new proposed requirements in this rulemaking 
but also include burdens associated with our current safety reporting 
requirements.

VI.A. Expedited Safety Reporting

    Proposed Sec. Sec.  310.305(c)(2)(i), 314.80(c)(2)(i), and 
600.80(c)(2)(i) would require manufacturers and applicants to submit a 
report to FDA for each SADR, received or otherwise obtained, that is 
both serious and unexpected, whether foreign or domestic, as soon as 
possible, but in no case later than 15 calendar days after receipt by 
the manufacturer or applicant of the minimum data set for the serious, 
unexpected SADR. Based on data concerning the number of expedited 
reports currently received by the agency, FDA estimates that 
approximately 350 expedited reports of serious and unexpected SADRs 
will be submitted annually under proposed Sec.  310.305(c)(2)(i); 
approximately 50,000 reports will be submitted annually under proposed 
Sec.  314.80(c)(2)(i); and approximately 3,000 reports will be 
submitted annually under proposed Sec.  600.80(c)(2)(i). FDA estimates 
that approximately 14 manufacturers under proposed Sec.  
310.305(c)(2)(i) will submit these reports; approximately 282 
applicants under proposed Sec.  314.80(c)(2)(i) will submit these 
reports; and approximately 69 applicants under proposed Sec.  
600.80(c)(2)(i) will submit these reports. Based on the agency's 
familiarity with the content of expedited reports for serious and 
unexpected SADRs, FDA estimates that it will take an average of 16 
hours for manufacturers and applicants to prepare and submit one of 
these reports to FDA. Preparation of an expedited report for a serious 
and unexpected SADR would include gathering information (proposed 
Sec. Sec.  310.305(b) and (c)(1), 314.80(b) and (c)(1), and 600.80(b) 
and (c)(1)), providing attachments, if applicable (proposed Sec. Sec.  
310.305(c)(2)(ix) and (c)(2)(x), 314.80(c)(2)(ix), and 
600.80(c)(2)(ix)), and formatting information (proposed Sec. Sec.  
310.305(c)(2)(xii), (d), and (e), 314.80(c)(2)(xi), (c)(4), and (e), 
and 600.80(c)(2)(xi), (c)(4), and (e)).
    Proposed Sec. Sec.  310.305(c)(2)(ii), 314.80(c)(2)(ii), and 
600.80(c)(2)(ii) would require manufacturers and applicants to submit a 
report to FDA concerning information, received or otherwise obtained, 
whether foreign or domestic, that would be sufficient, based upon 
appropriate medical judgment, to consider product administration 
changes (e.g., any significant unanticipated safety finding or data in 
the aggregate from an in vitro, animal, epidemiological, or clinical 
study, whether or not conducted under an IND, that suggests a 
significant human risk, such as reports of mutagenicity, 
teratogenicity, or carcinogenicity, or reports of a lack of efficacy 
with a drug or biological product used in treating a life-threatening 
or serious disease). Manufacturers and applicants would be required to 
submit this information to FDA as soon as possible, but in no case 
later than 15 calendar days after determination by the manufacturer or 
applicant that the information qualifies for expedited reporting. 
Expedited reports containing information that would be sufficient to 
consider changes in product administration are a new type of safety 
report. Based on data concerning voluntary reporting of this type of 
information to the agency, FDA estimates that approximately 5 expedited 
reports concerning information sufficient to consider product 
administration changes will be submitted annually under proposed Sec.  
310.305(c)(2)(ii); approximately 300 reports will be submitted annually 
under proposed Sec.  314.80(c)(2)(ii); and approximately 4 reports will 
be submitted annually under proposed Sec.  600.80(c)(2)(ii). FDA 
estimates that approximately 5 manufacturers under proposed Sec.  
310.305(c)(2)(ii) will submit these expedited reports; approximately 50 
applicants under proposed Sec.  314.80(c)(2)(ii) will submit these 
expedited reports; and approximately 4 applicants under proposed Sec.  
600.80(c)(2)(ii) will submit these expedited reports. Based on the 
content of the voluntary reports submitted to the agency, FDA estimates 
that it will take an average of 8 hours for manufacturers and 
applicants to prepare and submit an expedited report to FDA concerning 
information sufficient to consider product administration changes. 
Preparation of these expedited reports would include gathering 
information (proposed Sec. Sec.  310.305(b) and (c)(1), 314.80(b) and 
(c)(1), and 600.80(b) and (c)(1)), providing attachments, if applicable 
(proposed Sec. Sec.  310.305(c)(2)(ix) and (c)(2)(x), 314.80(c)(2)(ix), 
and 600.80(c)(2)(ix)), and formatting information (proposed Sec. Sec.  
310.305(c)(2)(xii), (d), and (e), 314.80(c)(2)(xi), (c)(4), and (e), 
and 600.80(c)(2)(xi), (c)(4), and (e)).
    Proposed Sec. Sec.  310.305(c)(2)(iii), 314.80(c)(2)(iii), and 
600.80(c)(2)(iii) would require manufacturers and applicants to submit 
a report to FDA for each SADR that is unexpected and for which the 
determination of an outcome is unattainable (i.e., SADR with unknown 
outcome) within 45 calendar days after initial receipt by the 
manufacturer or applicant of the minimum data set for an unexpected 
SADR. Expedited reports of unexpected SADRs with an unknown outcome are 
a new type of safety report. Based on data concerning the number of 
unexpected SADR reports with an unknown outcome currently received by 
the agency, FDA estimates that approximately 46 expedited reports of an 
unexpected SADR with an unknown outcome will be submitted annually 
under proposed Sec.  310.305(c)(2)(iii); approximately 912 reports will 
be submitted annually under proposed Sec.  314.80(c)(2)(iii); and 
approximately 25 reports will be submitted annually under proposed 
Sec.  600.80(c)(2)(iii). FDA estimates that approximately 10 
manufacturers under proposed Sec.  310.305(c)(2)(iii) will submit these 
expedited reports; approximately 109 applicants under proposed

[[Page 12465]]

Sec.  314.80(c)(2)(iii) will submit these expedited reports; and 
approximately 12 applicants under proposed Sec.  600.80(c)(2)(iii) will 
submit these expedited reports. Based on the agency's familiarity with 
the content of expedited reports for serious and unexpected SADRs, FDA 
estimates that it will take an average of 24 hours for manufacturers 
and applicants to prepare and submit an expedited report for an 
unexpected SADR with an unknown outcome to FDA. Preparation of 
expedited reports for unexpected SADRs with an unknown outcome would 
include gathering information (proposed Sec. Sec.  310.305(b) and 
(c)(1), 314.80(b) and (c)(1), and 600.80(b) and (c)(1)), providing 
attachments, if applicable (proposed Sec. Sec.  310.305(c)(2)(ix) and 
(c)(2)(x), 314.80(c)(2)(ix), and 600.80(c)(2)(ix)), and formatting 
information (proposed Sec. Sec.  310.305(c)(2)(xii), (d), and (e), 
314.80(c)(2)(xi), (c)(4), and (e), and 600.80(c)(2)(xi), (c)(4), and 
(e)).
    Proposed Sec. Sec.  310.305(c)(2)(iv), 314.80(c)(2)(iv), and 
600.80(c)(2)(iv) would require manufacturers and applicants to submit 
to FDA each SADR, received or otherwise obtained, whether foreign or 
domestic, that is the subject of an always expedited report. Certain 
medically significant SADRs (e.g., ventricular fibrillation, liver 
necrosis, confirmed or suspected transmission of an infectious agent by 
a marketed drug or biological product) which may jeopardize the patient 
or subject and/or require medical or surgical intervention to treat the 
patient or subject would be subject to an always expedited report. 
These SADRs would be submitted to FDA whether unexpected or expected 
and whether or not the SADR leads to a serious outcome. Always 
expedited reports would be submitted to the agency within 15 calendar 
days after initial receipt by the manufacturer or applicant of the 
minimum data set for the report. Always expedited reports are a new 
type of safety report. Based on data concerning the number of safety 
reports currently received by the agency for the SADRs specified under 
proposed Sec. Sec.  310.305(c)(2)(iv), 314.80(c)(2)(iv), and 
600.80(c)(2)(iv), FDA estimates that approximately 50 always expedited 
reports will be submitted annually under proposed Sec.  
310.305(c)(2)(iv); approximately 1,500 reports will be submitted 
annually under proposed Sec.  314.80(c)(2)(iv); and approximately 100 
reports will be submitted annually under proposed Sec.  
600.80(c)(2)(iv). FDA estimates that approximately 10 manufacturers 
under proposed Sec.  310.305(c)(2)(iv) will submit these expedited 
reports; approximately 100 applicants under proposed Sec.  
314.80(c)(2)(iv) will submit these expedited reports; and approximately 
10 applicants under proposed Sec.  600.80(c)(2)(iv) will submit these 
expedited reports. Based on the agency's familiarity with the content 
of expedited reports for serious and unexpected SADRs, FDA estimates 
that it will take an average of 16 hours for manufacturers and 
applicants to prepare and submit an always expedited report to the 
agency. Preparation of always expedited reports would include gathering 
information (proposed Sec. Sec.  310.305(b) and (c)(1), 314.80(b) and 
(c)(1), and 600.80(b) and (c)(1)), providing attachments, if applicable 
(proposed Sec. Sec.  310.305(c)(2)(ix) and (c)(2)(x), 314.80(c)(2)(ix), 
and 600.80(c)(2)(ix)), and formatting information (proposed Sec. Sec.  
310.305(c)(2)(xii), (d), and (e), 314.80(c)(2)(xi), (c)(4), and (e), 
and 600.80(c)(2)(xi), (c)(4), and (e)).
    Proposed Sec. Sec.  310.305(c)(2)(v), 314.80(c)(2)(v), and 
600.80(c)(2)(v) would require manufacturers and applicants to submit 
all domestic reports of medication errors, whether actual or potential. 
Expedited reports of medication errors are a new type of safety report. 
Based on data concerning the number of domestic reports of medication 
errors voluntarily submitted to the agency, FDA estimates that 
approximately 1,000 reports of medication errors will be submitted 
annually under proposed Sec.  310.305(c)(2)(v); approximately 100,000 
reports will be submitted annually under proposed Sec.  
314.80(c)(2)(v); and approximately 10,000 reports will be submitted 
annually under proposed Sec.  600.80(c)(2)(v). FDA estimates that 
approximately 10 manufacturers under proposed Sec.  310.305(c)(2)(v) 
will submit these expedited reports; approximately 150 applicants under 
proposed Sec.  314.80(c)(2)(v) will submit these expedited reports; and 
approximately 30 applicants under proposed Sec.  600.80(c)(2)(v) will 
submit these expedited reports. Based on the agency's familiarity with 
the content of expedited reports for serious and unexpected SADRs, FDA 
estimates that it will take an average of 16 hours for manufacturers 
and applicants to prepare and submit an expedited report of a 
medication error to the agency. Preparation of medication error reports 
would include gathering information (proposed Sec. Sec.  310.305(b) and 
(c)(1), 314.80(b) and (c)(1), and 600.80(b) and (c)(1)), providing 
attachments, if applicable (proposed Sec. Sec.  310.305(c)(2)(ix) and 
(c)(2)(x), 314.80(c)(2)(ix), and 600.80(c)(2)(ix)), and formatting 
information (proposed Sec. Sec.  310.305(c)(2)(xii), (d), and (e), 
314.80(c)(2)(xi), (c)(4), and (e), and 600.80(c)(2)(xi), (c)(4), and 
(e)).
    Proposed Sec. Sec.  310.305(c)(2)(vi), 314.80(c)(2)(vi), and 
600.80(c)(2)(vi) would require manufacturers and applicants to submit a 
30-day followup report to FDA for any expedited report under proposed 
Sec. Sec.  310.305(c)(2)(i), (c)(2)(iv), (c)(2)(v), 314.80(c)(2)(i), 
(c)(2)(iv), (c)(2)(v), 600.80(c)(2)(i), (c)(2)(iv), and (c)(2)(v) that 
does not contain a full data set. These 30-day followup reports would 
be submitted within 30 calendar days after submission of the expedited 
report. Thirty-day followup reports are a new type of safety report. 
Based on data concerning the number of followup reports received by the 
agency, FDA estimates that approximately 340 30-day followup reports 
will be submitted annually under proposed Sec.  310.305(c)(2)(vi); 
approximately 43,000 30-day followup reports will be submitted annually 
under proposed Sec.  314.80(c)(2)(vi); and approximately 3,000 30-day 
followup reports will be submitted annually under proposed Sec.  
600.80(c)(2)(vi). FDA estimates that approximately 7 manufacturers 
under proposed Sec.  310.305(c)(2)(vi) will submit 30-day follow up 
reports; approximately 140 applicants under proposed Sec.  
314.80(c)(2)(vi) will submit 30-day follow up reports; and 
approximately 69 applicants under proposed Sec.  600.80(c)(2)(vi) will 
submit 30-day followup reports. Based on the agency's familiarity with 
the content of followup reports for serious and unexpected SADRs, FDA 
estimates that it will take an average of 8 hours for manufacturers and 
applicants to prepare and submit a 30-day follow up report to the 
agency. Preparation of 30-day follow up reports would include gathering 
information (proposed Sec. Sec.  310.305(b) and (c)(1), 314.80(b) and 
(c)(1), and 600.80(b) and (c)(1)), providing attachments, if applicable 
(proposed Sec. Sec.  310.305(c)(2)(ix) and (c)(2)(x), 314.80(c)(2)(ix), 
and 600.80(c)(2)(ix)), and formatting information (proposed Sec. Sec.  
310.305(c)(2)(xii), (d), and (e), 314.80(c)(2)(xi), (c)(4), and (e), 
and 600.80(c)(2)(xi), (c)(4), and (e)).
    Proposed Sec. Sec.  310.305(c)(2)(vii), 314.80(c)(2)(vii), and 
600.80(c)(2)(vii) would require manufacturers and applicants to submit 
a 15-day followup report to FDA concerning any new information, 
received or otherwise obtained, after any initial expedited report or 
any followup report, except for

[[Page 12466]]

expedited reports which are subject to the 30-day followup reporting 
requirement under proposed Sec. Sec.  310.305(c)(2)(vi), 
314.80(c)(2)(vi), and 600.80(c)(2)(vi). Proposed Sec. Sec.  
310.305(b)(2), 314.80(b)(2), and 600.80(b)(2) would also require 
manufacturers and applicants to submit 15-day followup reports to FDA 
with any new information concerning an individual case safety report 
forwarded to the manufacturer or applicant by FDA. Proposed Sec. Sec.  
310.305(c)(2)(viii)(A), 314.80(c)(2)(viii)(A), and 
600.80(c)(2)(viii)(A) would also require manufacturers and applicants 
to submit to FDA as 15-day followup reports any documents required 
under these paragraphs that become available after submission of an 
expedited report. These 15-day followup reports would be submitted 
within 15 calendar days of initial receipt of the new information by 
the manufacturer or applicant. Based on data concerning the number of 
followup reports currently received by the agency, FDA estimates that 
approximately 55 15-day followup reports will be submitted annually 
under proposed Sec.  310.305(b)(2), (c)(2)(vii), and (c)(2)(viii)(A); 
approximately 10,000 15-day followup reports will be submitted annually 
under proposed Sec.  314.80(b)(2), (c)(2)(vii), and (c)(2)(viii)(A); 
and approximately 1,000 15-day followup reports will be submitted 
annually under proposed Sec.  600.80(b)(2), (c)(2)(vii), and 
(c)(2)(viii)(A). FDA estimates that approximately 10 manufacturers 
under proposed Sec.  310.305 will submit 15-day followup reports; 
approximately 184 applicants under proposed Sec.  314.80 will submit 
15-day followup reports; and approximately 69 applicants under proposed 
Sec.  600.80 will submit 15-day followup reports. Based on the agency's 
familiarity with the content of followup reports for serious and 
unexpected SADRs, FDA estimates that it will take an average of 4 hours 
for manufacturers and applicants to prepare and submit a 15-day 
followup report to FDA. Preparation of 15-day followup reports would 
include gathering information (proposed Sec. Sec.  310.305(b) and 
(c)(1), 314.80(b) and (c)(1), and 600.80(b) and (c)(1)), providing 
attachments, if applicable (proposed Sec. Sec.  310.305(c)(2)(ix) and 
(c)(2)(x), 314.80(c)(2)(ix), and 600.80(c)(2)(ix)), and formatting 
information (proposed Sec. Sec.  310.305(c)(2)(xii), (d), and (e), 
314.80(c)(2)(xi), (c)(4), and (e), and 600.80(c)(2)(xi), (c)(4), and 
(e)).
    Proposed Sec. Sec.  310.305(c)(2)(xi), 314.80(c)(2)(x), and 
600.80(c)(2)(x) would require contractors and shared manufacturers to 
submit safety reports of any SADRs or medication errors for the product 
to the manufacturer (proposed Sec. Sec.  310.305(c)(2)(xi)) or 
applicant (proposed Sec. Sec.  314.80(c)(2)(x) and 600.80(c)(2)(x)) 
within 5 calendar days of its receipt by the contractor or shared 
manufacturer. Based on information included in individual case safety 
reports currently submitted to the agency, FDA estimates that 
approximately 10 safety reports will be submitted to manufacturers 
annually under proposed Sec.  310.305(c)(2)(xi); approximately 11,370 
safety reports will be submitted to applicants annually under proposed 
Sec.  314.80(c)(2)(x); and approximately 250 safety reports will be 
submitted to applicants annually under proposed Sec.  600.80(c)(2)(x). 
FDA estimates that approximately 5 contractors under proposed Sec.  
310.305 will submit safety reports to the manufacturer; approximately 
100 contractors under proposed Sec.  314.80 will submit safety reports 
to the applicant; and approximately 20 contractors and shared 
manufacturers under proposed Sec.  600.80 will submit safety reports to 
the applicant. Based on the agency's familiarity with the content of 
individual case safety reports, FDA estimates that it will take an 
average of 2 hours for contractors and shared manufacturers to prepare 
and submit a safety report to a manufacturer or applicant.
    Proposed Sec.  312.32(c)(1)(i) would require sponsors to notify FDA 
and all participating investigators in a written IND safety report of 
any SADR, based on the opinion of the investigator or sponsor, that is 
both serious and unexpected, as soon as possible, but in no case later 
than 15 calendar days after receipt by the sponsor of the minimum data 
set for the serious, unexpected SADR. The sponsor would identify all 
safety reports previously filed with the IND concerning a similar SADR 
and would analyze the significance of the SADR in light of previous, 
similar reports. Based on data concerning the number of written IND 
safety reports currently received by the agency, FDA estimates that 
approximately 4,860 written IND safety reports of serious and 
unexpected SADRs will be submitted annually under proposed Sec.  
312.32(c)(1)(i) for human drugs, and approximately 2,980 written IND 
safety reports will be submitted annually under proposed Sec.  
312.32(c)(1)(i) for human biological products. FDA estimates that 
approximately 457 sponsors will submit written IND safety reports for 
human drugs, and approximately 602 sponsors will submit written IND 
safety reports for human biological products. Based on the agency's 
familiarity with the content of written IND safety reports for serious 
and unexpected SADRs, FDA estimates that it will take an average of 16 
hours for sponsors to prepare and submit one of these reports to FDA. 
Preparation of a written IND safety report for a serious and unexpected 
SADR would include gathering information (proposed Sec.  312.32(b)) and 
formatting information (proposed Sec.  312.32(c)(1)(iii)).
    Proposed Sec.  312.32(c)(1)(ii) would require sponsors to notify 
FDA and all participating investigators in a written IND safety report 
of information, based on appropriate medical judgment, that might 
materially influence the benefit-risk assessment of an investigational 
drug, or would be sufficient to consider changes in either product 
administration or in the overall conduct of a clinical investigation 
(e.g., any significant unanticipated safety finding or data in the 
aggregate from an in vitro, animal, epidemiological, or clinical study, 
whether or not conducted under an IND, that suggests a significant 
human risk, such as reports of mutagenicity, teratogenicity, or 
carcinogenicity, or reports of a lack of efficacy with a drug or 
biological product used in treating a life-threatening or serious 
disease). This information would be submitted as soon as possible, but 
in no case later than 15 calendar days after determination by the 
sponsor that the information qualifies for expedited reporting. Based 
on information contained in written IND safety reports that the agency 
has received in the past, FDA estimates that approximately 300 written 
IND safety reports concerning information that might materially 
influence the benefit-risk assessment of an investigational drug, or 
that would be sufficient to consider changes in either product 
administration or in the overall conduct of a clinical investigation 
will be submitted annually under proposed Sec.  312.32(c)(1)(ii) for 
human drugs, and approximately 300 reports will be submitted annually 
under proposed Sec.  312.32(c)(1)(ii) for human biological products. 
FDA estimates that approximately 100 sponsors will submit these written 
IND safety reports for human drugs, and approximately 100 sponsors will 
submit these reports for human biological products. Based on the 
agency's familiarity with the content of written IND safety reports, 
FDA estimates that it will take an average of 8 hours for sponsors to 
prepare and submit this type of written IND safety

[[Page 12467]]

report to FDA. Preparation of these written IND safety reports would 
include gathering information (proposed Sec.  312.32(b)) and formatting 
information (proposed Sec.  312.32(c)(1)(iii)).
    Proposed Sec.  312.32(c)(2) would require sponsors to notify FDA by 
telephone or by facsimile transmission of any unexpected fatal or life-
threatening SADR based on the opinion of the investigator or sponsor as 
soon as possible but in no case later than 7 calendar days after 
receipt by the sponsor of the minimum data set for an unexpected fatal 
or life-threatening SADR. Based on data concerning the number of 
telephone IND safety reports currently received by the agency, FDA 
estimates that approximately 490 telephone and facsimile IND safety 
reports will be submitted annually under proposed Sec.  312.32(c)(2) 
for human drugs, and approximately 290 reports will be submitted 
annually under proposed Sec.  312.32(c)(2) for human biological 
products. FDA estimates that approximately 135 sponsors will submit 
these reports for human drugs, and approximately 180 sponsors will 
submit these reports for human biological products. Based on the 
agency's familiarity with telephone and facsimile IND safety reports, 
FDA estimates that it will take an average of 4 hours for sponsors to 
prepare and submit one of these reports to FDA. Preparation of a 
telephone or facsimile IND safety report would include gathering 
information (proposed Sec.  312.32(b)).
    Proposed Sec.  312.64(b) would require an investigator to notify 
the sponsor of any serious SADR immediately and any other SADR promptly 
unless the protocol or investigator's brochure specifies a different 
timetable for reporting the SADR. Based on data concerning the number 
of sponsors currently conducting clinical investigations under an IND 
and the number of written IND safety reports currently received by the 
agency, FDA estimates that approximately 100,000 investigator safety 
reports will be submitted to sponsors annually under proposed Sec.  
312.64(b) for human drugs, and approximately 60,000 investigator safety 
reports will be submitted to sponsors annually under proposed Sec.  
312.64(b) for human biological products. FDA estimates that 
approximately 10,000 investigators will submit safety reports to 
sponsors for human drugs, and approximately 6,000 investigators will 
submit safety reports to sponsors for human biological products. Based 
on the agency's familiarity with the content of IND safety reports, FDA 
estimates that it will take an average of 2 hours for an investigator 
to prepare and submit one of these reports to the sponsor.
    Proposed Sec.  320.31(d)(3) would require persons conducting human 
bioavailability and bioequivalence studies that are not subject to an 
IND to submit to FDA written safety reports as prescribed under 
proposed Sec.  312.32(c)(1) and telephone and facsimile safety reports 
as prescribed under proposed Sec.  312.32(c)(2). These persons would 
submit these safety reports to all participating investigators and the 
appropriate FDA division in the Center for Drug Evaluation and Research 
(i.e., safety reports for the reference listed drug would be forwarded 
to the new drug review division that has responsibility for that drug; 
safety reports for the investigational drug product would be forwarded 
to the Director, Division of Bioequivalence, Office of Generic Drugs). 
These persons would be required to identify all safety reports 
previously filed for the bioavailability or bioequivalence study 
concerning a similar SADR, and analyze the SADR in light of previous 
similar reports, as required under proposed Sec.  312.32(c)(1)(i). 
Written, telephone, and facsimile safety reports for bioavailability 
and bioequivalence studies not subject to an IND are a new type of 
safety report. Based on data concerning voluntary reporting to the 
agency of safety information for these bioavailability and 
bioequivalence studies, FDA estimates that approximately 200 safety 
reports will be submitted annually under proposed Sec.  320.31(d)(3). 
FDA estimates that approximately 10 sponsors will submit these safety 
reports. Based on the agency's familiarity with the content of IND 
safety reports, FDA estimates that it will take an average of 14 hours 
for sponsors to prepare and submit a safety report to FDA.
    Proposed Sec.  606.170(b) would require blood establishments to 
notify FDA in a written report of any serious SAR, except a fatality, 
within 45 calendar days after determination of a serious SAR. These 
written reports would be submitted to FDA using the reporting format 
provided in proposed Sec.  600.80(c)(4). Based on data from the 
scientific literature and reports voluntarily received by the agency, 
FDA estimates that approximately 7,000 written reports will be 
submitted annually under proposed Sec.  606.170(b). FDA estimates that 
approximately 3,062 blood establishments will submit these written 
reports. Based on the agency's familiarity with the content of 
expedited reports for serious and unexpected SADRs, FDA estimates that 
it will take an average of 16 hours to prepare and submit each of these 
written reports to FDA.
    Proposed Sec.  606.170(c) would require blood establishments to 
notify FDA by telephone, facsimile, express mail, or electronically 
transmitted mail as soon as possible of an SAR that results in a 
fatality. Proposed Sec.  606.170(c) would also require these facilities 
to submit a written report to FDA within 7 calendar days after the 
fatality. The written reports would be submitted using the reporting 
format provided in proposed Sec.  600.80(c)(4). Based on data 
concerning the number of reports for fatalities associated with blood 
collection and transfusion currently received by the agency, FDA 
estimates that approximately 75 reports will be submitted annually 
under proposed Sec.  606.170(c). FDA estimates that approximately 75 
blood establishments will submit these reports. Based on the agency's 
familiarity with the content of written reports for a fatality, FDA 
estimates that it will take an average of 20 hours to prepare and 
submit each of these reports to FDA.

VI.B. Periodic Safety Reports

    Proposed Sec. Sec.  314.80(c)(3)(i) and 600.80(c)(3)(i) would 
require persons holding an application (i.e., NDA, ANDA, BLA) approved 
before January 1, 1998, to submit a TPSR every 5 years after U.S. 
approval of the application. These persons would also be required to 
submit a TPSR at 7.5 and 12.5 years after U.S. approval of the 
application. Based on data concerning postmarketing periodic safety 
reports currently received by the agency, FDA estimates that 
approximately 1,400 TPSRs will be submitted annually under proposed 
Sec.  314.80(c)(3)(i); approximately 35 TPSRs will be submitted 
annually under proposed Sec.  600.80(c)(3)(i). FDA estimates that 
approximately 80 applicants under proposed Sec.  314.80(c)(3)(i) will 
submit TPSRs, and approximately 20 applicants under proposed Sec.  
600.80(c)(3)(i) will submit TPSRs. Based on the agency's familiarity 
with the content of postmarketing periodic safety reports, FDA 
estimates that it will take an average of 20 hours for applicants to 
prepare and submit a TPSR to FDA. Preparation of a TPSR would include 
gathering information (proposed Sec. Sec.  314.80(b) and 600.80(b)), 
and providing attachments (proposed Sec. Sec.  314.80(c)(3) and 
600.80(c)(3)).
    Proposed Sec. Sec.  314.80(c)(3)(ii) and 600.80(c)(3)(ii) would 
require persons holding an application (i.e., NDA, ANDA, BLA) approved 
on or after January 1, 1998, to submit a PSUR to

[[Page 12468]]

FDA according to the following schedule: Semiannually for 2 years after 
U.S. approval of the application, annually for the next 3 years, and 
then every 5 years thereafter. Proposed Sec. Sec.  314.80(c)(3)(i) and 
600.80(c)(3)(i) would permit persons holding an application (i.e., NDA, 
ANDA, BLA) approved before January 1, 1998, to submit a PSUR, in lieu 
of a TPSR, every 5 years after U.S. approval of the application. 
Proposed Sec. Sec.  314.80(c)(3)(iv) and 600.80(c)(3)(iv) would require 
persons holding an approved supplement to an approved application for 
use of the human drug or biological product in the pediatric population 
to submit a PSUR (even if the supplement or application was approved 
prior to January 1, 1998) to FDA according to the following schedule: 
Semiannually for 2 years after U.S. approval of the supplement, 
annually for the next 3 years, and then every 5 years thereafter. Based 
on data concerning postmarketing periodic safety reports currently 
received by the agency, FDA estimates that approximately 2,500 PSURs 
will be submitted annually under proposed Sec.  314.80(c)(3)(i), 
(c)(3)(ii), and (c)(3)(iv), and approximately 35 PSURs will be 
submitted annually under proposed Sec.  600.80(c)(3)(i), (c)(3)(ii), 
and (c)(3)(iv). FDA estimates that approximately 200 applicants under 
proposed Sec.  314.80(c)(3) will submit PSURs, and approximately 20 
applicants under proposed Sec.  600.80(c)(3) will submit PSURs. Based 
on the agency's familiarity with the content of PSURs voluntarily 
submitted to the agency, FDA estimates that it will take an average of 
40 hours for applicants to prepare and submit a PSUR to the agency. 
Preparation of a PSUR would include gathering information (proposed 
Sec. Sec.  314.80(b) and 600.80(b)) and providing attachments (proposed 
Sec. Sec.  314.80(c)(3) and 600.80(c)(3)).
    Proposed Sec. Sec.  314.80(c)(3)(iii) and 600.80(c)(3)(iii) would 
require persons holding an application (i.e., NDA, ANDA, BLA) approved 
on or after January 1, 1998, to submit an IPSR to FDA 7.5 years and 
12.5 years after U.S. approval of the application. Proposed Sec. Sec.  
314.80(c)(3)(i) and 600.80(c)(3)(i) would permit persons holding an 
application (i.e., NDA, ANDA, BLA) approved before January 1, 1998, to 
submit an IPSR at 7.5 and 12.5 years after U.S. approval of the 
application. Proposed Sec. Sec.  314.80(c)(3)(iv) and 600.80(c)(3)(iv) 
would require persons holding an approved supplement to an approved 
application for use of the human drug or biological product in the 
pediatric population to submit an IPSR (even if the supplement or 
application was approved prior to January 1, 1998) to FDA at 7.5 and 
12.5 years after U.S. approval of the supplement. Based on data 
concerning postmarketing periodic safety reports currently received by 
the agency, FDA estimates that approximately 350 IPSRs will be 
submitted annually under proposed Sec.  314.80(c)(3)(i), (c)(3)(iii), 
and (c)(3)(iv), and approximately 3 IPSRs will be submitted annually 
under proposed Sec.  600.80(c)(3)(i), (c)(3)(iii), and (c)(3)(iv). FDA 
estimates that approximately 40 applicants under proposed Sec.  
314.80(c)(3) will submit IPSRs, and approximately 3 applicants under 
proposed Sec.  600.80(c)(3) will submit IPSRs. Based on the agency's 
familiarity with the content of PSURs voluntarily submitted to the 
agency, FDA estimates that it will take an average of 30 hours for 
applicants to prepare and submit an IPSR to FDA. Preparation of an IPSR 
would include gathering information (proposed Sec. Sec.  314.80(b) and 
600.80(b)) and providing attachments (proposed Sec. Sec.  314.80(c)(3) 
and 600.80(c)(3)).
    Proposed Sec. Sec.  314.80(c)(3)(v) and 600.80(c)(3)(v) would 
require persons holding an application (i.e., NDA, ANDA, BLA) to submit 
to FDA every 6 months after U.S. approval of the application a report 
that consists of individual case safety reports (i.e., FDA Form 3500As, 
VAERS forms for vaccines, CIOMS I forms, if desired, for foreign SADRs) 
for certain spontaneously reported SADRs for marketed human drug and 
biological products. Applicants that submit TPSRs to FDA would submit a 
report consisting of individual case safety reports for each 
spontaneously reported serious, expected SADR, whether domestic or 
foreign, and each spontaneously reported nonserious, unexpected SADR 
occurring in the United States during the reporting period. Reports for 
vaccines would include a VAERS form for each spontaneously reported 
nonserious, expected SAR and each expected SAR with unknown outcome 
occurring in the United States during the reporting period. Applicants 
that submit PSURs or IPSRs to FDA would submit a report consisting of 
individual case safety reports for each spontaneously reported serious, 
listed SADR, whether domestic or foreign, and each spontaneously 
reported nonserious, unlisted SADR occurring in the United States 
during the reporting period. Reports for vaccines would include a VAERS 
form for each spontaneously reported nonserious, listed SAR and each 
listed SAR with unknown outcome occurring in the United States during 
the reporting period. If a full data set is not available for a report 
of a serious SADR, the reason(s) for the lack of such information would 
be provided. Based on data concerning postmarketing periodic safety 
reports currently received by the agency, FDA estimates that 
approximately 4,726 of these reports will be submitted annually under 
proposed Sec.  314.80(c)(3)(v), and approximately 480 of these reports 
will be submitted annually under proposed Sec.  600.80(c)(3)(v). FDA 
estimates that approximately 285 applicants under proposed Sec.  
314.80(c)(3) will submit these reports, and approximately 69 applicants 
under proposed Sec.  600.80(c)(3) will submit reports. Based on the 
agency's familiarity with the content of postmarketing periodic safety 
reports, FDA estimates that it will take an average of 120 hours for 
applicants to prepare and submit a report under proposed Sec. Sec.  
314.80(c)(3)(v) and 600.80(c)(3)(v) to the agency. Preparation of a 
report under proposed Sec. Sec.  314.80(c)(3)(v) and 600.80(c)(3)(v) 
would include gathering information (proposed Sec. Sec.  314.80(b) and 
(c)(1), and 600.80(b) and (c)(1)), providing attachments, if applicable 
(proposed Sec. Sec.  314.80(c)(2)(ix) and (c)(3), and 600.80(c)(2)(ix) 
and (c)(3)), and formatting information (proposed Sec. Sec.  
314.80(c)(4) and (e), and 600.80(c)(4) and (e)).

VI.C. Other Reports

    Proposed Sec. Sec.  310.305(f)(1), 314.80(f), and 600.80(f) would 
require manufacturers, applicants, contractors, and shared 
manufacturers to submit to FDA, when appropriate, any or all records 
required to be maintained by these persons. These records would be 
required to be submitted within 5 calendar days after receipt of the 
request by the person. Records of all safety information pertaining to 
the person's product, received or otherwise obtained, including raw 
data, any correspondence relating to the safety information, and any 
reports of SADRs or medication errors not submitted to FDA or only 
provided to FDA in a summary tabulation would be included, as well as 
records required to be maintained under proposed Sec.  310.305 (Sec.  
310.305(c)(1)(ii), (c)(1)(iii)(A), (c)(2)(ii), (c)(2)(viii)(A), and 
(c)(2)(xi)(C)), proposed Sec.  314.80 (Sec.  314.80(c)(1)(ii), 
(c)(1)(iii)(A), (c)(2)(ii), (c)(2)(viii)(A), and (c)(2)(x)(C)), and 
proposed Sec.  600.80 (Sec.  600.80(c)(1)(ii), (c)(1)(iii)(A), 
(c)(2)(ii), (c)(2)(viii)(A), and (c)(2)(x)(C)). Submission of SADR 
records to FDA represents a new reporting requirement. Based on the 
agency's requests for voluntary

[[Page 12469]]

submission of safety records, FDA estimates that approximately 2 
requests for submission of records will be fulfilled annually under 
proposed Sec.  310.305(f)(1), approximately 15 requests for submission 
of records will be fulfilled annually under proposed Sec.  314.80(f), 
and approximately 4 requests for submission of records will be 
fulfilled annually under proposed Sec.  600.80(f). FDA estimates that 
approximately 2 manufacturers and contractors under proposed Sec.  
310.305 will submit these records, approximately 15 applicants and 
contractors under proposed Sec.  314.80 will submit these records, and 
approximately 4 applicants, contractors and shared manufacturers under 
proposed Sec.  600.80 will submit these records. Based on the volume of 
safety information voluntarily submitted to FDA in response to an 
agency request for such information, FDA estimates that it will take an 
average of 8 hours for manufacturers, applicants, contractors, and 
shared manufacturers to fulfill each request for submission of records 
to the agency.
    Proposed Sec.  314.81(b)(2) would require applicants of marketed 
drug products subject to an NDA to submit an annual report to FDA 
within 60 days of the anniversary date of U.S. approval of the 
application. This report would contain summary information; 
distribution data; chemistry, manufacturing, and controls changes; 
clinical data; and a status report of any postmarketing studies 
performed by, or on behalf of, the applicant. Based on data concerning 
the number of approved NDA annual reports received by the agency, FDA 
estimates that approximately 2,363 reports will be submitted under 
proposed Sec.  314.81(b)(2). FDA estimates that approximately 286 
applicants will submit these reports. Based on the agency's familiarity 
with the content of approved NDA annual reports, FDA estimates that it 
will take an average of 35.5 hours for applicants to prepare and submit 
one of these annual reports to FDA.
    Proposed Sec.  601.28 would require applicants of licensed 
biological products to submit an annual report of postmarketing 
pediatric studies to FDA within 60 days of the anniversary date of 
approval of the application. This report would contain summary 
information, clinical data in the pediatric population, and a status 
report of any postmarketing studies in the pediatric population. Based 
on data concerning the number of approved BLA annual reports received 
by the agency, FDA estimates that approximately 69 reports will be 
submitted under proposed Sec.  601.28. FDA estimates that approximately 
69 applicants will submit these reports. Based on the agency's 
familiarity with the content of approved BLA annual reports, FDA 
estimates that it will take an average of 25 hours for applicants to 
prepare and submit an annual report to the agency.

VI.D. Recordkeeping

    Proposed Sec. Sec.  310.305(c)(2)(xi)(B), 314.80(c)(2)(x)(B), and 
600.80(c)(2)(x)(B) would require that contracts between manufacturers 
and contractors (proposed Sec.  310.305(c)(2)(xi)(B)) and applicants 
and contractors (proposed Sec. Sec.  314.80(c)(2)(x)(B) and 
600.80(c)(2)(x)(B)) specify the safety reporting responsibilities of 
the contractor. For purposes of this section, a record represents a 
contract. Based on information contained in individual case safety 
reports submitted to the agency in the past (i.e., report source), FDA 
estimates that approximately 4 records will be maintained annually 
under proposed Sec.  310.305(c)(2)(xi)(B), approximately 480 records 
will be maintained annually under proposed Sec.  314.80(c)(2)(x)(B), 
and approximately 2 records will be maintained annually under proposed 
Sec.  600.80(c)(2)(x)(B). FDA estimates that approximately 2 
manufacturers under proposed Sec.  310.305 will maintain these records, 
approximately 160 applicants under proposed Sec.  314.80 will maintain 
these records, and approximately 2 applicants under proposed Sec.  
600.80 will maintain these records. Based on the agency's familiarity 
with recordkeeping processes, FDA estimates that it will take an 
average of 1 hour for manufacturers and applicants to maintain each 
record annually under proposed Sec. Sec.  310.305(c)(2)(xi)(B), 
314.80(c)(2)(x)(B), and 600.80(c)(2)(x)(B).
    Proposed Sec. Sec.  310.305(f), 314.80(f), and 600.80(f) would 
require manufacturers, applicants, contractors, and shared 
manufacturers to maintain for a period of 10 years records of all 
safety information, received or otherwise obtained, including raw data; 
any correspondence relating to the safety information; and any reports 
of SADRs or medication errors not submitted to FDA or only provided to 
FDA in a summary tabulation. These persons would also be required to 
retain for a period of 10 years any records required to be maintained 
under proposed Sec.  310.305 (Sec.  310.305(c)(1)(ii), (c)(1)(iii)(A), 
(c)(2)(ii), (c)(2)(viii)(A), and (c)(2)(xi)(C)), proposed Sec.  314.80 
(Sec.  314.80(c)(1)(ii), (c)(1)(iii)(A), (c)(2)(ii), (c)(2)(viii)(A), 
and (c)(2)(x)(C)), and proposed Sec.  600.80 (Sec.  600.80(c)(1)(ii), 
(c)(1)(iii)(A), (c)(2)(ii), (c)(2)(viii)(A), and (c)(2)(x)(C)). For the 
purposes of this section, a record includes any and all documentation 
regarding an individual SADR or medication error. Based on data 
concerning the number of SADRs currently reported to the agency, FDA 
estimates that approximately 500 records will be maintained annually 
under proposed Sec.  310.305(f), approximately 220,000 records will be 
maintained annually under proposed Sec.  314.80(f), and approximately 
20,000 records will be maintained annually under proposed Sec.  
600.80(f). FDA estimates that approximately 25 manufacturers and 
contractors under proposed Sec.  310.305 will maintain these records, 
approximately 700 applicants and contractors under proposed Sec.  
314.80 will maintain these records, and approximately 69 applicants, 
contractors, and shared manufacturers under proposed Sec.  600.80 will 
maintain these records. Based on the agency's familiarity with 
recordkeeping processes, FDA estimates that it will take an average of 
5 hours for manufacturers, applicants, contractors, and shared 
manufacturers to maintain each record annually under proposed 
Sec. Sec.  310.305, 314.80, and 600.80.
    Proposed Sec. Sec.  310.305(g), 314.80(g), and 600.80(g) would 
require manufacturers, applicants, contractors, and shared 
manufacturers to maintain written procedures for the surveillance, 
receipt, evaluation, and reporting of safety information to FDA. Based 
on the number of persons subject to the postmarketing safety reporting 
regulations, FDA estimates that approximately 25 records will be 
maintained annually under proposed Sec.  310.305(g), approximately 700 
records will be maintained annually under proposed Sec.  314.80(g), and 
approximately 69 records will be maintained annually under proposed 
Sec.  600.80(g). FDA estimates that approximately 25 manufacturers and 
contractors under proposed Sec.  310.305 will maintain these records, 
approximately 700 applicants and contractors under proposed Sec.  
314.80 will maintain these records, and approximately 69 applicants, 
contractors, and shared manufacturers under proposed Sec.  600.80 will 
maintain these records. Based on the agency's familiarity with 
recordkeeping processes, FDA estimates that it will take an average of 
1 hour for manufacturers, applicants, contractors, and shared 
manufacturers to maintain a record of the written procedures

[[Page 12470]]

annually under proposed Sec. Sec.  310.305(g), 314.80(g), and 
600.80(g).
    Proposed Sec.  312.32(c) would require sponsors to maintain records 
for reports of SADRs that do not contain a minimum data set. This would 
include any information received or otherwise obtained for the SADR 
along with a record of their efforts to obtain a minimum data set for 
the report. For the purposes of this section, a record includes any and 
all documentation regarding an individual SADR. Maintaining records of 
SADRs that do not contain a minimum data set represents a new 
recordkeeping requirement. Based on information contained in IND safety 
reports, FDA estimates that approximately 200 records will be 
maintained annually under proposed Sec.  312.32(c) for human drugs; 
approximately 240 records will be maintained annually under proposed 
Sec.  312.32(c) for human biological products. FDA estimates that 
approximately 50 sponsors will maintain these records for human drugs 
and approximately 60 sponsors will maintain these records for human 
biological products. Based on the agency's familiarity with 
recordkeeping processes, FDA estimates that it will take an average of 
1 hour for sponsors to maintain each record annually under proposed 
Sec.  312.32(c).
    Proposed Sec.  606.170(a) would require blood collection and 
transfusing facilities to maintain records for complaints of SARs 
regarding each unit of blood or blood product. These facilities must 
prepare a written report of the investigation of SARs, including 
followup and conclusions. Based on data for records currently 
maintained by blood collection and transfusing facilities, FDA 
estimates that approximately 4,512 records will be maintained annually 
under proposed Sec.  606.170(a). FDA estimates that approximately 376 
facilities will maintain these records. Based on the agency's 
familiarity with recordkeeping processes, FDA estimates that it will 
take an average of 12 hours for facilities to maintain each record 
annually under proposed Sec.  606.170(a).
    Description of Respondents: Business or other for-profit 
organizations.
    In compliance with section 3507(d) of the Paperwork Reduction Act 
of 1995 (44 U.S.C. 3507(d)), the agency has submitted a copy of this 
proposed rule to OMB for its review and approval of these information 
collections. Interested persons are requested to send comments 
regarding this information collection, including suggestions for 
reducing this burden, to the Office of Information and Regulatory 
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., rm. 10235, 
Washington, DC 20503, OMB, Attn: Stuart Shapiro, Desk Officer for FDA, 
FAX: 202-395-6974. Submit written comments on the information 
collection by April 14, 2003.

                                Table 21.--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                    Number of
         21 CFR section             Number of     responses per    Total annual      Hours per      Total hours
                                   respondents      respondent       responses       response
----------------------------------------------------------------------------------------------------------------
310.305(c)(2)(i) \2\...........              14             25               350              16           5,600
310.305(c)(2)(ii)..............               5              1                 5               8              40
310.305(c)(2)(iii).............              10              4.6              46              24           1,104
310.305(c)(2)(iv)..............              10              5                50              16             800
310.305(c)(2)(v)...............              10            100             1,000              16          16,000
310.305(c)(2)(vi)..............               7             48.6             340               8           2,720
310.305(b)(2), (c)(2)(vii), and              10              5.5              55               4             220
 (c)(2)(viii)(A)...............
310.305(c)(2)(xi)..............               5              2                10               2              20
310.305(f)(1)..................               2              1                 2               8              16
312.32(c)(1)(i) \3\--human                  457             10.6           4,860              16          77,760
 drugs.........................
312.32(c)(1)(ii)--human drugs..             100              3               300               8           2,400
312.32(c)(2)--human drugs......             135              3.6             490               4           1,960
312.32(c)(1)(i)--human                      602              4.9           2,980              16          47,680
 biological products...........
312.32(c)(1)(ii)--human                     100              3               300               8           2,400
 biological products...........
312.32(c)(2)--human biological              180              1.6             290               4           1,160
 products......................
312.64(b)--human drugs.........          10,000             10           100,000               2         200,000
312.64(b)--human biological               6,000             10            60,000               2         120,000
 products......................
314.80(c)(2)(i) \4\............             282            177.3          50,000              16         800,000
314.80(c)(2)(ii)...............              50              6               300               8           2,400
314.80(c)(2)(iii)..............             109              8.4             912              24          21,888
314.80(c)(2)(iv)...............             100             15             1,500              16          24,000
314.80(c)(2)(v)................             150            666.7         100,000              16       1,600,000
314.80(c)(2)(vi)...............             140            307.1          43,000               8         344,000
314.80(b)(2), (c)(2)(vii), and              184             54.3          10,000               4          40,000
 (c)(2)(viii)(A)...............
314.80(c)(2)(x)................             100            113.7          11,370               2          22,740
314.80(c)(3)(i)................              80             17.5           1,400              20          28,000
314.80(c)(3)(i), (c)(3)(ii),                200             12.5           2,500              40         100,000
 and (c)(3)(iv)................
314.80(c)(3)(i), (c)(3)(iii),                40              8.7             350              30          10,500
 and (c)(3)(iv)................
314.80(c)(3)(v)................             285             16.6           4,726             120         567,120
314.80(f)......................              15              1                15               8             120
314.81(b)(2)...................             286              8.3           2,363            35.5          83,886
320.31(d)(3)...................              10             20               200              14           2,800
600.80(c)(2)(i) \5\............              69             43.5           3,000              16          48,000
600.80(c)(2)(ii)...............               4              1                 4               8              32
600.80(c)(2)(iii)..............              12              2.1              25              24             600
600.80(c)(2)(iv)...............              10             10               100              16           1,600
600.80(c)(2)(v)................              30            333.3          10,000              16         160,000
600.80(c)(2)(vi)...............              69             43.5           3,000               8          24,000
600.80(b)(2), (c)(2)(vii), and               69             14.5           1,000               4           4,000
 (c)(2)(viii)(A)...............
600.80(c)(2)(x)................              20             12.5             250               2             500
600.80(c)(3)(i)................              20              1.8              35              20             700
600.80(c)(3)(i), (c)(3)(ii),                 20              1.8              35              40           1,400
 and (c)(3)(iv)................

[[Page 12471]]

 
600.80(c)(3)(i), (c)(3)(iii),                 3              1                 3              30              90
 and (c)(3)(iv)................
600.80(c)(3)(v)................              69              6.9             480             120          57,600
600.80(f)......................               4              1                 4               8              32
601.28.........................              69              1                69              25           1,725
606.170(b).....................           3,062              2.3           7,000              16         112,000
606.170(c).....................              75              1                75              20           1,500
                                -----------------
    Total......................          23,283          2,149.7         424,794           896.5      4,541,113
----------------------------------------------------------------------------------------------------------------
\1\ The estimates provided in this table are not only attributed to the new proposed requirements in this
  rulemaking but also include burdens associated with our current safety reporting requirements. There are no
  capital costs or operating and maintainence costs associated with this collection of information.
\2\ The paragraphs of Sec.   310.305 cited in the table include burdens associated with gathering information
  under Sec.   310.305(b) and (c)(1), providing attachments, if applicable, under Sec.   310.305(c)(2)(ix) and
  (c)(2)(x), and formatting information under Sec.   310.305(c)(2)(xii), (d), and (e).
\3\ The paragraphs of Sec.   312.32 cited in the table include burdens associated with gathering information
  under Sec.   312.32(b) and formatting information under Sec.   312.32(c)(1)(iii).
\4\ The paragraphs of Sec.   314.80 cited in the table include burdens associated with gathering information
  under Sec.   314.80(b) and (c)(1), providing attachments, if applicable, under Sec.   314.80(c)(2)(ix) and
  (c)(3), and formatting information under Sec.   314.80(c)(2)(xi), (c)(4), and (e).
\5\ The paragraphs of Sec.   600.80 cited in the table include burdens associated with gathering information
  under Sec.   600.80(b) and (c)(1), providing attachments, if applicable, under Sec.   600.80(c)(2)(ix) and
  (c)(3), and formatting information under Sec.   600.80(c)(2)(xi), (c)(4), and (e).


                              Table 22.--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Annual
        21 CFR section             Number of      frequency of     Total  annual     Hours per      Total hours
                                 recordkeepers    recordkeeping       records         record
----------------------------------------------------------------------------------------------------------------
310.305(c)(2)(xi)(B)..........               2               2                 4               1               4
310.305(f) \2\................              25              20               500               5           2,500
310.305(g)....................              25               1                25               1              25
312.32(c)--human drugs........              50               4               200               1             200
312.32(c)--human biological                 60               4               240               1             240
 products.....................
314.80(c)(2)(x)(B)............             160               3               480               1             480
314.80(f) \3\.................             700             314.3         220,000               5       1,100,000
314.80(g).....................             700               1               700               1             700
600.80(c)(2)(x)(B)............               2               1                 2               1               2
600.80(f) \4\.................              69             289.8          20,000               5         100,000
600.80(g).....................              69               1                69               1              69
606.170(a)....................             376              12             4,512              12          54,144
    Total.....................           2,238             653.1         246,732              35      1,258,364
----------------------------------------------------------------------------------------------------------------
\1\ The estimates provided in this table are not only attributed to the new proposed requirements in this
  rulemaking but also include burdens associated with our current safety reporting requirements. There are no
  capital costs or operating costs associated with this collection of information. There are maintenance costs
  of $2,025 annually per recordkeeper ($2,000 annually per recordkeeper for existing recordkeeping requirements
  (see 67 FR 47821) and $25 annually per recordkeeper for new proposed requirements in this rulemaking).
\2\ Includes records required to be maintained under Sec.   310.305(c)(1)(ii), (c)(1)(iii)(A), (c)(2)(ii),
  (c)(2)(viii)(A), and (c)(2)(xi)(C).
\3\ Includes records required to be maintained under Sec.   314.80(c)(1)(ii), (c)(1)(iii)(A), (c)(2)(ii),
  (c)(2)(viii)(A), and (c)(2)(x)(C).
\4\ Includes records required to be maintained under Sec.   600.80(c)(1)(ii), (c)(1)(iii)(A), (c)(2)(ii),
  (c)(2)(viii)(A), and (c)(2)(x)(C).

VII. Executive Order 13132: Federalism

    Executive Order 13132 requires Federal agencies to carefully 
examine regulatory actions to determine if they would have a 
significant impact on federalism. Using the criteria and principles set 
forth in the Executive order, the agency has considered the impact of 
this proposed rule on the States, on their relationship with the 
Federal Government, and on the distribution of power and 
responsibilities among the various levels of government.
    FDA is publishing this proposed rule to revise its regulations 
governing the format, content, and submission of safety reports to the 
agency for human drugs and biological products. The proposal would 
revise current regulations to implement definitions and reporting 
formats and standards recommended by ICH and CIOMS. The proposal would 
codify the agency's expectations for timely acquisition, evaluation, 
and submission of relevant safety information for marketed drugs and 
biological products. The proposal would require that postmarketing 
individual case safety reports of unexpected SADRs that cannot be 
classified as either serious or nonserious be submitted to the agency 
in an expedited manner. The proposal would also require that certain 
medically significant SADRs always be submitted to FDA in an expedited 
manner whether the SADR is unexpected or expected. The proposal would 
also require that all domestic reports of medication errors, whether 
actual or potential, be submitted to FDA in an expedited manner. The 
proposal would clarify certain safety reporting requirements and make 
other minor revisions. The proposal would also amend the agency's 
postmarketing annual reports regulations for applicants of human drugs 
and licensed biological products to revise the content for these 
reports. The proposal would also amend the agency's bioavailability and 
bioequivalence study regulations for sponsors of human drugs to require 
expedited safety reports for certain studies which are exempt from 
submission of an IND. Because enforcement of these safety reporting 
requirements would be a Federal responsibility, there would be little, 
if

[[Page 12472]]

any, impact on the States from this rule if finalized.
    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the rule does not contain policies that have substantial direct effects 
on the States, on the relationship between National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

List of Subjects

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 320

    Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

21 CFR Part 606

    Blood, Labeling, Laboratories, Reporting and recordkeeping 
requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 310, 
312, 314, 320, 600, 601, and 606 be amended as follows:

PART 310--NEW DRUGS

    1. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 
263b-263n.
    2. Section 310.305 is revised to read as follows:


Sec.  310.305  Safety reporting and recordkeeping for manufacturers of 
prescription drugs marketed for human use without an approved 
application.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Active query means direct verbal contact (i.e., in person or by 
telephone or other interactive means such as a video conference) with 
the initial reporter of a suspected adverse drug reaction (SADR) or a 
medication error by a health care professional (e.g., physician, 
physician assistant, pharmacist, dentist, nurse, any individual with 
some form of health care training) representing the manufacturer. For 
SADRs, active query entails, at a minimum, a focused line of 
questioning designed to capture clinically relevant information 
associated with the drug product and the SADR, including, but not 
limited to, information such as baseline data, patient history, 
physical exam, diagnostic results, and supportive lab results.
    Actual medication error means a medication error that involves an 
identifiable patient whether the error was prevented prior to 
administration of the product or, if the product was administered, 
whether the error results in a serious SADR, nonserious SADR, or no 
SADR.
    Contractor means any person (e.g., packer or distributor whether or 
not its name appears on the label of the product; licensee; contract 
research organization) that has entered into a contract with the 
manufacturer to manufacture, pack, sell, distribute, or develop the 
drug or to maintain, create, or submit records regarding SADRs or 
medication errors.
    Disability means a substantial disruption of a person's ability to 
conduct normal life functions.
    Full data set means completion of all the applicable elements on 
FDA Form 3500A (or on a Council for International Organizations of 
Medical Sciences (CIOMS) I form for reports of foreign SADRs), 
including a concise medical narrative of the case (i.e., an accurate 
summary of the relevant data and information pertaining to an SADR or 
medication error).
    Life-threatening SADR means any SADR that, in the view of the 
initial reporter, places the patient at immediate risk of death from 
the SADR as it occurred. It does not include an SADR that, had it 
occurred in a more severe form, might have caused death.
    Medication error means any preventable event that may cause or lead 
to inappropriate medication use or patient harm while the medication is 
in the control of the health care professional, patient, or consumer. 
Such events may be related to professional practice, health care 
products, procedures, and systems including: Prescribing; order 
communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; 
monitoring; and use.
    Minimum data set means the report includes an identifiable patient, 
an identifiable reporter, a suspect drug product, and an SADR.
    Nonserious SADR means any SADR that is determined not to be a 
serious SADR.
    Potential medication error means an individual case safety report 
of information or complaint about product name, labeling, or packaging 
similarities that does not involve a patient.
    SADR with unknown outcome means an SADR that cannot be classified, 
after active query, as either serious or nonserious.
    Serious SADR means any SADR that results in any of the following 
outcomes: Death, a life-threatening SADR, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious SADR when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
    Spontaneous report means a communication from an individual (e.g., 
health care professional, consumer) to a company or regulatory 
authority that describes an SADR or medication error. It does not 
include cases identified from information solicited by the manufacturer 
or contractor, such as individual case safety reports or findings 
derived from a study, company-sponsored patient support program, 
disease management program, patient registry, including pregnancy

[[Page 12473]]

registries, or any organized data collection scheme. It also does not 
include information compiled in support of class action lawsuits.
    Suspected adverse drug reaction (SADR) means a noxious and 
unintended response to any dose of a drug product for which there is a 
reasonable possibility that the product caused the response. In this 
definition, the phrase ``a reasonable possibility'' means that the 
relationship cannot be ruled out.
    Unexpected SADR means any SADR that is not included in the current 
U.S. labeling for the drug product. Reactions that may be 
symptomatically and pathophysiologically related to a reaction included 
in the U.S. labeling, but differ from the labeled reaction because of 
greater severity or specificity, would be unexpected. For example, 
under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the U.S. labeling only referred to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the U.S. labeling only included cerebral vascular 
accidents. ``Unexpected,'' as used in this definition, refers to an 
SADR that has not been previously observed (i.e., included in the U.S. 
labeling); it does not refer to an SADR that might be anticipated from 
the pharmacological properties of the drug product. SADRs that are 
mentioned in the U.S. labeling as occurring with a class of drugs but 
not specifically mentioned as occurring with the particular drug are 
considered unexpected.
    (b) Review of safety information. (1) Each manufacturer of a 
prescription drug product marketed for human use without an approved 
application must promptly review all safety information pertaining to 
its product obtained or otherwise received by the manufacturer from any 
source, foreign or domestic, including information derived from 
commercial marketing experience, postmarketing clinical investigations, 
postmarketing epidemiology/surveillance studies, animal or in vitro 
studies, electronic communications with manufacturers via the Internet 
(e.g., e-mail), reports in the scientific literature, and unpublished 
scientific papers, as well as reports from foreign regulatory 
authorities that have not been previously reported to the Food and Drug 
Administration (FDA) by the manufacturer.
    (2) Individual case safety reports that are forwarded to the 
manufacturer by FDA must not be resubmitted to the agency by the 
manufacturer; however, manufacturers must submit to FDA all followup 
information for these reports.
    (c) Reporting requirements. The manufacturer must submit to FDA one 
copy of each expedited report (described under paragraphs (c)(2)(i) 
through (c)(2)(vii) of this section) pertaining to its drug product. 
Upon written notice, FDA may require, when appropriate, that the 
manufacturer submit reports under this section to FDA at times other 
than those stated.
    (1) Determination of outcome, minimum data set, and full data set--
(i)(A) Initial determinations. Upon initial receipt of an SADR report, 
the manufacturer must immediately determine, the outcome for the SADR 
(whether the SADR is serious or nonserious) and at least the minimum 
data set for the individual case safety report. For reports of actual 
medication errors that do not result in an SADR and potential 
medication errors, the manufacturer must immediately determine the 
minimum information for the individual case safety report (minimum 
information described under paragraphs (c)(1)(iii)(B) and 
(c)(1)(iii)(C) of this section). If the manufacturer is not able to 
immediately determine the information in this paragraph, active query 
must be used to obtain it as soon as possible.
    (B) Spontaneous reports. For spontaneous reports, the manufacturer 
must always assume, for safety reporting purposes under this section, 
that there is at least a reasonable possibility, in the opinion of the 
initial reporter, that the drug product caused the spontaneously 
reported event.
    (C) Clinical trials. For a clinical trial, the possibility that the 
drug product caused the SADR or that a medication error has occurred 
must be assumed if either the investigator or the manufacturer believes 
that such a reasonable possibility exists.
    (ii) SADRs with unknown outcome. For an SADR with unknown outcome 
that cannot be immediately determined, the manufacturer must continue 
to use active query to attempt to determine the outcome of the SADR 
within 30 calendar days after initial receipt of the SADR report by the 
manufacturer. The manufacturer must maintain a record of its efforts to 
determine the outcome for an SADR with unknown outcome.
    (iii)(A) Minimum data set for SADR reports. The manufacturer must 
not submit an individual case safety report for an SADR to FDA if the 
report does not contain a minimum data set; instead, the manufacturer 
must maintain records of any information received or otherwise obtained 
for the SADR along with a record of its efforts to obtain a minimum 
data set.
    (B) Minimum information for reports of actual medication errors 
that do not result in an SADR. For reports of actual medication errors 
that do not result in an SADR, an individual case safety report must be 
submitted to FDA even though the report does not contain a minimum data 
set (i.e., does not have an SADR). These reports must contain at least 
an identifiable patient, an identifiable reporter, and a suspect drug 
product.
    (C) Minimum information for potential medication error reports. For 
reports of potential medication errors, an individual case safety 
report must be submitted to FDA even though the report does not contain 
a minimum data set (i.e., does not have an identifiable patient or an 
SADR). These reports must contain at least an identifiable reporter and 
a suspect drug product.
    (iv) Full data set. For reports of serious SADRs, always expedited 
reports (see paragraph (c)(2)(iv) of this section), and medication 
error reports (see paragraph (c)(2)(v) of this section), the 
manufacturer must submit a full data set. If a full data set is not 
available for the report, the manufacturer must use active query to 
obtain this information. If a full data set is not obtainable, after 
active query, the manufacturer must:
    (A) Submit all safety information, received or otherwise obtained, 
for the report;
    (B) Indicate the reason(s) for its inability to acquire a full data 
set; and
    (C) Document its efforts to obtain a full data set (i.e., 
description of unsuccessful steps taken to obtain this information).
    (v) Serious SADRs not initially reported by health care 
professional. For a serious SADR that was not initially reported to the 
manufacturer by a health care professional (e.g., report from a 
consumer), the manufacturer must contact the health care professional 
associated with the care of the patient using active query to gather 
further medical perspective on the case and to acquire a full data set 
for the report. If the manufacturer is unable to contact the health 
care professional, it must include in the report for the serious SADR:
    (A) The reason(s) for its inability to contact the health care 
professional; and
    (B) A description of its efforts to contact the health care 
professional.
    (2) Postmarketing ``expedited reports''--(i) Serious and unexpected 
SADR. The manufacturer must report to FDA each SADR, received or 
otherwise obtained, that is both serious and

[[Page 12474]]

unexpected, whether foreign or domestic, as soon as possible, but in no 
case later than 15 calendar days after receipt by the manufacturer of 
the minimum data set for the serious, unexpected SADR. If a full data 
set is not available for the serious and unexpected SADR report at the 
time of initial submission of the report to FDA, the manufacturer must 
submit the information required under paragraph (c)(1)(iv) of this 
section and also submit a 30-day followup report as required by 
paragraph (c)(2)(vi) of this section.
    (ii) Information sufficient to consider product administration 
changes. The manufacturer must also report to FDA information, received 
or otherwise obtained, whether foreign or domestic, that would be 
sufficient, based upon appropriate medical judgment, to consider 
changes in product administration. The manufacturer must submit this 
information to FDA, as soon as possible, but in no case later than 15 
calendar days after determination by the manufacturer that the 
information qualifies for expedited reporting. Examples of such 
information include any significant unanticipated safety finding or 
data in the aggregate from an in vitro, animal, epidemiological, or 
clinical study, whether or not conducted under an investigational new 
drug application (IND), that suggests a significant human risk, such as 
reports of mutagenicity, teratogenicity, or carcinogenicity, or reports 
of a lack of efficacy with a drug product used in treating a life-
threatening or serious disease. The manufacturer must maintain a record 
of its efforts to determine whether the information required to be 
reported under this paragraph qualifies for expedited reporting.
    (iii) Unexpected SADR with unknown outcome. The manufacturer must 
also report to FDA each SADR that is unexpected and for which the 
determination of an outcome is unattainable (i.e., SADR with unknown 
outcome) within 45 calendar days after initial receipt by the 
manufacturer of the minimum data set for the unexpected SADR. The 
manufacturer must document in the expedited report the reason(s) for 
the inability to determine the outcome.
    (iv) Always expedited report. (A) The manufacturer must also report 
to FDA each SADR, received or otherwise obtained, whether foreign or 
domestic, that is the subject of an always expedited report. These 
reports must be submitted to FDA as soon as possible, but in no case 
later than 15 calendar days after receipt by the manufacturer of the 
minimum data set for the report. The following medically significant 
SADRs, which may jeopardize the patient or subject and/or require 
medical or surgical intervention to treat the patient or subject, are 
subject to an always expedited report:
    (1) Congenital anomalies,
    (2) Acute respiratory failure,
    (3) Ventricular fibrillation,
    (4) Torsades de pointe,
    (5) Malignant hypertension,
    (6) Seizure,
    (7) Agranulocytosis,
    (8) Aplastic anemia,
    (9) Toxic epidermal necrolysis,
    (10) Liver necrosis,
    (11) Acute liver failure,
    (12) Anaphylaxis,
    (13) Acute renal failure,
    (14) Sclerosing syndromes,
    (15) Pulmonary hypertension,
    (16) Pulmonary fibrosis,
    (17) Confirmed or suspected transmission of an infectious agent by 
a marketed drug or biological product,
    (18) Confirmed or suspected endotoxin shock, and
    (19) Any other medically significant SADR that FDA determines to be 
the subject of an always expedited report (i.e., may jeopardize the 
patient or subject and/or require medical or surgical intervention to 
treat the patient or subject).
    (B) SADRs that are the subject of an always expedited report must 
be submitted to FDA whether unexpected or expected and whether or not 
the SADR leads to a serious outcome. If a full data set is not 
available for an always expedited report at the time of initial 
submission of the report to FDA, the manufacturer must submit the 
information required under paragraph (c)(1)(iv) of this section and 
also submit a 30-day followup report as required by paragraph 
(c)(2)(vi) of this section.
    (v) Medication errors--(A) Actual medication error. The 
manufacturer must also submit to FDA each domestic report of an actual 
medication error, received or otherwise obtained, as soon as possible, 
but in no case later than 15 calendar days after receipt by the 
manufacturer of the minimum data set for a report of an SADR or, if an 
SADR does not occur, the minimum information described under paragraph 
(c)(1)(iii)(B) of this section (i.e., identifiable patient, 
identifiable reporter, and suspect drug product).
    (B) Potential medication error. The manufacturer must also submit 
to FDA each domestic report of a potential medication error, received 
or otherwise obtained, as soon as possible, but in no case later than 
15 calendar days after receipt by the manufacturer of the minimum 
information described under paragraph (c)(1)(iii)(C) of this section 
(i.e., identifiable reporter and suspect drug product).
    (C) Full data set. If a full data set is not available for an 
actual or potential medication error report at the time of initial 
submission of the report to FDA, the manufacturer must submit the 
information required under paragraph (c)(1)(iv) of this section and 
also submit a 30-day followup report as required by paragraph 
(c)(2)(vi) of this section.
    (vi) The 30-day followup report. The manufacturer must use active 
query to obtain additional information for any expedited report under 
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that 
does not contain a full data set and must submit a followup report to 
FDA within 30 calendar days after initial submission of the expedited 
report to FDA by the manufacturer. If a full data set is still not 
obtainable, the 30-day followup report must contain the information 
required under paragraph (c)(1)(iv) of this section. Any new safety 
information in the 30-day followup report must be highlighted. Any new 
information, received or otherwise obtained, after submission of a 30-
day followup report must be submitted to FDA as a 15-day followup 
report under paragraph (c)(2)(vii) of this section.
    (vii) The 15-day followup report. The manufacturer must report to 
FDA any new information, received or otherwise obtained, for any 
expedited or followup report (except for initial expedited reports 
under paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section 
that do not contain a full data set) within 15 calendar days of initial 
receipt of the new information by the manufacturer. Expedited reports 
under paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section 
that do not contain a full data set at the time of initial submission 
of the report to FDA are subject to the 30-day followup reporting 
requirements under paragraph (c)(2)(vi) of this section rather than the 
15-day followup reporting requirements under this paragraph.
    (viii) Supporting documentation. (A) If the patient dies, the 
manufacturer must submit a copy of the autopsy report to FDA, if it is 
available. If an autopsy report is not available, the manufacturer must 
submit a death certificate to FDA. If an autopsy report becomes 
available after the manufacturer has submitted a death certificate to 
the agency, the autopsy report must be submitted to FDA. If the patient 
was hospitalized, the manufacturer must submit a copy of the hospital 
discharge summary to FDA, if it is available. If any of these documents 
is not in English, the document must be

[[Page 12475]]

accompanied by an English translation. Manufacturers must use active 
query to obtain these documents. These documents must be submitted to 
FDA as 15-day followup reports (see paragraph (c)(2)(vii) in this 
section) within 15 calendar days of initial receipt of the document by 
the manufacturer. If these documents are not submitted to FDA in a 15-
day followup report within 3 months after submission of the initial 
expedited report for the death or hospitalization, the agency will 
assume that active query by the manufacturer has not resulted in access 
to these documents. In this case, a record of the reason(s) for the 
lack of such documentation and the effort that was made to obtain the 
documentation must be maintained by the manufacturer.
    (B) Each expedited report must contain in the narrative a list of 
other relevant documents (e.g., medical records, laboratory results, 
data from studies) for the report that are maintained by the 
manufacturer. When appropriate, FDA may require a manufacturer to 
submit copies of one or more of these documents to the agency within 5 
calendar days after receipt of the request.
    (ix) Scientific literature. An expedited report based on 
information from the scientific literature applies only to reports 
found in scientific and medical journals. These expedited reports must 
be accompanied by a copy of the published article.
    (x) Attachments. Each expedited report must be accompanied by a 
copy of the current U.S. labeling for the drug product and a list of 
current addresses where all safety reports and other safety-related 
records for the drug product are maintained by manufacturers and 
contractors.
    (xi) Submission of safety reports by contractors. (A) Contractors 
must submit to the manufacturer safety reports of any SADRs or 
medication errors for the manufacturer's drug product, obtained or 
otherwise received, within 5 calendar days of initial receipt of the 
report by the contractor. The contractor must submit a safety report 
for an SADR to the manufacturer even if the report does not contain a 
minimum data set. Upon receipt of the safety report from a contractor, 
the manufacturer must comply with the postmarketing safety reporting 
requirements of this section.
    (B) A contract between the manufacturer and a contractor must 
specify the postmarketing safety reporting responsibilities of the 
contractor. The manufacturer is responsible for ensuring that the 
contractors of its drug products comply with these postmarketing safety 
reporting responsibilities.
    (C) The contractor must maintain a record of each submission to the 
manufacturer under paragraph (c)(2)(xi)(A) of this section that 
includes:
    (1) A copy of each safety report;
    (2) The date the report was initially received by the contractor;
    (3) The date the report was submitted to the manufacturer; and
    (4) The name and address of the manufacturer.
    (D) The recordkeeping, written procedures, and disclaimer 
provisions under paragraphs (f) through (h) of this section apply to 
contractors.
    (xii) Report identification. Each expedited report submitted to FDA 
under paragraphs (c)(2)(i) through (c)(2)(vii) of this section must 
bear prominent identification as to its contents, e.g., ``expedited 
report--Sec.  310.305--serious and unexpected SADR,'' ``expedited 
report--Sec.  310.305--30-day followup report.'' Each type of report 
(e.g., serious and unexpected SADR reports, 30-day followup reports) 
must be submitted to FDA under separate cover. Reports of medication 
errors must indicate whether the error is actual or potential and if 
actual, whether a serious SADR, nonserious SADR, or no SADR occurred, 
e.g., ``expedited report--Sec.  310.305--actual medication error--
nonserious SADR,'' ``expedited report--Sec.  310.305--potential 
medication error.''
    (d) Reporting format. (1)(i) Except as provided in paragraphs 
(d)(1)(ii), (d)(1)(iv), and (d)(5) of this section, the manufacturer 
must complete an FDA Form 3500A for each individual case safety report 
of an SADR. Reports based on information about individual cases or case 
series in the scientific literature must be submitted on an FDA Form 
3500A(s).
    (ii) Foreign SADRs may be submitted either on an FDA Form 3500A or, 
if preferred, on a CIOMS I form.
    (iii) Each domestic report of an actual or potential medication 
error must be submitted on an FDA Form 3500A.
    (iv) Reports of overall findings or data in the aggregate from 
published and unpublished in vitro, animal, epidemiological, or 
clinical studies must be submitted in a narrative format.
    (2) Each SADR in an individual case safety report must be coded on 
the FDA Form 3500A or CIOMS I form using the appropriate ``preferred 
term'' in the latest version of MedDRA (the medical dictionary for 
regulatory activities) in use at the time the manufacturer becomes 
aware of the individual case safety report. For individual case safety 
reports of medication errors, the report must be coded both as a 
medication error and, if applicable, with the preferred term for any 
SADRs associated with the medication error.
    (3) Each completed FDA Form 3500A or CIOMS I form should refer only 
to an individual case.
    (4) Each completed FDA Form 3500A or CIOMS I form must include the 
name and telephone number (and fax number and e-mail address, if 
available) for the licensed physician responsible for the content and 
medical interpretation of the data contained within the form (i.e., 
contact person for the company).
    (5) Instead of using FDA Form 3500A, the manufacturer may use a 
computer-generated facsimile of FDA Form 3500A provided that it is 
readable, includes appropriate identifying information, and contains 
all the elements (i.e., format, sections, blocks, titles, descriptors 
within blocks, text for disclaimer) of FDA Form 3500A in the identical 
enumerated sequence of the form. For individual case safety reports in 
which no suspect medical device is involved, a one-page FDA Form 3500A 
is acceptable.
    (e) Patient privacy. The names and addresses of individual patients 
should not be included in reports under this section; instead, the 
manufacturer and its contractors should assign a unique code to each 
report, preferably not more than eight characters (i.e., numbers/
letters) in length. The name of the reporter from whom the information 
was received should be included. Names of patients, individual 
reporters, health care professionals, hospitals, and geographic 
identifiers in safety reports are not releasable to the public under 
FDA's public information regulations in part 20 of this chapter.
    (f) Recordkeeping. (1) Each manufacturer must maintain for a period 
of 10 years records of all safety information pertaining to its drug 
product, received or otherwise obtained, including raw data, any 
correspondence relating to the safety information, and any reports of 
SADRs or medication errors not submitted to FDA. The manufacturer must 
also retain for a period of 10 years any records required to be 
maintained under this section. When appropriate, FDA may require a 
manufacturer to submit any or all of these records to the agency within 
5 calendar days after receipt of the request.
    (2) Manufacturers and packers may retain the records required in 
paragraph (f)(1) of this section as part of its complaint files 
maintained under Sec.  211.198 of this chapter.
    (3) Manufacturers must permit any authorized FDA employee, at all

[[Page 12476]]

reasonable times, to have access to and copy and verify the records 
established and maintained under this section.
    (g) Written procedures. Each manufacturer must develop and maintain 
written procedures for the surveillance, receipt, evaluation, and 
reporting of postmarketing safety information to FDA.
    (h) Disclaimer. A report or information submitted by a manufacturer 
under this section (and any release by FDA of that report or 
information) does not necessarily reflect a conclusion by the 
manufacturer or by FDA, that the report or information constitutes an 
admission that the drug caused or contributed to an SADR. The 
manufacturer need not admit, and may deny, that the report or 
information submitted under this section constitutes an admission that 
the drug caused or contributed to an SADR.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    3. The authority citation for 21 CFR part 312 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42 
U.S.C. 262.

    4. Section 312.32 is amended by revising paragraphs (a), (b), the 
introductory text of paragraph (c), paragraphs (c)(1) and (c)(4), and 
the first sentence of paragraph (c)(2); in paragraph (d)(3) by removing 
the phrase ``adverse drug experience'' and by adding in its place the 
abbreviation ``SADR'' and by removing the phrase ``such experience'' 
and by adding in its place the phrase ``such reaction''; and in 
paragraph (e) by removing the phrase ``adverse experience'' both times 
it appears and by adding in its place the abbreviation ``SADR'' to read 
as follows:


Sec.  312.32  IND safety reports.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Disability means a substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening suspected adverse drug reaction (SADR) means any 
SADR that, in the view of the investigator or sponsor, places the 
patient or subject at immediate risk of death from the SADR as it 
occurred. It does not include an SADR that, had it occurred in a more 
severe form, might have caused death.
    Minimum data set means the report includes an identifiable patient, 
an identifiable reporter, a suspect drug product, and an SADR.
    Serious SADR means any SADR that results in any of the following 
outcomes: Death, a life-threatening SADR, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious SADR when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
    Suspected adverse drug reaction (SADR) means a noxious and 
unintended response to any dose of a drug product for which there is a 
reasonable possibility that the product caused the response. In this 
definition, the phrase ``a reasonable possibility'' means that the 
relationship cannot be ruled out.
    Unexpected SADR means any SADR, the specificity or severity of 
which is not consistent with the current investigator brochure; or, if 
an investigator brochure is not required or available, the specificity 
or severity of which is not consistent with the risk information 
described in the general investigational plan or elsewhere in the 
current application, as amended. For example, under this definition, 
hepatic necrosis would be unexpected (by virtue of greater severity) if 
the investigator brochure only referred to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis 
would be unexpected (by virtue of greater specificity) if the 
investigator brochure only included cerebral vascular accidents. 
``Unexpected,'' as used in this definition, refers to an SADR that has 
not been previously observed (e.g., included in the investigator 
brochure); it does not refer to an SADR that might be anticipated from 
the pharmacological properties of the drug product. SADRs that are 
mentioned in the investigator's brochure as occurring with a class of 
drugs but not specifically mentioned as occurring with the particular 
drug are considered unexpected.
    (b) Review of safety information. The sponsor must promptly review 
all information relevant to the safety of the drug obtained or 
otherwise received by the sponsor from any source, foreign or domestic, 
including information derived from any clinical or epidemiological 
investigations, animal or in vitro studies, reports in the scientific 
literature, and unpublished scientific papers, as well as reports from 
foreign regulatory authorities that have not been previously reported 
to FDA by the sponsor and reports of foreign commercial marketing 
experience for drugs that are not marketed in the United States.
    (c) IND safety reports. The sponsor must not submit an individual 
case safety report for an SADR to FDA if the report does not contain a 
minimum data set; instead, the sponsor must maintain records of any 
information received or otherwise obtained for the SADR along with a 
record of its efforts to obtain a minimum data set.
    (1) Written reports--(i) Serious and unexpected SADR. The sponsor 
must notify FDA and all participating investigators in a written IND 
safety report of any SADR that, based on the opinion of the 
investigator or sponsor, is both serious and unexpected, as soon as 
possible, but in no case later than 15 calendar days after receipt by 
the sponsor of the minimum data set for the serious, unexpected SADR. 
The sponsor must identify all safety reports previously filed with the 
IND concerning a similar SADR, and must analyze the significance of the 
SADR in light of previous, similar reports.
    (ii) Information sufficient to consider product administration 
changes. The sponsor must also notify FDA and all participating 
investigators in a written IND safety report of information that, based 
upon appropriate medical judgment, might materially influence the 
benefit-risk assessment of an investigational drug or that would be 
sufficient to consider changes in either product administration or in 
the overall conduct of a clinical investigation. The sponsor must 
submit this information to FDA and all participating investigators as 
soon as possible, but in no case later than 15 calendar days after the 
determination by the sponsor that the information qualifies for 
reporting under this paragraph. Examples of such information include 
any significant unanticipated safety finding or data in the aggregate 
from an in vitro, animal, epidemiological, or clinical study, whether 
or not conducted under an IND, that suggests a significant human risk, 
such as reports of mutagenicity, teratogenicity, or carcinogenicity or 
reports of a lack of efficacy with a drug product used in treating a 
life-threatening or serious disease.
    (iii) Submission of written reports. Each written report may be 
submitted on an FDA Form 3500A or in a narrative format. Foreign SADRs 
may be

[[Page 12477]]

submitted either on an FDA Form 3500A or, if preferred, on a Council 
for International Organizations of Medical Sciences (CIOMS) I form. 
Reports of overall findings or data in the aggregate from published and 
unpublished in vitro, animal, epidemiological, or clinical studies must 
be submitted in a narrative format. Each written notice must bear 
prominent identification of its contents, i.e., ``IND safety report.'' 
Each written notification to FDA must be transmitted to the FDA review 
division that has responsibility for the review of the IND. If FDA 
determines that additional data are needed, the agency may require 
further data to be submitted.
    (2) Telephone and facsimile transmission safety reports. The 
sponsor must also notify FDA by telephone or by facsimile transmission 
of any unexpected fatal or life-threatening SADR based on the opinion 
of the investigator or sponsor as soon as possible but in no case later 
than 7 calendar days after receipt by the sponsor of the minimum data 
set for the unexpected fatal or life-threatening SADR. * * *
* * * * *
    (4) Investigations of marketed drugs. A sponsor of a clinical study 
under an IND for a drug marketed in the United States is only required 
to submit IND safety reports to FDA (review division that has 
responsibility for the IND) for SADRs from the clinical study itself, 
whether from domestic or foreign study sites of the IND. The sponsor 
must also submit to FDA safety information from these clinical studies 
as prescribed by the postmarketing safety reporting requirements under 
Sec. Sec.  310.305, 314.80, and 600.80 of this chapter.
* * * * *
    5. Section 312.64 is amended by revising paragraph (b) to read as 
follows:


Sec.  312.64  Investigator reports.

* * * * *
    (b) Safety reports. An investigator must report to the sponsor any 
serious SADR (as defined in Sec.  312.32(a)) immediately and any other 
SADR (as defined in Sec.  312.32(a)) promptly unless the protocol or 
investigator's brochure specifies a different timetable for reporting 
the SADR.
* * * * *

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

    6. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356, 
356a, 356b, 356c, 371, 374, 379e.

    7. Section 314.80 is revised to read as follows:


Sec.  314.80  Postmarketing safety reporting and recordkeeping.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Active query means direct verbal contact (i.e., in person or by 
telephone or other interactive means such as a video conference) with 
the initial reporter of a suspected adverse drug reaction (SADR) or 
medication error by a health care professional (e.g., physician, 
physician assistant, pharmacist, dentist, nurse, any individual with 
some form of health care training) representing the applicant. For 
SADRs, active query entails, at a minimum, a focused line of 
questioning designed to capture clinically relevant information 
associated with the drug product and the SADR, including, but not 
limited to, information such as baseline data, patient history, 
physical exam, diagnostic results, and supportive lab results.
    Actual medication error means a medication error that involves an 
identifiable patient whether the error was prevented prior to 
administration of the product or, if the product was administered, 
whether the error results in a serious SADR, nonserious SADR, or no 
SADR.
    Company core data sheet means a document prepared by the applicant 
containing, in addition to safety information, material relating to 
indications, dosing, pharmacology, and other information concerning the 
drug substance. The only purpose of this document is to provide the 
company core safety information (CCSI) for periodic safety update 
reports (PSURs), interim periodic safety reports (IPSRs), and certain 
individual case safety reports--semiannual submissions (i.e., if PSURs 
are submitted for the product).
    Company core safety information (CCSI) means all relevant safety 
information contained in the company core data sheet that the applicant 
proposes to include in the approved product labeling in all countries 
where the applicant markets the drug substance. It is the reference 
information by which an SADR is determined to be ``listed'' or 
``unlisted'' for PSURs, IPSRs, and certain individual case safety 
reports-semiannual submissions (i.e., if PSURs are submitted for the 
product).
    Contractor means any person (e.g., manufacturer, packer or 
distributor whether its name appears on the label of the product; 
licensee; contract research organization) that has entered into a 
contract with the applicant to manufacture, pack, sell, distribute, or 
develop the drug or to maintain, create, or submit records regarding 
SADRs or medication errors.
    Data lock point means the date designated as the cut-off date for 
data to be included in a postmarketing periodic safety report.
    Disability means a substantial disruption of a person's ability to 
conduct normal life functions.
    Full data set means completion of all the applicable elements on 
FDA Form 3500A (or on a Council for International Organizations of 
Medical Sciences (CIOMS) I form for reports of foreign SADRs), 
including a concise medical narrative of the case (i.e., an accurate 
summary of the relevant data and information pertaining to an SADR or 
medication error).
    International birth date means the date the first regulatory 
authority in the world approved the first marketing application for a 
human drug product containing the drug substance.
    Life-threatening SADR means any SADR that, in the view of the 
initial reporter, places the patient at immediate risk of death from 
the SADR as it occurred. It does not include an SADR that, had it 
occurred in a more severe form, might have caused death.
    Listed SADR means an SADR whose nature, specificity, severity, and 
outcome are consistent with the information in the CCSI.
    Medication error means any preventable event that may cause or lead 
to inappropriate medication use or patient harm, while the medication 
is in the control of the health care professional, patient or consumer. 
Such events may be related to professional practice, health care 
products, procedures, and systems including: Prescribing; order 
communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; 
monitoring; and use.
    Minimum data set means the report includes an identifiable patient, 
an identifiable reporter, a suspect drug product, and an SADR.
    Nonserious SADR means any SADR that is determined not to be a 
serious SADR.
    Potential medication error means an individual case safety report 
of information or complaint about product name, labeling, or packaging 
similarities that does not involve a patient.
    SADR with unknown outcome means an SADR that cannot be classified, 
after active query, as either serious or nonserious.

[[Page 12478]]

    Serious SADR means any SADR that results in any of the following 
outcomes: Death, a life-threatening SADR, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious SADR when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
    Spontaneous report means a communication from an individual (e.g., 
health care professional, consumer) to a company or regulatory 
authority that describes an SADR or medication error. It does not 
include cases identified from information solicited by the applicant or 
contractor, such as individual case safety reports or findings derived 
from a study, company-sponsored patient support program, disease 
management program, patient registry, including pregnancy registries, 
or any organized data collection scheme. It also does not include 
information compiled in support of class action lawsuits.
    Suspected adverse drug reaction (SADR) means a noxious and 
unintended response to any dose of a drug product for which there is a 
reasonable possibility that the product caused the response. In this 
definition, the phrase ``a reasonable possibility'' means that the 
relationship cannot be ruled out.
    Unexpected SADR means any SADR that is not included in the current 
U.S. labeling for the drug product. Reactions that may be 
symptomatically and pathophysiologically related to a reaction included 
in the U.S. labeling, but differ from the labeled reaction because of 
greater severity or specificity, would be unexpected. For example, 
under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the U.S. labeling only referred to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the U.S. labeling only included cerebral vascular 
accidents. ``Unexpected,'' as used in this definition, refers to an 
SADR that has not been previously observed (i.e., included in the U.S. 
labeling); it does not refer to an SADR that might be anticipated from 
the pharmacological properties of the drug product. SADRs that are 
mentioned in the U.S. labeling as occurring with a class of drugs but 
not specifically mentioned as occurring with the particular drug are 
considered unexpected.
    Unlisted SADR means an SADR whose nature, specificity, severity, or 
outcome is not consistent with the information included in the CCSI.
    (b) Review of safety information. (1) Each applicant having an 
approved application for a drug product under section 505(c) of the act 
must promptly review all safety information pertaining to its product 
obtained or otherwise received by the applicant from any source, 
foreign or domestic, including information derived from commercial 
marketing experience, postmarketing clinical investigations, 
postmarketing epidemiology/surveillance studies, animal or in vitro 
studies, electronic communications with applicants via the Internet 
(e.g., e-mail), reports in the scientific literature, and unpublished 
scientific papers, as well as reports from foreign regulatory 
authorities that have not been previously reported to FDA by the 
applicant.
    (2) Individual case safety reports that are forwarded to the 
applicant by FDA must not be resubmitted to the agency by the 
applicant; however, applicants must include information from these 
individual case safety reports in any comprehensive safety analysis 
subsequently submitted to FDA. In addition, applicants must submit to 
FDA all followup information for these individual case safety reports.
    (c) Reporting requirements. The applicant must submit to FDA two 
copies of each postmarketing expedited report (described under 
paragraphs (c)(2)(i) through (c)(2)(vii) of this section) and one copy 
of each postmarketing periodic safety report of an individual case 
safety reports--semiannual submission (described under paragraph 
(c)(3)(v) of this section) pertaining to its drug product. The 
applicant must also submit to FDA one copy of a PSUR, IPSR, or 
traditional periodic safety report (TPSR)) along with one copy for each 
approved application for a human drug product covered by the report. 
FDA may waive the requirement for multiple copies in appropriate 
instances. Upon written notice, FDA may require, when appropriate, that 
the applicant submit reports under this section to FDA at times other 
than those stated. An applicant that wishes to submit reports under 
this section at different intervals must submit to FDA a request for a 
waiver under Sec.  314.90.
    (1) Determination of outcome, minimum data set, and full data set--
(i)(A) Initial determinations. Upon initial receipt of an SADR report, 
the applicant must immediately determine the outcome for the SADR 
(whether the SADR is serious or nonserious) and at least the minimum 
data set for the individual case safety report. For reports of actual 
medication errors that do not result in an SADR and potential 
medication errors the applicant must immediately determine the minimum 
information for the individual case safety report (minimum information 
described under paragraphs (c)(1)(iii)(B) and (c)(1)(iii)(C) of this 
section). If the applicant is not able to immediately determine the 
information in this paragraph, active query must be used to obtain it 
as soon as possible.
    (B) Spontaneous reports. For spontaneous reports, the applicant 
must always assume, for safety reporting purposes under this section, 
that there is at least a reasonable possibility, in the opinion of the 
initial reporter, that the drug product caused the spontaneously 
reported event.
    (C) Clinical trials. For a clinical trial, the possibility that the 
drug product caused the SADR or that a medication error has occurred 
must be assumed if either the investigator or the applicant believes 
that such a reasonable possibility exists.
    (ii) SADRs with unknown outcome. For an SADR with unknown outcome 
that cannot be immediately determined, the applicant must continue to 
use active query to attempt to determine the outcome of the SADR within 
30 calendar days after initial receipt of the SADR report by the 
applicant. The applicant must maintain a record of its efforts to 
determine the outcome for an SADR with unknown outcome.
    (iii)(A) Minimum data set for SADR reports. The applicant must not 
submit an individual case safety report for an SADR to FDA if the 
report does not contain a minimum data set; instead, the applicant must 
maintain records of any information received or otherwise obtained for 
the SADR along with a record of its efforts to obtain a minimum data 
set.
    (B) Minimum information for reports of actual medication errors 
that do not result in an SADR. For reports of actual medication errors 
that do not result in an SADR, an individual case safety report must be 
submitted to FDA even though the report does not contain a minimum data 
set (i.e., does not have an SADR). These reports must contain at

[[Page 12479]]

least an identifiable patient, an identifiable reporter, and a suspect 
drug product.
    (C) Minimum information for potential medication error reports. For 
reports of potential medication errors, an individual case safety 
report must be submitted to FDA even though the report does not contain 
a minimum data set (i.e., does not have an identifiable patient or an 
SADR). These reports must contain at least an identifiable reporter and 
a suspect drug product.
    (iv) Full data set. For reports of serious SADRs, always expedited 
reports (see paragraph (c)(2)(iv) of this section), and medication 
error reports (see paragraph (c)(2)(v) of this section), the applicant 
must submit a full data set. If a full data set is not available for 
the report, the applicant must use active query to obtain this 
information. If a full data set is not obtainable, after active query, 
the applicant must:
    (A) Submit all safety information, received or otherwise obtained, 
for the report;
    (B) Indicate the reason(s) for its inability to acquire a full data 
set; and
    (C) Document its efforts to obtain a full data set (i.e., 
description of unsuccessful steps taken to obtain this information).
    (v) Serious SADRs not initially reported by a health care 
professional. For a serious SADR that was not initially reported to the 
applicant by a health care professional (e.g., report from a consumer), 
the applicant must contact the health care professional associated with 
the care of the patient using active query to gather further medical 
perspective on the case and to acquire a full data set for the report. 
If the applicant is unable to contact the health care professional, it 
must include in the report for the serious SADR:
    (A) The reason(s) for its inability to contact the health care 
professional; and
    (B) A description of its efforts to contact the health care 
professional.
    (vi) Nonserious SADRs. For reports of nonserious SADRs with a 
minimum data set, except for those resulting from a medication error, 
all safety information received or otherwise obtained by the applicant 
must be submitted to FDA even though information in addition to the 
minimum data set is not required to be acquired. Reports of nonserious 
SADRs resulting from a medication error require a full data set under 
paragraph (c)(1)(iv) of this section.
    (2) Postmarketing ``expedited reports''--(i) Serious and unexpected 
SADR. The applicant must report to FDA each SADR, received or otherwise 
obtained, that is both serious and unexpected, whether foreign or 
domestic, as soon as possible, but in no case later than 15 calendar 
days after receipt by the applicant of the minimum data set for the 
serious unexpected SADR. If a full data set is not available for the 
serious and unexpected SADR at the time of initial submission of the 
expedited report to FDA, the applicant must submit the information 
required under paragraph (c)(1)(iv) of this section and also submit a 
30-day followup report as required by paragraph (c)(2)(vi) of this 
section.
    (ii) Information sufficient to consider product administration 
changes. The applicant must also report to FDA information, received or 
otherwise obtained, whether foreign or domestic, that would be 
sufficient, based upon appropriate medical judgment, to consider 
changes in product administration. The applicant must submit this 
information to FDA as soon as possible, but in no case later than 15 
calendar days after determination by the applicant that the information 
qualifies for expedited reporting. Examples of such information include 
any significant unanticipated safety finding or data in the aggregate 
from an in vitro, animal, epidemiological, or clinical study, whether 
or not conducted under an investigational new drug application (IND), 
that suggests a significant human risk, such as reports of 
mutagenicity, teratogenicity, or carcinogenicity, or reports of a lack 
of efficacy with a drug product used in treating a life-threatening or 
serious disease. The applicant must maintain a record of its efforts to 
determine whether the information required to be reported under this 
paragraph qualifies for expedited reporting.
    (iii) Unexpected SADR with unknown outcome. The applicant must also 
report to FDA each SADR that is unexpected and for which the 
determination of an outcome is unattainable (i.e., SADR with unknown 
outcome) within 45 calendar days after initial receipt by the applicant 
of the minimum data set for the unexpected SADR. The applicant must 
document in the expedited report the reason(s) for the inability to 
determine the outcome.
    (iv) Always expedited report. (A) The applicant must also report to 
FDA each SADR, received or otherwise obtained, whether foreign or 
domestic, that is the subject of an always expedited report. These 
reports must be submitted to FDA as soon as possible, but in no case 
later than 15 calendar days after receipt by the applicant of the 
minimum data set for the report. The following medically significant 
SADRs, which may jeopardize the patient or subject and/or require 
medical or surgical intervention to treat the patient or subject are 
subject to an always expedited report:
    (1) Congenital anomalies,
    (2) Acute respiratory failure,
    (3) Ventricular fibrillation,
    (4) Torsades de pointe,
    (5) Malignant hypertension,
    (6) Seizure,
    (7) Agranulocytosis,
    (8) Aplastic anemia,
    (9) Toxic epidermal necrolysis,
    (10) Liver necrosis,
    (11) Acute liver failure,
    (12) Anaphylaxis,
    (13) Acute renal failure,
    (14) Sclerosing syndromes,
    (15) Pulmonary hypertension,
    (16) Pulmonary fibrosis,
    (17) Confirmed or suspected transmission of an infectious agent by 
a marketed drug or biological product,
    (18) Confirmed or suspected endotoxin shock, and
    (19) Any other medically significant SADR that FDA determines to be 
the subject of an always expedited report (i.e., may jeopardize the 
patient or subject and/or require medical or surgical intervention to 
treat the patient or subject).
    (B) SADRs that are the subject of an always expedited report must 
be submitted to FDA whether unexpected or expected and whether the SADR 
leads to a serious outcome or not. If a full data set is not available 
for an always expedited report at the time of initial submission of the 
report to FDA, the applicant must submit the information required under 
paragraph (c)(1)(iv) of this section and also submit a 30-day followup 
report as required by paragraph (c)(2)(vi) of this section.
    (v) Medication errors--(A) Actual medication error. The applicant 
must also submit to FDA each domestic report of an actual medication 
error, received or otherwise obtained, as soon as possible, but in no 
case later than 15 calendar days after receipt by the applicant of the 
minimum data set for a report of an SADR or, if an SADR does not occur, 
the minimum information described under paragraph (c)(1)(iii)(B) of 
this section (i.e., identifiable patient, identifiable reporter, and 
suspect drug product).
    (B) Potential medication error. The applicant must also submit to 
FDA each domestic report of a potential medication error, received or 
otherwise obtained, as soon as possible, but in no case later than 15 
calendar days after receipt by the applicant of the minimum information 
described under paragraph (c)(1)(iii)(C) of this section (i.e., 
identifiable reporter and suspect drug product).

[[Page 12480]]

    (C) Full data set. If a full data set is not available for an 
actual or potential medication error report at the time of initial 
submission of the report to FDA, the applicant must submit the 
information required under paragraph (c)(1)(iv) of this section and 
also submit a 30-day followup report as required by paragraph 
(c)(2)(vi) of this section.
    (vi) The 30-day followup report. The applicant must use active 
query to obtain additional information for any expedited report under 
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that 
does not contain a full data set and must submit a followup report to 
FDA within 30 calendar days after initial submission of the expedited 
report to FDA by the applicant. If a full data set is still not 
obtainable, the 30-day followup report must contain the information 
required under paragraph (c)(1)(iv) of this section. Any new safety 
information in the 30-day followup report must be highlighted. Any new 
information, received or otherwise obtained, after submission of a 30-
day followup report must be submitted to FDA as a 15-day followup 
report under paragraph (c)(2)(vii) of this section.
    (vii) The 15-day followup report. The applicant must report to FDA 
any new information, received or otherwise obtained, for any expedited 
or followup report (except for initial expedited reports under 
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that do 
not contain a full data set) within 15 calendar days of initial receipt 
of the new information by the applicant. Expedited reports under 
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that do 
not contain a full data set at the time of initial submission of the 
report to FDA are subject to the 30-day followup reporting requirements 
under paragraph (c)(2)(vi) of this section rather than the 15-day 
followup reporting requirements under this paragraph.
    (viii) Supporting documentation. (A) If the patient dies, the 
applicant must submit a copy of the autopsy report to FDA, if it is 
available. If an autopsy report is not available, the applicant must 
submit a death certificate to FDA. If an autopsy report becomes 
available after the applicant has submitted a death certificate to the 
agency, the autopsy report must be submitted to FDA. If the patient was 
hospitalized, the applicant must submit a copy of the hospital 
discharge summary to FDA, if it is available. If any of these documents 
is not in English, the document must be accompanied by an English 
translation. Applicants must use active query to obtain these 
documents. These documents must be submitted to FDA as 15-day followup 
reports (see paragraph (c)(2)(vii) of this section) within 15 calendar 
days of initial receipt of the document by the applicant. If these 
documents are not submitted to FDA in a 15-day followup report within 3 
months after submission of the initial expedited report for the death 
or hospitalization, the agency will assume that active query by the 
applicant has not resulted in access to these documents. In this case, 
a record of the reason(s) for the lack of such documentation and the 
effort that was made to obtain the documentation must be maintained by 
the applicant.
    (B) Each expedited report must contain in the narrative a list of 
other relevant documents (e.g., medical records, laboratory results, 
data from studies) for the report that are maintained by the applicant. 
When appropriate, FDA may require an applicant to submit copies of one 
or more of these documents to the agency within 5 calendar days after 
receipt of the request.
    (ix) Scientific literature. An expedited report based on 
information from the scientific literature applies only to reports 
found in scientific and medical journals. These expedited reports must 
be accompanied by a copy of the published article.
    (x) Submission of safety reports by contractors. (A) Contractors 
must submit to the applicant safety reports of any SADRs or medication 
errors for the applicant's drug product, obtained or otherwise 
received, within 5 calendar days of initial receipt of the report by 
the contractor. The contractor must submit a safety report for an SADR 
to the applicant even if the report does not contain a minimum data 
set. Upon receipt of the safety report from the contractor, the 
applicant must comply with the postmarketing safety reporting 
requirements of this section.
    (B) A contract between the applicant and a contractor must specify 
the postmarketing safety reporting responsibilities of the contractor. 
The applicant is responsible for assuring that the contractors of its 
drug products comply with these postmarketing safety reporting 
responsibilities.
    (C) The contractor must maintain a record of each submission to the 
applicant under paragraph (c)(2)(x)(A) of this section that includes:
    (1) A copy of each safety report;
    (2) The date the report was initially received by the contractor;
    (3) The date the report was submitted to the applicant; and
    (4) The name and address of the applicant.
    (D) The recordkeeping, written procedures and disclaimer provisions 
under paragraphs (f), (g), and (i) of this section apply to 
contractors.
    (xi) Report identification. Each expedited report submitted to FDA 
under paragraphs (c)(2)(i) through (c)(2)(vii) of this section must 
bear prominent identification as to its contents, e.g., ``expedited 
report--serious and unexpected SADR,'' ``expedited report--30-day 
followup.'' Each type of report (e.g., serious and unexpected SADR 
reports, 30-day followup reports) must be submitted to FDA under 
separate cover. Reports of medication errors must indicate whether the 
error is actual or potential and, if actual, whether a serious SADR, 
nonserious SADR, or no SADR occurred, e.g., ``expedited report--actual 
medication error--nonserious SADR,'' ``Expedited report--potential 
medication error.''
    (3) Postmarketing periodic safety reports. The applicant must 
submit postmarketing periodic safety reports under this section (i.e., 
TPSRs, PSURs, IPSRs, individual case safety reports-semiannual 
submission) to FDA within 60 calendar days after the data lock point 
for the report. The applicant must include a cover letter containing a 
list of the new drug application number(s) (i.e., NDA number(s)) for 
the human drug product(s) covered by the postmarketing periodic safety 
report. The international birth date for combination products is the 
international birth date of the human drug product containing the drug 
substance most recently approved for marketing.
    (i) Traditional periodic safety reports (TPSRs). An applicant 
holding an application for a human drug product approved under section 
505(c) of the act before January 1, 1998, must submit either a PSUR as 
prescribed under paragraph (c)(3)(ii) of this section or a TPSR as 
described under this paragraph every 5 years after U.S. approval of the 
application. In addition, these applicants must submit either an IPSR 
as described under paragraph (c)(3)(iii) of this section or a TPSR as 
described under this paragraph 7.5 years and 12.5 years after U.S. 
approval of the application. The data lock point for the TPSR, PSUR, or 
IPSR is the month and day of the international birth date of the drug 
product or any other month and day agreed on by the applicant and FDA. 
Each TPSR must contain:
    (A) Summary. This section of the TPSR includes:
    (1) A narrative summary and analysis of serious, expected SADRs and 
nonserious, unexpected SADRs

[[Page 12481]]

occurring in the United States that were submitted to the applicant 
during the reporting period from all spontaneous sources (i.e., health 
care professionals and other individuals) (with an index consisting of 
a line listing of the applicant's manufacturer report number and SADR 
term(s));
    (2) An analysis of the expedited reports submitted during the 
reporting period under paragraphs (c)(2)(i) through (c)(2)(vii) of this 
section (all expedited reports must be appropriately referenced by the 
applicant's manufacturer report number, SADR term(s), if appropriate, 
and date of submission to FDA);
    (3) A discussion of any increased reporting frequency of serious, 
expected SADRs, including comments on whether it is believed that the 
data reflect a meaningful change in SADR occurrence, and an assessment 
of whether it is believed that the frequency of lack of efficacy 
reports, obtained or otherwise received during the reporting period, is 
greater than would be predicted by the premarketing clinical trials for 
the drug product; and
    (4) The applicants' conclusion as to what, if any, safety-related 
actions should be taken based on the analysis of the safety data in the 
TPSR (e.g., labeling changes, studies initiated);
    (B) Summary tabulations. This section of the TPSR includes summary 
tabulations (i.e., lists of all SADR terms and counts of occurrences) 
presented by body system or by standard organ system classification 
scheme for:
    (1) All serious expected SADRs, nonserious unexpected SADRs, 
nonserious expected SADRs, and expected SADRs with unknown outcome 
occurring in the United States that are submitted to the applicant 
during the reporting period from all spontaneous sources (i.e., health 
care professionals and other individuals);
    (2) All serious unexpected SADRs, unexpected SADRs with unknown 
outcome, and always expedited reports that were previously submitted to 
FDA in an expedited report under paragraphs (c)(2)(i), (c)(2)(iii), and 
(c)(2)(iv) of this section (include cumulative data for serious 
unexpected SADRs, i.e., all cases reported to date);
    (3) All reports of SADRs not previously submitted to FDA by the 
applicant (e.g., reports submitted to applicants by FDA, reports 
obtained from FDA from freedom of information requests at the 
discretion of the applicant, reports from class action lawsuits); and
    (4) All domestic reports of medication errors previously submitted 
to FDA under paragraph (c)(2)(v) of this section. For actual medication 
errors, provide summary tabulations of serious SADRs, nonserious SADRs, 
and no SADRs. For potential medication errors, provide the number of 
reports for specific errors;
    (C) History of safety-related actions taken. This section of the 
TPSR includes a history of safety-related actions taken since the last 
periodic safety report (e.g., labeling changes, studies initiated);
    (D) Location of safety records. This section of the TPSR includes a 
list of the current address(es) where all safety reports and other 
safety-related records for the drug product are maintained; and
    (E) Contact person. This section of the TPSR includes the name and 
telephone number for the licensed physician(s) responsible for the 
content and medical interpretation of the information contained within 
the TPSR. Include, if available, the fax number and e-mail address for 
the licensed physician(s).
    (ii) Periodic safety update report (PSUR). An applicant holding an 
application for a human drug product approved under section 505(c) of 
the act on or after January 1, 1998, must submit a PSUR to FDA 
according to the following schedule: Semiannually (i.e., every 6 
months) for 2 years after U.S. approval of the application, annually 
for the next 3 years and then every 5 years thereafter. The data lock 
point for the PSUR is the month and day of the international birth date 
of the drug substance or any other month and day agreed on by the 
applicant and FDA. Each PSUR must contain:
    (A) Title page, table of contents, and introduction. (1) The title 
page includes, at a minimum, the following information:
    (i) Name and international birth date of the drug substance that is 
the subject of the PSUR,
    (ii) Various dosage forms and formulations of the drug substance 
covered by the PSUR,
    (iii) Name and address of the applicant,
    (iv) Reporting period covered by the PSUR, and
    (v) Date of the PSUR.
    (2) The introduction:
    (i) Provides a brief description of how the PSUR relates to 
previous reports and circumstances;
    (ii) References relevant drug products or substances reported in 
other periodic safety reports (e.g., a combination product reported in 
a separate PSUR); and
    (iii) Indicates any data duplication with other PSURs.
    (B) Worldwide marketing status. This section of the PSUR contains a 
table of the chronological history of the worldwide marketing status of 
the drug product(s) covered by the PSUR from the date the product(s) 
was first approved (i.e., the international birth date) through its 
current status (i.e., cumulative information). The table consists of:
    (1) Dates of drug approval and renewal;
    (2) Safety-related restrictions on product use;
    (3) Indications for use and special populations covered by the drug 
approval;
    (4) Lack of approval of the drug substance in any dosage form or 
for any indication for use by any regulatory authority(ies);
    (5) Withdrawal of a pending marketing application for the drug 
product by the applicant for safety- or efficacy-related reasons;
    (6) Dates of market launches; and
    (7) Trade name(s).
    (C) Actions taken for safety reasons. (1) This section of the PSUR 
includes details on the following types of regulatory authority-
initiated (e.g., by FDA) and/or applicant-initiated actions related to 
safety that were taken during the period covered by the PSUR and 
between the data lock point and PSUR submission (i.e., ``late-
breaking'' safety concerns):
    (i) Withdrawal or suspension of drug product approval or indication 
for use approval;
    (ii) Failure to obtain a marketing authorization renewal or to 
obtain an approval for a new indication for use;
    (iii) Restrictions on distribution (e.g., products recalled for 
safety reasons);
    (iv) Clinical trial suspension;
    (v) Dosage modification;
    (vi) Changes in target population or indications; and
    (vii) Formulation changes.
    (2) This section of the PSUR also contains a narrative identifying 
the safety-related reasons that led to these actions with relevant 
documentation appended when appropriate.
    (3) Any communication with health care professionals (e.g., Dear 
Healthcare Professional letters) resulting from such actions must also 
be described with copies appended.
    (D) Changes to CCSI. This section of the PSUR describes changes to 
the CCSI (e.g., new contraindications, precautions, warnings, SADRs, or 
interactions) made during the period covered by the PSUR. A copy of any 
modified section of the CCSI must be included. The applicant must use 
the CCSI in effect at the beginning of the reporting period for the 
PSUR. The revised CCSI is to be used as the reference document for the 
next reporting period.

[[Page 12482]]

    (E) Worldwide patient exposure. (1) This section of the PSUR 
includes, for the reporting period, an estimate of the worldwide 
patient exposure to the drug product(s) covered by the PSUR (i.e., 
number of patients, average or median dose received, and average or 
median length of treatment). The method used to estimate patient 
exposure must always be described. If the patient exposure is 
impossible to estimate or is meaningless, an explanation of and 
justification for such conclusions must be provided. If patient 
exposure is impossible to estimate, other measures of exposure, such as 
patient-days, number of prescriptions, or number of dosage units, may 
be used. If these or other more precise measures are not available and 
an adequate explanation for the lack of such information is provided, 
bulk sales may be used.
    (2) When possible, data broken down by gender and age (especially 
pediatric versus adult) must be provided. For the pediatric population, 
data must be reported, if possible, by age group (e.g., neonates, 
infants, children, adolescents). If these data are not available, an 
explanation must be included.
    (3) When a pattern of reports indicates a potential problem, 
details by country (with locally recommended dosage regimens) or other 
segmentation (e.g., indication, dosage form) must be presented.
    (F) Individual case safety reports. (1) This section of the PSUR 
includes summary tabulations of individual case safety reports (e.g., 
serious unlisted SADRs, serious listed SADRs, nonserious unlisted 
SADRs, nonserious listed SADRs) for the following SADRs obtained or 
otherwise received during the reporting period:
    (i) All serious and nonserious SADRs from spontaneous sources that 
were submitted to applicants by a health care professional;
    (ii) All serious SADRs from studies, individual patient INDs, or, 
in foreign countries, from named-patient ``compassionate'' use;
    (iii) All serious SADRs and nonserious unlisted SADRs from the 
scientific literature;
    (iv) All serious SADRs from regulatory authorities; and
    (v) Serious SADRs from other sources such as reports created by 
poison control centers and epidemiological data bases.
    (2) The summary tabulations must be made up of lists by body system 
or by standard organ system classification scheme of all SADR terms and 
counts of occurrences. For SADRs that are determined to be both serious 
and unlisted, include cumulative data (i.e., all cases reported to 
date).
    (3) The applicant must conclude this section with a brief 
discussion of the data concerning the individual case safety reports in 
the PSUR (e.g., discussion of medical significance or mechanism).
    (G) Safety studies. This section of the PSUR contains a discussion 
of nonclinical, clinical, and epidemiological studies that contain 
important safety information, as follows:
    (1) All applicant-sponsored studies newly analyzed during the 
reporting period (copies of full reports should be appended only if new 
safety issues are raised or confirmed; FDA may request copies of other 
studies, if necessary);
    (2) New studies specifically planned, initiated, or continuing 
during the reporting period that examine a safety issue, whether actual 
or hypothetical; and
    (3) Published safety studies in the scientific and medical 
literature, including relevant published abstracts from meetings 
(provide literature citation).
    (H) Other information. This section of the PSUR includes:
    (1) A discussion of medically relevant lack of efficacy reports 
(e.g., might represent a significant hazard to the treated population) 
for a product(s) used to treat serious or life-threatening diseases; 
and
    (2) Any important new information received after the data lock 
point (e.g., significant new cases).
    (I) Overall safety evaluation. This section of the PSUR contains a 
concise, yet comprehensive, analysis of all of the safety information 
provided in the PSUR, including new information provided under 
paragraph (c)(3)(ii)(H)(2) of this section. In addition, this section 
of the PSUR includes an assessment by the applicant of the significance 
of the data collected during the reporting period, as well as from the 
perspective of cumulative experience.
    (1) The applicant must highlight any new information on:
    (i) Serious, unlisted SADRs;
    (ii) Increased reporting frequencies of listed SADRs, including 
comments on whether it is believed that the data reflect a meaningful 
change in SADR occurrence;
    (iii) A change in characteristics of listed SADRs (e.g., severity, 
outcome, target population); and
    (iv) Nonserious, unlisted SADRs.
    (2) As part of the overall safety evaluation, the applicant must 
also explicitly address any new safety issue including but not limited 
to the following (lack of significant new information for each of the 
following must be mentioned):
    (i) Drug interactions;
    (ii) Experience with overdose, whether deliberate or accidental, 
and its treatment;
    (iii) Drug abuse or intentional misuse;
    (iv) Positive or negative experiences during pregnancy or 
lactation;
    (v) Effects with long-term treatment; and
    (vi) Experience in special patient groups (e.g., pediatric, 
geriatric, organ impaired). For the pediatric population, data must be 
evaluated, if possible, by age group (e.g., neonates, infants, 
children, adolescents).
    (J) Conclusion. This section of the PSUR:
    (1) Indicates new safety information that is not in accord with 
previous cumulative experience and with the CCSI in use at the 
beginning of the reporting period (e.g., new evidence that strengthens 
a possible causal relationship between the drug product and an SADR 
such as positive rechallenge, an epidemiological association, or new 
laboratory studies); and
    (2) Specifies and justifies any action recommended or initiated, 
including changes in the CCSI.
    (K) Appendices. This section of the PSUR includes:
    (1) Company core data sheet. Provide a copy of the company core 
data sheet covered by this PSUR (i.e., in effect at the beginning of 
the period covered by the PSUR) as well as the company core data sheet 
for the next reporting period. Company core data sheets must be 
numbered and dated and include the date of last revision.
    (2) U.S. labeling. Provide a copy of the current approved U.S. 
labeling. Specify any safety information that is included in the CCSI 
but not in the U.S. labeling and provide an explanation for the 
discrepancy. Describe any safety-related changes or proposed changes to 
the U.S. labeling made during the reporting period (include the 
supplement number(s) and date(s) of submission for the supplement(s)) 
and any suggested change(s) that should be considered based on the 
safety analysis in the PSUR.
    (3) Spontaneous reports submitted to the applicant by an individual 
other than a health care professional. Provide summary tabulations 
(e.g., serious unlisted SADRs, serious listed SADRs, nonserious 
unlisted SADRs, nonserious listed SADRs) for all spontaneously reported 
serious SADRs, whether domestic or foreign, and all spontaneously 
reported nonserious

[[Page 12483]]

SADRs occurring in the United States, obtained or otherwise received 
during the reporting period by the applicant from an individual other 
than a health care professional (e.g., reports from consumers). These 
summary tabulations must consist of lists by body system or by standard 
organ system classification scheme of all SADR terms and counts of 
occurrences. For those SADRs that are determined to be both serious and 
unlisted, include cumulative data (i.e., all cases reported to date by 
individuals other than a health care professional). Include a brief 
discussion of the impact of the spontaneous reports described in this 
appendix on the overall safety evaluation.
    (4) SADRs with unknown outcome. Provide summary tabulations for 
unlisted and listed SADRs with unknown outcome from all spontaneous 
sources (i.e., health care professionals and other individuals), 
obtained or otherwise received by the applicant during the reporting 
period. These summary tabulations must consist of lists by body system 
or by standard organ system classification scheme of all SADR terms and 
counts of occurrences. Include a brief discussion of the impact of the 
spontaneous reports described in this appendix on the overall safety 
evaluation.
    (5) Class action lawsuits. Provide summary tabulations (e.g., 
serious unlisted SADRs, serious listed SADRs, nonserious unlisted 
SADRs, nonserious listed SADRs) for all SADRs obtained or otherwise 
received during the reporting period by the applicant from class action 
lawsuits. These summary tabulations must consist of lists by body 
system or by standard organ system classification scheme of all SADR 
terms and counts of occurrences. For those SADRs that are determined to 
be both serious and unlisted, include cumulative data. Include a brief 
discussion of the impact of the reports described in this appendix on 
the overall safety evaluation.
    (6) Lack of efficacy reports. Provide an assessment of whether it 
is believed that the frequency of lack of efficacy reports, obtained or 
otherwise received during the reporting period, is greater than would 
be predicted by the premarketing clinical trials for the drug product.
    (7) Information on resistance to antimicrobial drug products. 
Provide information, received or otherwise obtained by the applicant, 
on resistance to antimicrobial drug products intended to treat 
infectious diseases. Include information on changes in U.S. microbial 
in vitro susceptibility, the relationship of changes in U.S. microbial 
in vitro susceptibility and clinical outcomes, therapeutic failure that 
may possibly be due to resistance to the antimicrobial drug product, 
and whether the U.S. labeling should be revised because of the 
information on antimicrobial resistance learned during the period 
covered by this PSUR.
    (8) Medication errors. Provide summary tabulations of all domestic 
reports of medication errors submitted during the reporting period 
under paragraph (c)(2)(v) of this section. For actual medication 
errors, provide summary tabulations for serious SADRs, nonserious 
SADRs, and no SADRs (for serious SADRs include cumulative data, i.e., 
all cases reported to date). For potential medication errors, provide 
the number of reports for specific errors. If an SADR occurs, the 
summary tabulations must consist of lists by body system or by standard 
organ system classification scheme of all SADR terms and counts of 
occurrences. Include a brief discussion of the impact on the overall 
safety evaluation of these reports.
    (9) U.S. patient exposure. Provide, for the reporting period, an 
estimate of the U.S. patient exposure to the drug product(s) covered by 
the PSUR (i.e., number of patients, average or median dose received, 
and average or median length of treatment). The method used to estimate 
patient exposure must always be described. If the patient exposure is 
impossible to estimate or is meaningless, an explanation of and 
justification for such conclusions must be provided. If patient 
exposure is impossible to estimate, other measures of exposure, such as 
patient-days, number of prescriptions, or number of dosage units, may 
be used. If these or other more precise measures are not available and 
an adequate explanation for the lack of such information is provided, 
bulk sales may be used.
    (10) Location of safety records. Provide a list of the current 
address(es) where all safety reports and other safety-related records 
for the drug product(s) are maintained.
    (11) Contact person. Provide the name and telephone number of the 
licensed physician(s) responsible for the content and medical 
interpretation of the data and information contained within the PSUR. 
Include, if available, the fax number and e-mail address of the 
licensed physician(s).
    (iii) Interim periodic safety report (IPSR). An applicant holding 
an application for a human drug product approved under section 505(c) 
of the act on or after January 1, 1998, must submit an IPSR to FDA 7.5 
years and 12.5 years after U.S. approval of the application. The data 
lock point for the IPSR is the month and day of the international birth 
date of the drug substance or any other month and day agreed on by the 
applicant and FDA. The reporting period for the IPSR covers the period 
between the last PSUR or TPSR and the data lock point for the IPSR 
(e.g., between years 5 and 7.5 for an IPSR with a data lock point 7.5 
years after U.S. approval of the application). Each IPSR must contain:
    (A) Title page, table of contents, and introduction. (1) The title 
page includes, at a minimum, the following information:
    (i) Name and international birth date of the drug substance that is 
the subject of the IPSR,
    (ii) Various dosage forms and formulations of the drug substance 
covered by the IPSR,
    (iii) Name and address of the applicant,
    (iv) Reporting period covered by the IPSR, and
    (v) Date of the IPSR.
    (2) The introduction:
    (i) Provides a brief description of how the IPSR relates to 
previous reports and circumstances,
    (ii) References relevant drug products or substances reported in 
other periodic safety reports (e.g., a combination product reported in 
a separate IPSR), and
    (iii) Indicates any data duplication with other IPSRs.
    (B) Worldwide marketing status. This section of the IPSR contains a 
table of the chronological history of the worldwide marketing status of 
the drug product(s) covered by the IPSR from the date the product(s) 
was first approved (i.e., the international birth date) through its 
current status (i.e., cumulative information). The table consists of:
    (1) Dates of drug approval and renewal;
    (2) Safety-related restrictions on product use;
    (3) Indications for use and special populations covered by the drug 
approval;
    (4) Lack of approval of the drug substance in any dosage form or 
for any indication for use by any regulatory authority(ies);
    (5) Withdrawal of a pending marketing application for a drug 
product by the applicant for safety or efficacy related reasons;
    (6) Dates of market launches; and
    (7) Trade name(s).
    (C) Actions taken for safety reasons. (1) This section of the IPSR 
includes details on the following types of regulatory authority-
initiated (e.g., by FDA) and/or applicant-initiated actions

[[Page 12484]]

related to safety that were taken during the period covered by the IPSR 
and between the data lock point and IPSR submission (i.e., ``late-
breaking'' safety concerns):
    (i) Withdrawal or suspension of drug product approval or indication 
for use approval;
    (ii) Failure to obtain a marketing authorization renewal or to 
obtain an approval for a new indication for use;
    (iii) Restrictions on distribution (e.g., products recalled for 
safety reasons);
    (iv) Clinical trial suspension;
    (v) Dosage modification;
    (vi) Changes in target population or indications; and
    (vii) Formulation changes.
    (2) This section of the IPSR also contains a narrative identifying 
the safety-related reasons that led to these actions with relevant 
documentation appended when appropriate.
    (3) Any communication with health care professionals (e.g., Dear 
Healthcare Professional letters) resulting from such actions must also 
be described with copies appended.
    (D) Changes to CCSI. This section of the IPSR describes changes to 
the CCSI (e.g., new contraindications, precautions, warnings, SADRs, or 
interactions) made during the period covered by the IPSR. A copy of any 
modified section of the CCSI must be included. The applicant must use 
the CCSI in effect at the beginning of the reporting period for the 
IPSR. The revised CCSI is to be used as the reference document for the 
next reporting period.
    (E) Worldwide patient exposure. (1) This section of the IPSR 
includes, for the reporting period, an estimate of the worldwide 
patient exposure to the drug product(s) covered by the IPSR (i.e., 
number of patients, average or median dose received, and average or 
median length of treatment). The method used to estimate patient 
exposure must always be described. If the patient exposure is 
impossible to estimate or is meaningless, an explanation of and 
justification for such conclusions must be provided. If patient 
exposure is impossible to estimate, other measures of exposure, such as 
patient-days, number of prescriptions, or number of dosage units, may 
be used. If these or other more precise measures are not available and 
an adequate explanation for the lack of such information is provided, 
bulk sales may be used.
    (2) When possible, data broken down by gender and age (especially 
pediatric versus adult) must be provided. For the pediatric population, 
data must be reported, if possible, by age group (e.g., neonates, 
infants, children, adolescents). If these data are not available, an 
explanation must be included.
    (3) When a pattern of reports indicates a potential problem, 
details by country (with locally recommended dosage regimens) or other 
segmentation (e.g., indication, dosage form) must be presented.
    (F) Safety studies. This section of the IPSR contains a discussion 
of nonclinical, clinical, and epidemiological studies that contain 
important safety information, as follows:
    (1) All applicant-sponsored studies newly analyzed during the 
reporting period (copies of full reports should be appended only if new 
safety issues are raised or confirmed; FDA may request copies of other 
studies, if necessary);
    (2) New studies specifically planned, initiated, or continuing 
during the reporting period that examine a safety issue, whether actual 
or hypothetical; and
    (3) Published safety studies in the scientific and medical 
literature, including relevant published abstracts from meetings 
(provide literature citation).
    (G) Other information. This section of the IPSR includes a 
discussion of medically relevant lack of efficacy reports (e.g., might 
represent a significant hazard to the treated population) for a 
product(s) used to treat serious or life-threatening diseases.
    (H) Overall safety evaluation. This section of the IPSR contains a 
concise, yet comprehensive, analysis of all of the safety information 
provided in the IPSR. In addition, this section of the IPSR must 
include an assessment by the applicant of the significance of the data 
collected during the reporting period, as well as from the perspective 
of cumulative experience.
    (1) The applicant must highlight any new information on:
    (i) Serious, unlisted SADRs;
    (ii) Increased reporting frequencies of listed SADRs, including 
comments on whether it is believed that the data reflect a meaningful 
change in SADR occurrence;
    (iii) A change in characteristics of listed SADRs (e.g., severity, 
outcome, target population); and
    (iv) Nonserious, unlisted SADRs.
    (2) As part of the overall safety evaluation, the applicant must 
also explicitly address any new safety issue including but not limited 
to the following (lack of significant new information for each of the 
following must be mentioned):
    (i) Drug interactions;
    (ii) Experience with overdose, whether deliberate or accidental, 
and its treatment;
    (iii) Drug abuse or intentional misuse;
    (iv) Positive or negative experiences during pregnancy or 
lactation;
    (v) Effects with long-term treatment; and
    (vi) Experience in special patient groups (e.g., pediatric, 
geriatric, organ impaired). For the pediatric population, data must be 
evaluated, if possible, by age group (e.g., neonates, infants, 
children, adolescents).
    (I) Conclusion. This section of the IPSR:
    (1) Indicates new safety information that is not in accord with 
previous cumulative experience and with the CCSI in use at the 
beginning of the reporting period (e.g., new evidence that strengthens 
a possible causal relationship between the drug product and an SADR 
such as positive rechallenge, an epidemiological association or new 
laboratory studies); and
    (2) Specifies and justifies any action recommended or initiated, 
including changes in the CCSI.
    (J) Appendices. This section of the IPSR includes:
    (1) Company core data sheet. Provide a copy of the company core 
data sheet covered by this IPSR (i.e., in effect at the beginning of 
the period covered by the IPSR), as well as the company core data sheet 
for the next reporting period. Company core data sheets must be 
numbered and dated and include the date of last revision.
    (2) U.S. labeling. Provide a copy of the current approved U.S. 
labeling. Specify any safety information that is included in the CCSI 
but not in the U.S. labeling and provide an explanation for the 
discrepancy. Describe any safety-related changes or proposed changes to 
the U.S. labeling made during the reporting period (include the 
supplement number(s) and date(s) of submission for the supplement(s)) 
and any suggested change(s) that should be considered based on the 
safety analysis in this IPSR.
    (3) Spontaneous reports submitted to the applicant by an individual 
other than a health care professional. Provide a brief discussion of 
the impact on the overall safety evaluation of any spontaneously 
reported serious SADRs, whether domestic or foreign, and any 
spontaneously reported nonserious SADRs occurring in the United States, 
obtained or otherwise received during the reporting period by the 
applicant from an individual other than a health care professional 
(e.g., reports from consumers).

[[Page 12485]]

    (4) SADRs with unknown outcome. Provide a brief discussion of the 
impact on the overall safety evaluation of any spontaneously reported 
unlisted and listed SADRs with unknown outcome obtained or otherwise 
received during the reporting period by the applicant from health care 
professionals and other individuals.
    (5) Class action lawsuits. Provide a brief discussion of the impact 
on the overall safety evaluation of any safety information obtained or 
otherwise received during the reporting period by the applicant from 
class action lawsuits.
    (6) Lack of efficacy reports. Provide an assessment of whether it 
is believed that the frequency of any lack of efficacy reports, 
obtained or otherwise received during the reporting period, is greater 
than would be predicted by the premarketing clinical trials for the 
drug product.
    (7) Information on resistance to antimicrobial drug products. 
Provide information, received or otherwise obtained by the applicant, 
on resistance to antimicrobial drug products intended to treat 
infectious diseases. Include information on changes in U.S. microbial 
in vitro susceptibility, the relationship of changes in U.S. microbial 
in vitro susceptibility and clinical outcomes, therapeutic failure that 
may possibly be due to resistance to the antimicrobial drug product, 
and whether the U.S. labeling should be revised because of the 
information on antimicrobial resistance learned during the period 
covered by this IPSR.
    (8) Medication errors. Provide a brief discussion of the impact on 
the overall safety evaluation of all domestic reports of medication 
errors submitted during the reporting period under paragraph (c)(2)(v) 
of this section.
    (9) U.S. patient exposure. Provide, for the reporting period, an 
estimate of the U.S. patient exposure to the drug product(s) covered by 
the IPSR (i.e., number of patients, average or median dose received, 
and average or median length of treatment). The method used to estimate 
patient exposure must always be described. If the patient exposure is 
impossible to estimate or is meaningless, an explanation of and 
justification for such conclusions must be provided. If patient 
exposure is impossible to estimate, other measures of exposure, such as 
patient-days, number of prescriptions, or number of dosage units, may 
be used. If these or other more precise measures are not available and 
an adequate explanation for the lack of such information is provided, 
bulk sales may be used.
    (10) Location of safety records. Provide a list of the current 
address(es) where all safety reports and other safety-related records 
for the drug product are maintained.
    (11) Contact person. Provide the name and telephone number for the 
licensed physician(s) responsible for the content and medical 
interpretation of the information contained within the IPSR. Include, 
if available, the fax number and e-mail address for the licensed 
physician(s).
    (iv) Pediatric use supplements. After approval of a pediatric use 
supplement to an approved application (i.e., a supplement for use of 
the human drug product in the pediatric population), the applicant must 
submit PSURs to FDA as prescribed under paragraph (c)(3)(ii) of this 
section according to the following schedule: Semiannually for 2 years 
after U.S. approval of the supplement, annually for the next 3 years, 
and then every 5 years thereafter. These applicants must also submit 
IPSRs to FDA as prescribed under paragraph (c)(3)(iii) of this section 
at 7.5 years and 12.5 years after U.S. approval of the supplement. The 
data lock point for the PSUR and IPSR is the month and day of the 
international birth date of the drug substance or any other month and 
day agreed on by the applicant and FDA.
    (v) Semiannual submission of individual case safety reports. (A) An 
applicant holding an application for a human drug product approved 
under section 505(c) of the act must submit to FDA semiannually (i.e., 
every 6 months) after U.S. approval of the application a separate 
report that consists of individual case safety reports for certain 
spontaneously reported SADRs for the human drug product. The individual 
case safety reports must be submitted to FDA on the form designated by 
the agency under paragraph (c)(4) of this section. The data lock point 
for the report is the month and day of the international birth date of 
the drug product or any other month and day agreed on by the applicant 
and FDA. This report must be identified as ``individual case safety 
reports--semiannual submission.''
    (B) Applicants that submit TPSRs to FDA for the drug product must 
submit an individual case safety report for each serious, expected 
SADR, whether domestic or foreign, and each nonserious, unexpected SADR 
occurring in the United States that is submitted to the applicant 
during the reporting period from all spontaneous sources (i.e., health 
care professionals and other individuals). Applicants that submit PSURs 
to FDA for the drug product must submit an individual case safety 
report for each serious, listed SADR, whether domestic or foreign, and 
each nonserious, unlisted SADR occurring in the United States that is 
submitted to the applicant during the reporting period from all 
spontaneous sources. If a full data set is not available for a serious 
SADR, the applicant must submit the information required under 
paragraph (c)(1)(iv) of this section.
    (C) Followup information on SADRs submitted in an individual case 
safety report--semiannual submission may be submitted in the next 
individual case safety report--semiannual submission unless such 
information changes the classification of the SADR to a serious, 
unexpected SADR. In these cases, the followup information must be 
submitted to FDA as a 15-day followup report (see paragraph (c)(2)(vii) 
of this section).
    (4) Reporting format. (i)(A) Except as provided in paragraphs 
(c)(4)(i)(B), (c)(4)(i)(D), and (c)(4)(v) of this section, the 
applicant must complete an FDA Form 3500A for each individual case 
safety report of an SADR. Reports based on information about individual 
cases or case series in the scientific literature must be submitted on 
an FDA Form 3500A(s).
    (B) Foreign SADRs may be submitted either on an FDA Form 3500A or, 
if preferred, on a CIOMS I form.
    (C) Each domestic report of an actual or potential medication error 
must be submitted on an FDA Form 3500A.
    (D) Reports of overall findings or data in the aggregate from 
published and unpublished in vitro, animal, epidemiological, or 
clinical studies must be submitted in a narrative format.
    (ii) Each SADR in an individual case safety report must be coded on 
the FDA Form 3500A or CIOMS I form using the appropriate ``preferred 
term'' in the latest version of MedDRA (the medical dictionary for 
regulatory activities) in use at the time the applicant becomes aware 
of the individual case safety report. For individual case safety 
reports of medication errors, the report must be coded both as a 
medication error and, if applicable, with the preferred term for any 
SADRs associated with the medication error.
    (iii) Each completed FDA Form 3500A or CIOMS I form should refer 
only to an individual case.
    (iv) Each completed FDA Form 3500A or CIOMS I form must include the 
name and telephone number (and fax number and e-mail address, if 
available) for the licensed physician responsible for the content and 
medical interpretation of the data contained within the form (i.e., 
contact person for the company).
    (v) Instead of using FDA Form 3500A, the applicant may use a 
computer-generated facsimile of FDA Form 3500A provided that it is 
readable, includes

[[Page 12486]]

appropriate identifying information, and contains all the elements 
(i.e., format, sections, blocks, titles, descriptors within blocks, 
text for disclaimer) of FDA Form 3500A in the identical enumerated 
sequence of the form. For individual case safety reports in which no 
suspect medical device is involved, a one-page FDA Form 3500A is 
acceptable.
    (d) Multiple reports. An applicant should not include in reports 
under this section any SADRs that occurred in clinical trials if they 
were previously submitted as part of the approved application. If a 
report applies to a drug for which an applicant holds more than one 
approved application, the applicant should submit the report to the 
application that was first approved. If a report refers to more than 
one drug marketed by an applicant, the applicant should submit the 
report to the application for the drug listed first in the report.
    (e) Patient privacy. The names and addresses of individual patients 
should not be included in reports under this section; instead, the 
applicant and its contractors should assign a unique code to each 
report, preferably not more than eight characters (i.e., numbers and/or 
letters) in length. The name of the reporter from whom the information 
was received should be included. Names of patients, individual 
reporters, health care professionals, hospitals, and geographic 
identifiers in safety reports are not releasable to the public under 
FDA's public information regulations in part 20 of this chapter.
    (f) Recordkeeping. Each applicant must maintain for a period of 10 
years records of all safety information pertaining to its drug product, 
received or otherwise obtained, including raw data, any correspondence 
relating to the safety information, and any reports of SADRs or 
medication errors not submitted to FDA or only provided to FDA in a 
summary tabulation. Each applicant must also retain for a period of 10 
years any records required to be maintained under this section. When 
appropriate, FDA may require an applicant to submit any or all of these 
records to the agency within 5 calendar days after receipt of the 
request.
    (g) Written procedures. Each applicant must develop and maintain 
written procedures for the surveillance, receipt, evaluation, and 
reporting of postmarketing safety information to FDA.
    (h) Withdrawal of approval. If an applicant fails to establish and 
maintain records and make reports required under this section, FDA may 
withdraw approval of the application and, thus, prohibit continued 
marketing of the drug product that is the subject of the application.
    (i) Disclaimer. A report or information submitted by an applicant 
under this section (and any release by FDA of that report or 
information) does not necessarily reflect a conclusion by the applicant 
or FDA that the report or information constitutes an admission that the 
drug caused or contributed to an SADR. An applicant need not admit, and 
may deny, that the report or information submitted under this section 
constitutes an admission that the drug caused or contributed to an 
SADR.
    8. Section 314.81 is amended by removing paragraph (b)(2)(v), by 
redesignating paragraphs (b)(2)(vi) through (b)(2)(ix) as paragraphs 
(b)(2)(v) through (b)(2)(viii), respectively, and by revising paragraph 
(b)(2)(i) and newly redesignated paragraph (b)(2)(v) to read as 
follows:


Sec.  314.81  Other postmarketing reports.

* * * * *
    (b) * * *
    (2) * * *
    (i) Summary. A brief summary of significant new information from 
the previous year that might affect the effectiveness of the drug 
product or the sections of the drug product labeling that are not 
related to safety. The report must also contain a brief description of 
actions the applicant has taken or intends to take as a result of this 
new information, for example, submit an efficacy labeling supplement or 
initiate a new study. The summary must briefly state whether 
supplements for pediatric use have been submitted and whether new 
studies in the pediatric population to support appropriate labeling for 
the pediatric population have been initiated.
* * * * *
    (v) Clinical data. (A) Published clinical trials of the drug (or 
abstracts of them), including clinical trials on effectiveness; 
clinical trials on new uses; and biopharmaceutic, pharmacokinetic, and 
clinical pharmacology studies conducted by or otherwise obtained by the 
applicant. Review articles, papers describing safety related 
information or the use of the drug product in medical practice, papers 
and abstracts in which the drug is used as a research tool, promotional 
articles, press clippings, and papers that do not contain tabulations 
or summaries of original data should not be reported.
    (B) Summaries of completed unpublished clinical trials, or 
prepublication manuscripts if available, conducted by, or otherwise 
obtained by, the applicant. Supporting information should not be 
reported. (A study is considered completed 1 year after it is 
concluded.)
    (C) Analysis of available efficacy data in the pediatric population 
and changes proposed in the labeling based on this information. An 
assessment of data needed to ensure appropriate labeling for the 
pediatric population must be included.
* * * * *
    9. Section 314.98 is amended in paragraph (a) by adding the 
abbreviation ``(ANDA)'' after the phrase ``abbreviated new drug 
application'', by removing the citation ``Sec.  314.94'' and by adding 
in its place the phrase ``section 505(j) of the Act'', by removing the 
phrase ``adverse drug experiences'' and by adding in its place the 
phrase ``suspected adverse drug reactions'', and by adding two 
sentences to the end of the paragraph; and in paragraph (b) by removing 
the phrase ``Division of Epidemiology and Surveillance (HFD-730), 
Center for Drug Evaluation and Research, Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857'' and by adding in its place the 
word ``FDA'' to read as follows:


Sec.  314.98  Postmarketing reports.

    (a) * * * For purposes of postmarketing periodic safety reporting, 
applicants must determine the data lock point (i.e., month and day of 
the international birth date or any other month and day agreed by the 
applicant and FDA) for their periodic safety reports based on the data 
lock point of postmarketing periodic safety reports for other drug 
products containing the same drug substance (i.e., innovator new drug 
application (NDA) product that is the same drug product as the ANDA 
product, or other ANDA products with the same drug substance if the 
innovator NDA product is no longer on the market). Applicants must 
determine the type of postmarketing periodic safety report required to 
be submitted to FDA (i.e., traditional periodic safety report (TPSR), 
periodic safety update report (PSUR) or interim periodic safety report 
(IPSR)) and the frequency of submission for these reports based on the 
U.S. approval date of the application for the innovator NDA product.
* * * * *

PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS

    10. The authority citation for 21 CFR part 320 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 371.


[[Page 12487]]


    11. Section 320.31 is amended by revising paragraph (d) to read as 
follows:


Sec.  320.31  Applicability of requirements regarding an 
``Investigational New Drug Application.''

* * * * *
    (d) A bioavailability or bioequivalence study in humans other than 
one described in paragraphs (a) through (c) of this section is exempt 
from the requirements of part 312 of this chapter, except for the 
safety reporting requirements under Sec.  312.32 of this chapter, if 
the following conditions are satisfied:
    (1) If the study is one described under Sec.  320.38(b) or Sec.  
320.63, the person conducting the study, including any contract 
research organization, must retain reserve samples of any test article 
and reference standard used in the study and release the reserve 
samples to FDA upon request in accordance with and for the period 
specified in Sec.  320.38;
    (2) An in vivo bioavailability or bioequivalence study in humans 
must be conducted in compliance with the requirements for institutional 
review set forth in part 56 of this chapter and informed consent set 
forth in part 50 of this chapter; and
    (3) Safety reports as prescribed under Sec.  312.32 of this chapter 
must be transmitted to all participating investigators and the 
appropriate FDA division in the Center for Drug Evaluation and Research 
(i.e., safety reports for the reference listed drug must be sent to the 
new drug review division that has responsibility for that drug, safety 
reports for the investigational drug product must be sent to the 
Director, Division of Bioequivalence, Office of Generic Drugs). Each 
written notification under this paragraph must bear prominent 
identification of its contents, i.e., ``bioavailability/bioequivalence 
safety report.'' For reporting purposes under this paragraph, an 
unexpected suspected adverse drug reaction (SADR) is any SADR, the 
specificity or severity of which is not consistent with the U.S. 
labeling for the reference listed drug.

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    12. The authority citation for 21 CFR part 600 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

    13. Section 600.80 is revised to read as follows:


Sec.  600.80  Postmarketing reporting of suspected adverse reactions.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Active query means direct verbal contact (i.e., in person or by 
telephone or other interactive means such as a video conference) with 
the initial reporter of a suspected adverse reaction (SAR) or 
medication error by a health care professional (e.g., physician, 
physician assistant, pharmacist, dentist, nurse, any individual with 
some form of health care training) representing the applicant. For 
SARs, active query entails, at a minimum, a focused line of questioning 
designed to capture clinically relevant information associated with the 
licensed biological product and the SAR, including, but not limited to, 
information such as baseline data, patient history, physical exam, 
diagnostic results, and supportive lab results.
    Actual medication error means a medication error that involves an 
identifiable patient whether the error was prevented prior to 
administration of the product or, if the product was administered, 
whether the error results in a serious SAR, nonserious SAR, or no SAR.
    Blood component means as defined in Sec.  606.3(c) of this chapter.
    Company core data sheet means a document prepared by the applicant 
containing, in addition to safety information, material relating to 
indications, dosing, pharmacology, and other information concerning the 
biological product. The only purpose of this document is to provide the 
company core safety information (CCSI) for periodic safety update 
reports (PSURs), interim periodic safety reports (IPSRs), and certain 
individual case safety reports--semiannual submissions (i.e., if PSURs 
are submitted for the product).
    Company core safety information (CCSI) means all relevant safety 
information contained in the company core data sheet that the applicant 
proposes to include in the approved product labeling in all countries 
where the applicant markets the biological product. It is the reference 
information by which an SAR is determined to be ``listed'' or 
``unlisted'' for PSURs, IPSRs, and certain individual case safety 
reports--semiannual submissions (i.e., if PSURs are submitted for the 
product).
    Contractor means any person (e.g., manufacturer, joint 
manufacturer, packer, or distributor whether or not its name appears on 
the label of the product; licensee; contract research organization) 
that has entered into a contract with the applicant (includes 
participants involved in divided manufacturing) to manufacture, pack, 
sell, distribute, or develop the licensed biological product or to 
maintain, create, or submit records regarding SARs or medication 
errors.
    Data lock point means the date designated as the cut-off date for 
data to be included in a postmarketing periodic safety report.
    Disability means a substantial disruption of a person's ability to 
conduct normal life functions.
    Full data set means completion of all the applicable elements on 
FDA Form 3500A or the vaccine adverse event reporting system (VAERS) 
form (or on a Council for International Organizations of Medical 
Sciences (CIOMS) I form for reports of foreign SARs), including a 
concise medical narrative of the case (i.e., an accurate summary of the 
relevant data and information pertaining to an SAR or medication 
error).
    International birth date means the date the first regulatory 
authority in the world approved the first marketing application for a 
human biological product.
    Life-threatening SAR means any SAR that, in the view of the initial 
reporter, places the patient at immediate risk of death from the SAR as 
it occurred. It does not include an SAR that, had it occurred in a more 
severe form, might have caused death.
    Listed SAR means an SAR whose nature, specificity, severity, and 
outcome are consistent with the information in the CCSI.
    Medication error means any preventable event that may cause or lead 
to inappropriate medication use or patient harm while the medication is 
in the control of the health care professional, patient, or consumer. 
Such events may be related to professional practice, health care 
products, procedures, and systems including: Prescribing; order 
communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; 
monitoring; and use.
    Minimum data set means the report includes an identifiable patient, 
an identifiable reporter, a suspect biological product, and an SAR.
    Nonserious SAR means any SAR that is determined not to be a serious 
SAR.
    Potential medication error means an individual case safety report 
of information or complaint about product name, labeling, or packaging 
similarities that does not involve a patient.
    SAR with unknown outcome means an SAR that cannot be classified, 
after

[[Page 12488]]

active query, as either serious or nonserious.
    Serious SAR means any SAR that results in any of the following 
outcomes: Death, a life-threatening SAR, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious SAR when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
    Spontaneous report means a communication from an individual (e.g., 
health care professional, consumer) to a company or regulatory 
authority that describes an SAR or medication error. It does not 
include cases identified from information solicited by the applicant, 
shared manufacturer, or contractor, such as individual case safety 
reports or findings derived from a study, company-sponsored patient 
support program, disease management program, patient registry, 
including pregnancy registries, or any organized data collection 
scheme. It also does not include information compiled in support of 
class action lawsuits.
    Suspected adverse reaction (SAR) means a noxious and unintended 
response to any dose of a biological product for which there is a 
reasonable possibility that the product caused the response. In this 
definition, the phrase ``a reasonable possibility'' means that the 
relationship cannot be ruled out.
    Unexpected SAR means any SAR that is not included in the current 
U.S. labeling for the licensed biological product. Reactions that may 
be symptomatically and pathophysiologically related to a reaction 
included in the U.S. labeling, but differ from the labeled reaction 
because of greater severity or specificity, would be unexpected. For 
example, under this definition, hepatic necrosis would be unexpected 
(by virtue of greater severity) if the U.S. labeling only referred to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue 
of greater specificity) if the U.S. labeling only included cerebral 
vascular accidents. ``Unexpected,'' as used in this definition, refers 
to an SAR that has not been previously observed (i.e., included in the 
U.S. labeling); it does not refer to an SAR that might be anticipated 
from the pharmacological properties of the licensed biological product. 
SARs that are mentioned in the U.S. labeling as occurring with a class 
of products but not specifically mentioned as occurring with the 
particular product are considered unexpected.
    Unlisted SAR means an SAR whose nature, specificity, severity, or 
outcome is not consistent with the information included in the CCSI.
    (b) Review of safety information. (1) Any person having a biologics 
license under Sec.  601.20 of this chapter must promptly review all 
safety information pertaining to its product obtained or otherwise 
received by the applicant from any source, foreign or domestic, 
including information derived from commercial marketing experience, 
postmarketing clinical investigations, postmarketing epidemiology/
surveillance studies, animal or in vitro studies, electronic 
communications with applicants via the Internet (e.g., e-mail), reports 
in the scientific literature, and unpublished scientific papers, as 
well as reports from foreign regulatory authorities that have not been 
previously reported to the Food and Drug Administration (FDA) by the 
applicant.
    (2) Individual case safety reports that are forwarded to the 
applicant by FDA must not be resubmitted to the agency by the 
applicant; however, applicants must include information from these 
individual case safety reports in any comprehensive safety analysis 
subsequently submitted to FDA. In addition, applicants must submit to 
FDA all followup information for these individual case safety reports.
    (c) Reporting requirements. For nonvaccine biological products, the 
applicant must submit to FDA two copies of each postmarketing expedited 
report (described under paragraphs (c)(2)(i) through (c)(2)(vii) of 
this section) and each postmarketing periodic safety report of an 
individual case safety reports--semiannual submission (described under 
paragraph (c)(3)(v) of this section) pertaining to its product. For 
nonvaccine biological products, the applicant must also submit to FDA 
one copy of a PSUR, IPSR, or traditional periodic safety report (TPSR) 
along with one copy for each approved application for a human licensed 
biological product covered by the report. For vaccines, the applicant 
must submit to VAERS two copies of each safety report pertaining to its 
product and required under this section. FDA may waive the requirement 
for multiple copies in appropriate instances. Upon written notice, FDA 
may require, when appropriate, that the applicant submit reports under 
this section to the agency at times other than those stated. An 
applicant that wishes to submit reports under this section at different 
intervals must submit to FDA a request for a waiver under Sec.  600.90.
    (1) Determination of outcome, minimum data set, and full data set--
(i)(A) Initial determinations. Upon initial receipt of an SAR report, 
the applicant must immediately determine the outcome for the SAR 
(whether the SAR is serious or nonserious) and at least the minimum 
data set for the individual case safety report. For reports of actual 
medication errors that do not result in an SAR and potential medication 
errors, the applicant must immediately determine the minimum 
information for the individual case safety report (minimum information 
described under paragraphs (c)(1)(iii)(B) and (c)(1)(iii)(C) of this 
section). If the applicant is not able to immediately determine the 
information in this paragraph, active query must be used to obtain it 
as soon as possible.
    (B) Spontaneous reports. For spontaneous reports, the applicant 
must always assume, for safety reporting purposes under this section, 
that there is at least a reasonable possibility, in the opinion of the 
initial reporter, that the biological product caused the spontaneously 
reported event.
    (C) Clinical trials. For a clinical trial, the possibility that the 
biological product caused the SAR or that a medication error has 
occurred must be assumed if either the investigator or the applicant 
believes that such a reasonable possibility exists.
    (ii) SARs with unknown outcome. For an SAR with unknown outcome 
that cannot be immediately determined, the applicant must continue to 
use active query to attempt to determine the outcome of the SAR within 
30 calendar days after initial receipt of the SAR report by the 
applicant. The applicant must maintain a record of its efforts to 
determine the outcome for an SAR with unknown outcome.
    (iii) (A) Minimum data set for SAR reports. The applicant must not 
submit an individual case safety report for an SAR to FDA if the report 
does not contain a minimum data set; instead, the applicant must 
maintain records of any information received or otherwise obtained for 
the SAR along with a record of its efforts to obtain a minimum data 
set.

[[Page 12489]]

    (B) Minimum information for reports of actual medication errors 
that do not result in an SAR. For reports of actual medication errors 
that do not result in an SAR, an individual case safety report must be 
submitted to FDA even though the report does not contain a minimum data 
set (i.e., does not have an SAR). These reports must contain at least 
an identifiable patient, an identifiable reporter, and a suspect 
biological product.
    (C) Minimum information for potential medication error reports. For 
reports of potential medication errors, an individual case safety 
report must be submitted to FDA even though the report does not contain 
a minimum data set (i.e., does not have an identifiable patient or an 
SAR). These reports must contain at least an identifiable reporter and 
a suspect biological product.
    (iv) Full data set. For reports of serious SARs, always expedited 
reports (see paragraph (c)(2)(iv) of this section), and medication 
error reports (see paragraph (c)(2)(v) of this section), the applicant 
must submit a full data set. If a full data set is not available for 
the report, the applicant must use active query to obtain this 
information. If a full data set is not obtainable after active query, 
the applicant must:
    (A) Submit all safety information, received or otherwise obtained, 
for the report;
    (B) Indicate the reason(s) for its inability to acquire a full data 
set; and
    (C) Document its efforts to obtain a full data set (i.e., 
description of unsuccessful steps taken to obtain this information).
    (v) Serious SARs not initially reported by a health care 
professional. For a serious SAR that was not initially reported to the 
applicant by a health care professional (e.g., report from a consumer), 
the applicant must contact the health care professional associated with 
the care of the patient using active query to gather further medical 
perspective on the case and to acquire a full data set for the report. 
If the applicant is unable to contact the health care professional, it 
must include in the report for the serious SADR:
    (A) The reason(s) for its inability to contact the health care 
professional; and
    (B) A description of its efforts to contact the health care 
professional.
    (vi) Nonserious SARs. For reports of nonserious SARs with a minimum 
data set, except for those resulting from a medication error, all 
safety information received or otherwise obtained by the applicant must 
be submitted to FDA even though information in addition to the minimum 
data set is not required to be acquired. Reports of nonserious SARs 
resulting from a medication error require a full data set under 
paragraph (c)(1)(iv) of this section.
    (2) Postmarketing ``expedited reports''--(i) Serious and unexpected 
SAR. The applicant must report to FDA each SAR, received or otherwise 
obtained, that is both serious and unexpected, whether foreign or 
domestic, as soon as possible, but in no case later than 15 calendar 
days after receipt by the applicant of the minimum data set for the 
serious, unexpected SAR. If a full data set is not available for the 
serious and unexpected SAR report at the time of initial submission of 
the report to FDA, the applicant must submit the information required 
under paragraph (c)(1)(iv) of this section and also submit a 30-day 
followup report as required by paragraph (c)(2)(vi) of this section.
    (ii) Information sufficient to consider product administration 
changes. The applicant must also report to FDA information, received or 
otherwise obtained, whether foreign or domestic, that would be 
sufficient, based upon appropriate medical judgment, to consider 
changes in product administration. The applicant must submit this 
information to FDA as soon as possible, but in no case later than 15 
calendar days after determination by the applicant that the information 
qualifies for expedited reporting. Examples of such information include 
any significant unanticipated safety finding or data in the aggregate 
from an in vitro, animal, epidemiological, or clinical study, whether 
or not conducted under an investigational new drug application (IND), 
that suggests a significant human risk, such as reports of 
mutagenicity, teratogenicity, or carcinogenicity, or reports of a lack 
of efficacy with a biological product used in treating a life-
threatening or serious disease. The applicant must maintain a record of 
its efforts to determine whether the information required to be 
reported under this paragraph qualifies for expedited reporting.
    (iii) Unexpected SAR with unknown outcome. The applicant must also 
report to FDA each SAR that is unexpected and for which the 
determination of an outcome is unattainable (i.e., SAR with unknown 
outcome) within 45 calendar days after initial receipt by the applicant 
of the minimum data set for the unexpected SAR. The applicant must 
document in the expedited report the reason(s) for the inability to 
determine the outcome.
    (iv) Always expedited report. (A) The applicant must also report to 
FDA each SAR, received or otherwise obtained, whether foreign or 
domestic, that is the subject of an always expedited report. These 
reports must be submitted to FDA as soon as possible, but in no case 
later than 15 calendar days after receipt by the applicant of the 
minimum data set for the report. The following medically significant 
SARs, which may jeopardize the patient or subject and/or require 
medical or surgical intervention to treat the patient or subject, are 
subject to an always expedited report:
    (1) Congenital anomalies,
    (2) Acute respiratory failure,
    (3) Ventricular fibrillation,
    (4) Torsades de pointe,
    (5) Malignant hypertension,
    (6) Seizure,
    (7) Agranulocytosis,
    (8) Aplastic anemia,
    (9) Toxic epidermal necrolysis,
    (10) Liver necrosis,
    (11) Acute liver failure,
    (12) Anaphylaxis,
    (13) Acute renal failure,
    (14) Sclerosing syndromes,
    (15) Pulmonary hypertension,
    (16) Pulmonary fibrosis,
    (17) Confirmed or suspected transmission of an infectious agent by 
a marketed drug or biological product,
    (18) Confirmed or suspected endotoxin shock, and
    (19) Any other medically significant SAR that FDA determines to be 
the subject of an always expedited report (i.e., may jeopardize the 
patient or subject and/or require medical or surgical intervention to 
treat the patient or subject).
    (B) SARs that are the subject of an always expedited report must be 
submitted to FDA whether unexpected or expected and whether or not the 
SAR leads to a serious outcome. If a full data set is not available for 
an always expedited report at the time of initial submission of the 
report to FDA, the applicant must submit the information required under 
paragraph (c)(1)(iv) of this section and also submit a 30-day followup 
report as required by paragraph (c)(2)(vi) of this section.
    (v) Medication error--(A) Actual medication error. The applicant 
must also submit to FDA each domestic report of an actual medication 
error, received or otherwise obtained, as soon as possible, but in no 
case later than 15 calendar days after receipt by the applicant of the 
minimum data set for a report of an SAR or, if an SAR does not occur, 
the minimum information described under paragraph (c)(1)(iii)(B) of 
this section (i.e., identifiable patient, identifiable reporter, and 
suspect biological product).
    (B) Potential medication error. The applicant must also submit to 
FDA each domestic report of a potential

[[Page 12490]]

medication error, received or otherwise obtained, as soon as possible, 
but in no case later than 15 calendar days after receipt by the 
applicant of the minimum information described under paragraph 
(c)(1)(iii)(C) of this section (i.e., identifiable reporter and suspect 
biological product).
    (C) Full data set. If a full data set is not available for an 
actual or potential medication error report at the time of initial 
submission of the report to FDA, the applicant must submit the 
information required under paragraph (c)(1)(iv) of this section and 
also submit a 30-day followup report as required by paragraph 
(c)(2)(vi) of this section.
    (vi) The 30-day followup report. The applicant must use active 
query to obtain additional information for any expedited report under 
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that 
does not contain a full data set and must submit a followup report to 
FDA within 30 calendar days after initial submission of the expedited 
report to FDA by the applicant. If a full data set is still not 
obtainable, the 30-day followup report must contain the information 
required under paragraph (c)(1)(iv) of this section. Any new safety 
information in the 30-day followup report must be highlighted. Any new 
information received or otherwise obtained after submission of a 30-day 
followup report must be submitted to FDA as a 15-day followup report 
under paragraph (c)(2)(vii) of this section.
    (vii) The 15-day followup report. The applicant must report to FDA 
any new information, received or otherwise obtained, for any expedited 
or followup report (except for initial expedited reports under 
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that do 
not contain a full data set) within 15 calendar days of initial receipt 
of the new information by the applicant. Expedited reports under 
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that do 
not contain a full data set at the time of initial submission of the 
report to FDA are subject to the 30-day followup reporting requirements 
under paragraph (c)(2)(vi) of this section rather than the 15-day 
followup reporting requirements under this paragraph.
    (viii) Supporting documentation. (A) If the patient dies, the 
applicant must submit a copy of the autopsy report to FDA, if it is 
available. If an autopsy report is not available, the applicant must 
submit a death certificate to FDA. If an autopsy report becomes 
available after the applicant has submitted a death certificate to the 
agency, the autopsy report must be submitted to FDA. If the patient was 
hospitalized, the applicant must submit a copy of the hospital 
discharge summary to FDA, if it is available. If any of these documents 
is not in English, the document must be accompanied by an English 
translation. Applicants must use active query to obtain these 
documents. These documents must be submitted to FDA as 15-day followup 
reports (see paragraph (c)(2)(vii) of this section) within 15 calendar 
days of initial receipt of the document by the applicant. If these 
documents are not submitted to FDA in a 15-day followup report within 3 
months after submission of the initial expedited report for the death 
or hospitalization, the agency will assume that active query by the 
applicant has not resulted in access to these documents. In this case, 
a record of the reason(s) for the lack of such documentation and the 
effort that was made to obtain the documentation must be maintained by 
the applicant.
    (B) Each expedited report must contain in the narrative a list of 
other relevant documents (e.g., medical records, laboratory results, 
data from studies) for the report that are maintained by the applicant. 
When appropriate, FDA may require an applicant to submit copies of one 
or more of these documents to the agency within 5 calendar days after 
receipt of the request.
    (ix) Scientific literature. An expedited report based on 
information from the scientific literature applies only to reports 
found in scientific and medical journals. These expedited reports must 
be accompanied by a copy of the published article.
    (x) Submission of safety reports by contractors and shared 
manufacturers. (A) Contractors and shared manufacturers must submit to 
the applicant (includes participants involved in divided manufacturing) 
safety reports of any SARs or medication errors for the applicant's 
biological product, obtained or otherwise received, within 5 calendar 
days of initial receipt of the report by the contractor or shared 
manufacturer. The contractor and shared manufacturer must submit a 
safety report for an SAR to the applicant even if the report does not 
contain a minimum data set. Upon receipt of the safety report from a 
contractor or shared manufacturer, the applicant must comply with the 
postmarketing safety reporting requirements of this section.
    (B) A contract between the applicant and a contractor must specify 
the postmarketing safety reporting responsibilities of the contractor. 
The applicant is responsible for ensuring that the contractors and 
shared manufacturers of its licensed biological products comply with 
these postmarketing safety reporting responsibilities.
    (C) The contractor and shared manufacturer must maintain a record 
of each submission to the applicant under paragraph (c)(2)(x)(A) of 
this section that includes:
    (1) A copy of each safety report;
    (2) The date the report was initially received by the contractor or 
shared manufacturer;
    (3) The date the report was submitted to the applicant; and
    (4) The name and address of the applicant.
    (D) The recordkeeping, written procedures, and disclaimer 
provisions under paragraphs (f), (g), and (j) of this section apply to 
contractors and shared manufacturers.
    (xi) Report identification. Each expedited report submitted to FDA 
under paragraphs (c)(2)(i) through (c)(2)(vii) of this section must 
bear prominent identification as to its contents, e.g., ``expedited 
report--serious and unexpected SAR,'' ``expedited report--30-day 
followup report.'' Each type of report (e.g., serious and unexpected 
SAR reports, 30-day followup reports) must be submitted to FDA under 
separate cover. Reports of medication errors must indicate whether the 
error is actual or potential and if actual, whether a serious SAR, 
nonserious SAR, or no SAR occurred, e.g., ``expedited report--actual 
medication error--nonserious SAR,'' ``expedited report--potential 
medication error.''
    (3) Postmarketing periodic safety reports. The applicant must 
submit postmarketing periodic safety reports under this section (i.e., 
TPSRs, PSURs, IPSRs, individual case safety reports--semiannual 
submission) to FDA within 60 calendar days after the data lock point 
for the report. The applicant must include a cover letter containing a 
list of the biologics license application number(s) (i.e., BLA 
number(s)) for the human biological product(s) covered by the 
postmarketing periodic safety report. The international birth date for 
combination products is the international birth date of the human 
licensed biological product most recently approved for marketing.
    (i) Traditional periodic safety reports (TPSRs). Each applicant 
holding a biologics license under Sec.  601.20 of this chapter for a 
human biological product approved before January 1, 1998, must submit 
either a PSUR as prescribed under paragraph (c)(3)(ii) of this section 
or a TPSR as described under this paragraph every 5 years after U.S.

[[Page 12491]]

approval of the application. In addition, these applicants must submit 
either an IPSR as described under paragraph (c)(3)(iii) of this section 
or a TPSR as described under this paragraph 7.5 years and 12.5 years 
after U.S. approval of the application. The data lock point for the 
TPSR, PSUR, or IPSR is the month and day of the international birth 
date of the licensed biological product or any other month and day 
agreed on by the applicant and FDA. Each TPSR must contain:
    (A) Summary. This section of the TPSR includes:
    (1) A narrative summary and analysis of serious, expected SARs and 
nonserious, unexpected SARs occurring in the United States that were 
submitted to the applicant during the reporting period from all 
spontaneous sources (i.e., health care professionals and other 
individuals) (with an index consisting of a line listing of the 
applicant's manufacturer report number and SAR term(s));
    (2) An analysis of the expedited reports submitted during the 
reporting period under paragraphs (c)(2)(i) through (c)(2)(vii) of this 
section (all expedited reports must be appropriately referenced by the 
applicant's manufacturer report number, SAR term(s), if appropriate, 
and date of submission to FDA);
    (3) A discussion of any increased reporting frequency of serious, 
expected SARs, including comments on whether it is believed that the 
data reflect a meaningful change in SAR occurrence, and an assessment 
of whether it is believed that the frequency of lack of efficacy 
reports is greater than would be predicted by the premarketing clinical 
trials for the biological product; and
    (4) The applicant's conclusion as to what, if any, safety-related 
actions should be taken based on the analysis of the safety data in the 
TPSR (e.g., labeling changes, studies initiated).
    (B) Summary tabulations. This section of the TPSR includes summary 
tabulations (i.e., lists of all SAR terms and counts of occurrences) 
presented by body system or by standard organ system classification 
scheme for:
    (1) All serious expected SARs, nonserious unexpected SARs, 
nonserious expected SARs, and expected SARs with unknown outcome 
occurring in the United States that are submitted to the applicant 
during the reporting period from all spontaneous sources (i.e., health 
care professionals and other individuals);
    (2) All serious unexpected SARs, unexpected SARs with unknown 
outcome, and always expedited reports that were previously submitted to 
FDA in an expedited report under paragraphs (c)(2)(i), (c)(2)(iii), and 
(c)(2)(iv) of this section (include cumulative data for serious 
unexpected SARs, i.e., all cases reported to date);
    (3) All reports of SARs not previously submitted to FDA by the 
applicant (e.g., reports submitted to applicants by FDA, reports 
obtained from FDA from freedom of information requests at the 
discretion of the applicant, reports from class action lawsuits); and
    (4) All domestic reports of medication errors previously submitted 
to FDA under paragraph (c)(2)(v) of this section. For actual medication 
errors, provide summary tabulations of serious SARs, nonserious SARs, 
and no SARs. For potential medication errors, provide the number of 
reports for specific errors;
    (C) History of safety-related actions taken. This section of the 
TPSR includes a history of safety-related actions taken since the last 
periodic safety report (e.g., labeling changes, studies initiated);
    (D) Location of safety records. This section of the TPSR includes a 
list of the current address(es) where all safety reports and other 
safety-related records for the licensed biological product(s) are 
maintained; and
    (E) Contact person. This section of the TPSR includes the name and 
telephone number for the licensed physician(s) responsible for the 
content and medical interpretation of the information contained within 
the TPSR. Include, if available, the fax number and e-mail address for 
the licensed physician(s).
    (ii) Periodic safety update report (PSUR). An applicant holding a 
biologics license under Sec.  601.20 of this chapter for a human 
biological product approved on or after January 1, 1998, must submit a 
PSUR to FDA according to the following schedule: Semiannually (i.e., 
every 6 months) for 2 years after U.S. approval of the application, 
annually for the next 3 years, and then every 5 years thereafter. The 
data lock point for the PSUR is the month and day of the international 
birth date of the licensed biological product or any other month and 
day agreed on by the applicant and FDA. Each PSUR must contain:
    (A) Title page, table of contents, and introduction. (1) The title 
page includes, at a minimum, the following information:
    (i) Name and international birth date of the licensed biological 
product(s) that is the subject of the PSUR,
    (ii) Various dosage forms and formulations of the biological 
product(s) covered by the PSUR,
    (iii) Name and address of the applicant,
    (iv) Reporting period covered by the PSUR, and
    (v) Date of the PSUR.
    (2) The introduction:
    (i) Provides a brief description of how the PSUR relates to 
previous reports and circumstances;
    (ii) References relevant biological products reported in other 
periodic safety reports (e.g., a combination product reported in a 
separate PSUR); and
    (iii) Indicates any data duplication with other PSURs.
    (B) Worldwide marketing status. This section of the PSUR contains a 
table of the chronological history of the worldwide marketing status of 
the biological product(s) covered by the PSUR from the date the 
product(s) was first approved (i.e., the international birth date) 
through its current status (i.e., cumulative information). This table 
consists of:
    (1) Dates of biological product approval and renewal;
    (2) Safety-related restrictions on product use;
    (3) Indications for use and special populations covered by the 
biological product approval;
    (4) Lack of approval of the biological product in any dosage form 
or for any indication for use by any regulatory authority(ies);
    (5) Withdrawal of a pending marketing application for the 
biological product by the applicant for safety- or efficacy-related 
reasons;
    (6) Dates of market launches; and
    (7) Trade name(s).
    (C) Actions taken for safety reasons. (1) This section of the PSUR 
includes details on the following types of regulatory authority-
initiated (e.g., by FDA) and/or applicant-initiated actions related to 
safety that were taken during the period covered by the PSUR and 
between the data lock point and PSUR submission (i.e., ``late-
breaking'' safety concerns):
    (i) Withdrawal or suspension of biological product approval or 
indication for use approval;
    (ii) Failure to obtain a marketing authorization renewal or to 
obtain an approval for a new indication for use;
    (iii) Restrictions on distribution (products recalled for safety 
reasons);
    (iv) Clinical trial suspension;
    (v) Dosage modification;
    (vi) Changes in target population or indications; and
    (vii) Formulation changes.
    (2) This section of the PSUR also contains a narrative identifying 
the safety-related reasons that led to these actions with relevant 
documentation appended when appropriate.

[[Page 12492]]

    (3) Any communication with health care professionals (e.g., Dear 
Healthcare Professional letters) resulting from such actions must also 
be described with copies appended.
    (D) Changes to CCSI. This section of the PSUR describes changes to 
the CCSI (e.g., new contraindications, precautions, warnings, SARs, or 
interactions) made during the period covered by the PSUR. A copy of any 
modified section of the CCSI must be included. The applicant must use 
the CCSI in effect at the beginning of the reporting period for the 
PSUR. The revised CCSI is to be used as the reference document for the 
next reporting period.
    (E) Worldwide patient exposure. (1) This section of the PSUR 
includes, for the reporting period, an estimate of the worldwide 
patient exposure to the biological product(s) covered by the PSUR 
(i.e., number of patients, average or median dose received, and average 
or median length of treatment). The method used to estimate patient 
exposure must always be described. If the patient exposure is 
impossible to estimate or is meaningless, an explanation of and 
justification for such conclusions must be provided. If patient 
exposure is impossible to estimate, other measures of exposure, such as 
patient-days, number of prescriptions, or number of dosage units, may 
be used. If these or other more precise measures are not available and 
an adequate explanation for the lack of such information is provided, 
bulk sales may be used.
    (2) When possible, data broken down by gender and age (especially 
pediatric versus adult) must be provided. For the pediatric population, 
data must be reported, if possible, by age group (e.g., neonates, 
infants, children, adolescents). If these data are not available, an 
explanation must be included.
    (3) When a pattern of reports indicates a potential problem, 
details by country (with locally recommended dosage regimens) or other 
segmentation (e.g., indication, dosage form) must be presented.
    (F) Individual case safety reports. (1) This section of the PSUR 
includes summary tabulations of individual case safety reports (e.g., 
serious unlisted SARs, serious listed SARs, nonserious unlisted SARs, 
nonserious listed SARs) for the following SARs obtained or otherwise 
received during the reporting period:
    (i) All serious and nonserious SARs from spontaneous sources that 
were submitted to applicants by a health care professional,
    (ii) All serious SARs from studies, individual patient INDs, or, in 
foreign countries, from named-patient ``compassionate'' use,
    (iii) All serious SARs and nonserious unlisted SARs from the 
scientific literature,
    (iv) All serious SARs from regulatory authorities, and
    (v) Serious SARs from other sources such as reports created by 
poison control centers and epidemiological data bases.
    (2) The summary tabulations must be made up of lists by body system 
or by standard organ system classification scheme of all SAR terms and 
counts of occurrences. For SARs that are determined to be both serious 
and unlisted, include cumulative data (i.e., all cases reported to 
date).
    (3) The applicant must conclude this section with a brief 
discussion of the data concerning the individual case safety reports in 
the PSUR (e.g., discussion of medical significance or mechanism).
    (G) Safety studies. This section of the PSUR contains a discussion 
of nonclinical, clinical, and epidemiological studies that contain 
important safety information, as follows:
    (1) All applicant-sponsored studies newly analyzed during the 
reporting period (copies of full reports should be appended only if new 
safety issues are raised or confirmed; FDA may request copies of other 
studies, if necessary);
    (2) New studies specifically planned, initiated, or continuing 
during the reporting period that examine a safety issue, whether actual 
or hypothetical; and
    (3) Published safety studies in the scientific and medical 
literature, including relevant published abstracts from meetings 
(provide literature citation).
    (H) Other information. This section of the PSUR includes:
    (1) A discussion of medically relevant lack of efficacy reports 
(e.g., might represent a significant hazard to the treated population) 
for a product(s) used to treat serious or life-threatening diseases; 
and
    (2) Any important new information received after the data lock 
point (e.g., significant new cases).
    (I) Overall safety evaluation. This section of the PSUR contains a 
concise, yet comprehensive, analysis of all of the safety information 
provided in the PSUR, including new information provided under 
paragraph (c)(3)(ii)(H)(2) of this section. In addition, this section 
of the PSUR includes an assessment by the applicant of the significance 
of the data collected during the reporting period, as well as from the 
perspective of cumulative experience.
    (1) The applicant must highlight any new information on:
    (i) Serious, unlisted SARs;
    (ii) Increased reporting frequencies of listed SARs, including 
comments on whether it is believed that the data reflect a meaningful 
change in SAR occurrence;
    (iii) A change in characteristics of listed SARs (e.g., severity, 
outcome, target population); and
    (iv) Nonserious, unlisted SARs.
    (2) As part of the overall safety evaluation, the applicant must 
also explicitly address any new safety issue including but not limited 
to the following (lack of significant new information for each of the 
following must be mentioned):
    (i) Drug interactions;
    (ii) Experience with overdose, whether deliberate or accidental, 
and its treatment;
    (iii) Drug abuse or intentional misuse;
    (iv) Positive or negative experiences during pregnancy or 
lactation;
    (v) Effects with long-term treatment; and
    (vi) Experience in special patient groups (e.g., pediatric, 
geriatric, organ impaired). For the pediatric population, data must be 
evaluated, if possible, by age group (e.g., neonates, infants, 
children, adolescents).
    (J) Conclusion. This section of the PSUR:
    (1) Indicates new safety information that is not in accord with 
previous cumulative experience and with the CCSI in use at the 
beginning of the reporting period (e.g., new evidence that strengthens 
a possible causal relationship between the biological product and an 
SAR, such as positive rechallenge, an epidemiological association, or 
new laboratory studies); and
    (2) Specifies and justifies any action recommended or initiated, 
including changes in the CCSI.
    (K) Appendices. This section of the PSUR includes:
    (1) Company core data sheet. Provide a copy of the company core 
data sheet covered by this PSUR (i.e., in effect at the beginning of 
the period covered by the PSUR), as well as the company core data sheet 
for the next reporting period. Company core data sheets must be 
numbered and dated and include the date of last revision.
    (2) U.S. labeling. Provide a copy of the current approved U.S. 
labeling. Specify any safety information that is included in the CCSI 
but not in the U.S. labeling, and provide an explanation for the

[[Page 12493]]

discrepancy. Describe any safety-related changes or proposed changes to 
the U.S. labeling made during the reporting period (include the 
supplement number(s) and date(s) of submission for the supplement(s)) 
and any suggested change(s) that should be considered based on the 
safety analysis in this PSUR.
    (3) Spontaneous reports submitted to the applicant by an individual 
other than a health care professional. Provide summary tabulations 
(e.g., serious unlisted SARs, serious listed SARs, nonserious unlisted 
SARs, nonserious listed SARs) for all spontaneously reported serious 
SARs, whether domestic or foreign, and all spontaneously reported 
nonserious SARs occurring in the United States, obtained or otherwise 
received during the reporting period by the applicant from an 
individual other than a health care professional (e.g., reports from 
consumers). These summary tabulations must consist of lists by body 
system or by standard organ system classification scheme of all SAR 
terms and counts of occurrences. For those SARs that are determined to 
be both serious and unlisted, include cumulative data (i.e., all cases 
reported to date by individuals other than a health care professional). 
Include a brief discussion of the impact of the spontaneous reports 
described in this appendix on the overall safety evaluation.
    (4) SARs with unknown outcome. Provide summary tabulations for 
unlisted and listed SARs with unknown outcome from all spontaneous 
sources (i.e., health care professionals and other individuals), 
obtained or otherwise received by the applicant during the reporting 
period. These summary tabulations must consist of lists by body system 
or by standard organ system classification scheme of all SAR terms and 
counts of occurrences. Include a brief discussion of the impact of the 
spontaneous reports described in this appendix on the overall safety 
evaluation.
    (5) Class action lawsuits. Provide summary tabulations (e.g., 
serious unlisted SARs, serious listed SARs, nonserious unlisted SARs, 
nonserious listed SARs) for all SARs obtained or otherwise received 
during the reporting period by the applicant from class action 
lawsuits. These summary tabulations must consist of lists by body 
system or by standard organ system classification scheme of all SAR 
terms and counts of occurrences. For those SARs that are determined to 
be both serious and unlisted, include cumulative data. Include a brief 
discussion of the impact of the reports described in this appendix on 
the overall safety evaluation.
    (6) Lack of efficacy reports. Provide an assessment of whether it 
is believed that the frequency of lack of efficacy reports, obtained or 
otherwise received during the reporting period, is greater than would 
be predicted by the premarketing clinical trials for the biological 
product.
    (7) Medication errors. Provide summary tabulations of all domestic 
reports of medication errors submitted during the reporting period 
under paragraph (c)(2)(v) of this section. For actual medication 
errors, provide summary tabulations of serious SARs, nonserious SARs, 
and no SARs (for serious SARs, include cumulative data, i.e., all cases 
reported to date). For potential medication errors, provide the number 
of reports for specific errors. If an SAR occurs, the summary 
tabulations must consist of lists by body system or by standard organ 
system classification scheme of all SAR terms and counts of 
occurrences. Include a brief discussion of the impact on the overall 
safety evaluation of these reports.
    (8) U.S. patient exposure. Provide, for the reporting period, an 
estimate of the U.S. patient exposure to the biological product(s) 
covered by the PSUR (i.e., number of patients, average or median dose 
received, and average or median length of treatment). The method used 
to estimate patient exposure must always be described. If the patient 
exposure is impossible to estimate or is meaningless, an explanation of 
and justification for such conclusions must be provided. If patient 
exposure is impossible to estimate, other measures of exposure, such as 
patient-days, number of prescriptions, or number of dosage units, may 
be used. If these or other more precise measures are not available and 
an adequate explanation for the lack of such information is provided, 
bulk sales may be used.
    (9) Location of safety records. Provide a list of the current 
address(es) where all safety reports and other safety-related records 
for the licensed biological product(s) are maintained.
    (10) Contact person. Provide the name and telephone number for the 
licensed physician(s) responsible for the content and medical 
interpretation of the data and information contained within the PSUR. 
Include, if available, the fax number and e-mail address for the 
licensed physician(s).
    (iii) Interim periodic safety report (IPSR). An applicant holding a 
biologics license under Sec.  601.20 of this chapter for a human 
biological product approved on or after January 1, 1998, must submit an 
IPSR to FDA 7.5 years and 12.5 years after U.S. approval of the 
application. The data lock point for the IPSR is the month and day of 
the international birth date of the licensed biological product or any 
other month and day agreed on by the applicant and FDA. The reporting 
period for the IPSR covers the period between the last PSUR or TPSR and 
the data lock point for the IPSR (e.g., between years 5 and 7.5 for an 
IPSR with a data lock point 7.5 years after U.S. approval of the 
application). Each IPSR must contain:
    (A) Title page, table of contents, and introduction. (1) The title 
page includes, at a minimum, the following information:
    (i) Name and international birth date of the licensed biological 
product(s) that is the subject of the IPSR,
    (ii) Various dosage forms and formulations of the biological 
product(s) covered by the IPSR,
    (iii) Name and address of the applicant,
    (iv) Reporting period covered by the IPSR, and
    (v) Date of the IPSR.
    (2) The introduction: (i) Provides a brief description of how the 
IPSR relates to previous reports and circumstances,
    (ii) References relevant biological products reported in other 
periodic safety reports (e.g., a combination product reported in a 
separate IPSR), and
    (iii) Indicates any data duplication with other IPSRs.
    (B) Worldwide marketing status. This section of the IPSR contains a 
table of the chronological history of the worldwide marketing status of 
the biological product(s) covered by the IPSR from the date the 
product(s) was first approved (i.e., the international birth date) 
through its current status (i.e., cumulative information). This table 
consists of:
    (1) Dates of biological product approval and renewal;
    (2) Safety-related restrictions on product use;
    (3) Indications for use and special populations covered by the 
biological approval;
    (4) Lack of approval of the biological product in any dosage form 
or for any indication for use by any regulatory authority(ies);
    (5) Withdrawal of a pending marketing application for the 
biological product by the applicant for safety- or efficacy-related 
reasons;
    (6) Dates of market launches; and
    (7) Trade name(s).
    (C) Actions taken for safety reasons. (1) This section of the IPSR 
includes details on the following types of regulatory authority-
initiated (e.g., by FDA) and/or applicant-initiated actions

[[Page 12494]]

related to safety that were taken during the period covered by the IPSR 
and between the data lock point and IPSR submission (i.e., ``late-
breaking'' safety concerns):
    (i) Withdrawal or suspension of biological product approval or 
indication for use approval;
    (ii) Failure to obtain a marketing authorization renewal or to 
obtain an approval for a new indication for use;
    (iii) Restrictions on distribution (products recalled for safety 
reasons);
    (iv) Clinical trial suspension;
    (v) Dosage modification;
    (vi) Changes in target population or indications; and
    (vii) Formulation changes.
    (2) This section of the IPSR also contains a narrative identifying 
the safety-related reasons that led to these actions with relevant 
documentation appended when appropriate.
    (3) Any communication with health care professionals (e.g., Dear 
Healthcare Professional letters) resulting from such actions must also 
be described with copies appended.
    (D) Changes to CCSI. This section of the IPSR describes changes to 
the CCSI (e.g., new contraindications, precautions, warnings, SARs, or 
interactions) made during the period covered by the IPSR. A copy of any 
modified section of the CCSI must be included. The applicant must use 
the CCSI in effect at the beginning of the reporting period for the 
IPSR. The revised CCSI is to be used as the reference document for the 
next reporting period.
    (E) Worldwide patient exposure. (1) This section of the IPSR 
includes, for the reporting period, an estimate of the worldwide 
patient exposure to the biological product(s) covered by the IPSR 
(i.e., number of patients, average or median dose received, and average 
or median length of treatment). The method used to estimate patient 
exposure must always be described. If the patient exposure is 
impossible to estimate or is meaningless, an explanation of and 
justification for such conclusions must be provided. If patient 
exposure is impossible to estimate, other measures of exposure, such as 
patient-days, number of prescriptions, or number of dosage units, may 
be used. If these or other more precise measures are not available and 
an adequate explanation for the lack of such information is provided, 
bulk sales may be used.
    (2) When possible, data broken down by gender and age (especially 
pediatric versus adult) must be provided. For the pediatric population, 
data must be reported, if possible, by age group (e.g., neonates, 
infants, children, adolescents). If these data are not available, an 
explanation must be included.
    (3) When a pattern of reports indicates a potential problem, 
details by country (with locally recommended dosage regimens) or other 
segmentation (e.g., indication, dosage form) must be presented.
    (F) Safety studies. This section of the IPSR contains a discussion 
of nonclinical, clinical, and epidemiological studies that contain 
important safety information, as follows:
    (1) All applicant-sponsored studies newly analyzed during the 
reporting period (copies of full reports should be appended only if new 
safety issues are raised or confirmed; FDA may request copies of other 
studies, if necessary);
    (2) New studies specifically planned, initiated, or continuing 
during the reporting period that examine a safety issue, whether actual 
or hypothetical; and
    (3) Published safety studies in the scientific and medical 
literature, including relevant published abstracts from meetings 
(provide literature citation).
    (G) Other information. This section of the IPSR includes a 
discussion of medically relevant lack of efficacy reports (e.g., might 
represent a significant hazard to the treated population) for a 
product(s) used to treat serious or life-threatening diseases.
    (H) Overall safety evaluation. This section of the IPSR contains a 
concise, yet comprehensive, analysis of all of the safety information 
provided in the IPSR. In addition, this section of the IPSR includes an 
assessment by the applicant of the significance of the data collected 
during the reporting period, as well as from the perspective of 
cumulative experience.
    (1) The applicant must highlight any new information on:
    (i) Serious, unlisted SARs;
    (ii) Increased reporting frequencies of listed SARs, including 
comments on whether it is believed that the data reflect a meaningful 
change in SAR occurrence;
    (iii) A change in characteristics of listed SARs (e.g., severity, 
outcome, target population); and
    (iv) Nonserious, unlisted SARs.
    (2) As part of the overall safety evaluation, the applicant must 
also explicitly address any new safety issue including but not limited 
to the following (lack of significant new information for each of the 
following must be mentioned):
    (i) Drug interactions;
    (ii) Experience with overdose, whether deliberate or accidental, 
and its treatment;
    (iii) Drug abuse or intentional misuse;
    (iv) Positive or negative experiences during pregnancy or 
lactation;
    (v) Effects with long-term treatment; and
    (vi) Experience in special patient groups (e.g., pediatric, 
geriatric, organ impaired). For the pediatric population, data must be 
evaluated, if possible, by age group (e.g., neonates, infants, 
children, adolescents).
    (I) Conclusion. This section of the IPSR:
    (1) Indicates new safety information that is not in accord with 
previous cumulative experience and with the CCSI in use at the 
beginning of the reporting period (e.g., new evidence that strengthens 
a possible causal relationship between the biological product and an 
SAR, such as positive rechallenge, an epidemiological association or 
new laboratory studies); and
    (2) Specifies and justifies any action recommended or initiated, 
including changes in the CCSI.
    (J) Appendices. This section of the IPSR includes:
    (1) Company core data sheet. Provide a copy of the company core 
data sheet covered by this IPSR (i.e., in effect at the beginning of 
the period covered by the IPSR), as well as the company core data sheet 
for the next reporting period. Company core data sheets must be 
numbered and dated and include the date of last revision.
    (2) U.S. labeling. Provide a copy of the current approved U.S. 
labeling. Specify any safety information that is included in the CCSI 
but not in the U.S. labeling and provide an explanation for the 
discrepancy. Describe any safety-related changes or proposed changes to 
the U.S. labeling made during the reporting period (include the 
supplement number(s) and date(s) of submission for the supplement(s)) 
and any suggested change(s) that should be considered based on the 
safety analysis in this IPSR.
    (3) Spontaneous reports submitted to the applicant by an individual 
other than a health care professional. Provide a brief discussion of 
the impact on the overall safety evaluation of any spontaneously 
reported serious SARs, whether domestic or foreign, and any 
spontaneously reported nonserious SARs occurring in the United States, 
obtained or otherwise received during the reporting period by the 
applicant from an individual other than a health care professional 
(e.g., reports from consumers).

[[Page 12495]]

    (4) SARs with unknown outcome. Provide a brief discussion of the 
impact on the overall safety evaluation of any spontaneously reported 
unlisted and listed SARs with unknown outcome obtained or otherwise 
received during the reporting period by the applicant from health care 
professionals and other individuals.
    (5) Class action lawsuits. Provide a brief discussion of the impact 
on the overall safety evaluation of any safety information obtained or 
otherwise received during the reporting period by the applicant from 
class action lawsuits.
    (6) Lack of efficacy reports. Provide an assessment of whether it 
is believed that the frequency of any lack of efficacy reports, 
obtained or otherwise received during the reporting period, is greater 
than would be predicted by the premarketing clinical trials for the 
biological product.
    (7) Medication errors. Provide a brief discussion of the impact on 
the overall safety evaluation of all domestic reports of medication 
errors submitted during the reporting period under paragraph (c)(2)(v) 
of this section.
    (8) U.S. patient exposure. Provide, for the reporting period, an 
estimate of the U.S. patient exposure to the biological product(s) 
covered by the IPSR (i.e., number of patients, average or median dose 
received, and average or median length of treatment). The method used 
to estimate patient exposure must always be described. If the patient 
exposure is impossible to estimate or is meaningless, an explanation of 
and justification for such conclusions must be provided. If patient 
exposure is impossible to estimate, other measures of exposure, such as 
patient-days, number of prescriptions, or number of dosage units, may 
be used. If these or other more precise measures are not available and 
an adequate explanation for the lack of such information is provided, 
bulk sales may be used.
    (9) Location of safety records. Provide a list of the current 
address(es) where all safety reports and other safety-related records 
for the licensed biological product(s) are maintained.
    (10) Contact person. Provide the name and telephone number for the 
licensed physician(s) responsible for the content and medical 
interpretation of the information contained within the IPSR. Include, 
if available, the fax number and e-mail address for the licensed 
physician(s).
    (iv) Pediatric use supplements. After approval of a pediatric use 
supplement to an approved application (i.e., a supplement for use of 
the human biological product in the pediatric population), the 
applicant must submit PSURs to FDA as prescribed under paragraph 
(c)(3)(ii) of this section according to the following schedule: 
Semiannually for 2 years after U.S. approval of the supplement, 
annually for the next 3 years, and then every 5 years thereafter. These 
applicants must also submit IPSRs to FDA as prescribed under paragraph 
(c)(3)(iii) of this section at 7.5 years and 12.5 years after U.S. 
approval of the supplement. The data lock point for the PSUR and IPSR 
is the month and day of the international birth date of the licensed 
biological product or any other month and day agreed on by the 
applicant and FDA.
    (v) Semiannual submission of individual case safety reports. (A) An 
applicant holding a biologics license under Sec.  601.20 of this 
chapter for a human biological product must submit to FDA semiannually 
(i.e., every 6 months) after U.S. approval of the application a 
separate report that consists of individual case safety reports for 
certain spontaneously reported SARs for the biological product. The 
individual case safety reports must be submitted on the form designated 
by the agency under paragraph (c)(4) of this section. The data lock 
point for the report is the month and day of the international birth 
date of the licensed biological product or any other month and day 
agreed on by the applicant and FDA. This report must be identified as 
``individual case safety reports--semiannual submission.''
    (B) Applicants that submit TPSRs to FDA for the licensed biological 
product must submit an individual case safety report for each serious, 
expected SAR, whether domestic or foreign, and each nonserious, 
unexpected SAR occurring in the United States that is submitted to the 
applicant during the reporting period from all spontaneous sources 
(i.e., health care professionals and other individuals). Reports for 
vaccines must include an individual case safety report for each 
nonserious, expected SAR and each expected SAR with unknown outcome 
occurring in the United States that is submitted to the applicant 
during the reporting period from all spontaneous sources. Applicants 
that submit PSURs to FDA for the licensed biological product must 
submit an individual case safety report for each serious, listed SAR, 
whether domestic or foreign, and each nonserious, unlisted SAR 
occurring in the United States that is submitted to the applicant 
during the reporting period from all spontaneous sources. Reports for 
vaccines must include an individual case safety report for each 
nonserious, listed SAR and each listed SAR with unknown outcome 
occurring in the United States that is submitted to the applicant 
during the reporting period from all spontaneous sources. If a full 
data set is not available for a report of a serious SAR, the applicant 
must submit the information required under paragraph (c)(1)(iv) of this 
section.
    (C) Followup information to SARs submitted in an individual case 
safety report--semiannual submission may be submitted in the next 
individual case safety report--semiannual submission unless such 
information changes the classification of the SAR to a serious, 
unexpected SAR. In these cases, the followup information must be 
submitted to FDA as a 15-day followup report (see paragraph (c)(2)(vii) 
of this section).
    (4) Reporting format. (i)(A) Except as provided in paragraphs 
(c)(4)(i)(B), (c)(4)(i)(D), and (c)(4)(v) of this section, the 
applicant must complete the reporting form designated by FDA for each 
individual case safety report of an SAR (FDA Form 3500A or, for 
vaccines, a VAERS form). Reports based on information about individual 
cases or case series in the scientific literature must be submitted on 
an FDA Form 3500A(s) or, for vaccines, on a VAERS form(s).
    (B) Foreign SARs may be submitted either on an FDA Form 3500A or, 
if preferred, on a CIOMS I form; foreign SARs for vaccines may be 
submitted either on a VAERS form or, if preferred, on a CIOMS I form.
    (C) Each domestic report of an actual or potential medication error 
must be submitted on an FDA Form 3500A, or, for vaccines, on a VAERS 
form.
    (D) Reports of overall findings or data in the aggregate from 
published and unpublished in vitro, animal, epidemiological, or 
clinical studies must be submitted in a narrative format.
    (ii) Each SAR in an individual case safety report must be coded on 
the FDA Form 3500A, VAERS form, or CIOMS I form using the appropriate 
``preferred term'' in the latest version of MedDRA (the medical 
dictionary for regulatory activities) in use at the time the applicant 
becomes aware of the individual case safety report. For individual case 
safety reports of medication errors, the report must be coded both as a 
medication error and, if applicable, with the preferred term for any 
SARs associated with the medication error.
    (iii) Each completed FDA Form 3500A, VAERS form, or CIOMS I form 
should refer only to an individual case.
    (iv) Each completed FDA Form 3500A, VAERS form or CIOMS I form must 
include the name and telephone number (and fax number and e-mail 
address, if available) for the licensed

[[Page 12496]]

physician responsible for the content and medical interpretation of the 
data contained within the form (i.e., contact person for the company).
    (v) Instead of using FDA Form 3500A (or a VAERS form for vaccines), 
the applicant may use a computer-generated facsimile of FDA Form 3500A 
(or the VAERS form for vaccines) provided that it is readable, includes 
appropriate identifying information, and contains all the elements 
(i.e., format, sections, blocks, titles, descriptors within blocks, 
text for disclaimer) of FDA Form 3500A (or the VAERS form for vaccines) 
in the identical enumerated sequence of the form. For individual case 
safety reports in which no suspect medical device is involved, a one-
page FDA Form 3500A is acceptable.
    (d) Multiple reports. An applicant should not include in reports 
under this section any SARs that occurred in clinical trials if they 
were previously submitted as part of the license application. If a 
report refers to more than one biological product marketed by an 
applicant, the applicant should submit the report to the license for 
the product listed first in the report.
    (e) Patient privacy. For nonvaccine biological products, the names 
and addresses of individual patients should not be included in reports 
under this section; instead, the applicant, shared manufacturer and 
contractors should assign a unique code to each report, preferably not 
more than eight characters (i.e., numbers and/or letters) in length. 
The name of the reporter from whom the information was received should 
be included. Names of patients, individual reporters, health care 
professionals, hospitals, and geographic identifiers in safety reports 
are not releasable to the public under FDA's public information 
regulations in part 20 of this chapter. For vaccine SAR reports, these 
data will become part of the CDC Privacy Act System 09-20-0136, 
``Epidemiologic Studies and Surveillance of Disease Problems.'' 
Information identifying the person who received the vaccine or that 
person's legal representative will not be made available to the public, 
but may be available to the vaccinee or legal representative.
    (f) Recordkeeping. Each applicant must maintain for a period of 10 
years records of all safety information pertaining to its product, 
received or otherwise obtained, including raw data, any correspondence 
relating to the safety information, and any reports of SARs or 
medication errors not submitted to FDA or only provided to FDA in a 
summary tabulation. Each applicant must also retain for a period of 10 
years any records required to be maintained under this section. When 
appropriate, FDA may require an applicant to submit any or all of these 
records to the agency within 5 calendar days after receipt of the 
request.
    (g) Written procedures. Each applicant must develop and maintain 
written procedures for the surveillance, receipt, evaluation, and 
reporting of safety information to FDA.
    (h) Revocation of license. If an applicant fails to establish and 
maintain records and make reports required under this section with 
respect to a licensed biological product, FDA may revoke the license 
for such a product in accordance with the procedures of Sec.  601.5 of 
this chapter.
    (i) Exemptions. Manufacturers of the following listed products are 
not required to submit safety reports under this section:
    (1) Whole blood or components of whole blood. These products are 
subject to the reporting requirements for blood and blood components in 
Sec.  606.170 of this chapter.
    (2) In vitro diagnostic products, including assay systems for the 
detection of antibodies or antigens to retroviruses. These products are 
subject to the reporting requirements for devices.
    (j) Disclaimer. A report or information submitted by an applicant 
under this section (and any release by FDA of that report or 
information) does not necessarily reflect a conclusion by the applicant 
or FDA that the report or information constitutes an admission that the 
biological product caused or contributed to an SAR. An applicant need 
not admit, and may deny, that the report or information submitted under 
this section constitutes an admission that the biological product 
caused or contributed to an SAR.

PART 601--LICENSING

    14. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec. 122, Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note).


Sec.  601.28  [AMENDED]

    15. Section 601.28 Annual reports of postmarketing pediatric 
studies is amended by removing the second sentence in paragraph (a) and 
the phrase ``safety and'' in the first sentence in paragraph (b).

PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD 
COMPONENTS

    16. The authority citation for 21 CFR part 606 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 
374; 42 U.S.C. 216, 262, 263a, 264.

    17. Section 606.170 is revised to read as follows:


Sec.  606.170  Suspected adverse reaction investigation and reporting.

    (a) Any reports of complaints of suspected adverse reactions 
(SARs), as defined in Sec.  600.80(a) of this chapter, regarding each 
unit of blood or blood product arising as a result of blood collection 
or transfusion must be investigated promptly and thoroughly. Records of 
the complaint and investigation must be maintained. The collection or 
transfusing facility must prepare and maintain a written report of the 
investigation of SARs, including followup and conclusions, as part of 
the record for that lot or unit of final product. If it is determined 
that there was an SAR related to transfusion or possibly related to the 
collection procedure, then copies of all such reports must be forwarded 
to and maintained by the manufacturer or collection facility.
    (b) For any serious SAR, as defined in Sec.  600.80(a) of this 
chapter, except for a fatality, the facility performing the 
compatibility testing (if the SAR is related to transfusion) or the 
collecting facility (if the SAR is related to the blood collection 
procedure), must submit a written report to the Center for Biologics 
Evaluation and Research (CBER), at FDA within 45 calendar days after 
determination of the serious SAR. The written report must be submitted 
using the reporting format provided in Sec.  600.80(c)(4) of this 
chapter.
    (c) For an SAR that results in a fatality, the Director, Office of 
Compliance and Biologics Quality, at CBER must be notified by 
telephone, facsimile, express mail, or electronically transmitted mail 
as soon as possible. Within 7 calendar days after the fatality, the 
collection facility (if the fatality is related to blood collection) or 
the facility performing the compatibility tests (if the fatality is 
related to transfusion) must submit a written report to CBER, FDA, 
using the reporting format provided in Sec.  600.80(c)(4) of this 
chapter.

(Information collection requirements approved by the Office of 
Management and Budget under control number 0910-0116)


[[Page 12497]]


    Dated: December 13, 2002.
Mark B. McClellan,
Commissioner of Food and Drugs.
    Dated: January 29, 2003.
Tommy G. Thompson,
Secretary of Health and Human Services.
[FR Doc. 03-5204 Filed 3-13-03; 8:45 am]
BILLING CODE 4160-01-P