[Federal Register Volume 63, Number 214 (Thursday, November 5, 1998)]
[Proposed Rules]
[Pages 59746-59750]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-29564]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 314, and 600

[Docket No. 98N-0750]

RIN 0910-AB42


Electronic Reporting of Postmarketing Adverse Drug Reactions; 
Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Advance notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that it 
is considering preparing a proposed rule that would require applicants, 
manufacturers, packers, and distributors of marketed human drugs and 
licensed biological products to submit postmarketing expedited 
individual case safety reports and individual case safety reports 
contained in periodic safety reports to the agency electronically using 
standardized medical terminology, data elements, and electronic 
transmission standards recommended by the International Conference on 
Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). The proposed rule would help 
harmonize reporting of postmarketing safety information worldwide and 
expedite detection of safety problems for marketed drugs, thus 
enhancing FDA's ability to protect and promote public health. FDA is 
soliciting comments from interested persons to assist with the 
development of the proposed rule. The agency is specifically seeking 
comments on whether exemptions from any electronic safety reporting 
requirements should be granted to any entity and, if so, the basis on 
which they should be granted, the cost benefits or burdens of such 
requirements, and timeframes for implementing the requirements.

DATES: Written information and comments by February 3, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville MD 20852.

FOR FURTHER INFORMATION CONTACT: Thomas C. Kuchenberg, Center for Drug 
Evaluation and Research (HFD-7), 5600 Fishers Lane, Rockville, MD 
20857, 301-594-5621 (Internet electronic mail: 
[email protected]) or Marcel Salive, Center for Biologics 
Evaluation and Research (HFM-220), 1401 Rockville Pike, Rockville, MD 
20852, 301-827-3974 (Internet electronic mail: [email protected]).

SUPPLEMENTARY INFORMATION:

I. Background

A. International Harmonization

    For several years, FDA has cooperated with industry associations 
and the regulatory authorities of certain other nations to promote 
international harmonization of regulatory requirements. Much of this 
effort has been coordinated through ICH, which is facilitating 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 Industries 
Associations, the Japanese Ministry of Health and Welfare, the Japanese 
Pharmaceutical Manufacturers Association, the Centers for Drug 
Evaluation and Research and Biologics Evaluation and Research at FDA, 
and the Pharmaceutical Research and Manufacturers of America. The ICH 
Secretariat, which coordinates the preparation of documentation, is 
provided by the International Federation of Pharmaceutical 
Manufacturers Associations (IFPMA).
    The ICH Steering Committee includes representatives from each of 
the ICH sponsors and the IFPMA, as well as observers from the World 
Health Organization (WHO), the Canadian Therapeutic Products 
Directorate, and the European Free Trade Area.
    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 individual case safety reports and 
periodic safety reports for human drugs and biological products. In the 
Federal Register of March 1, 1995 (60 FR 11284), FDA published an ICH 
final guidance entitled ``Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting'' (the ICH E2A guidance). In the 
Federal Register of May 19, 1997 (62 FR 27470), FDA published an ICH 
final guidance entitled ``Clinical Safety Data Management: Periodic 
Safety Update Reports for Marketed Drugs'' (the ICH E2C guidance). 
Under the auspices of ICH, standards for electronic submission of 
safety information have been developed, as described in the Appendices, 
including a standard

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medical terminology for regulatory purposes, ICH M1 (see Appendix A in 
section VII.A of this document); electronic standards for the transfer 
of regulatory information, ICH M2 (see Appendix B in section VII.B of 
this document); and standardized data elements for transmission of 
individual case safety reports, ICH E2B format (see Appendix C in 
section VII.C of this document). FDA believes the changes recommended 
by ICH will result in more effective and efficient safety reporting to 
regulatory authorities worldwide.
    There is now international agreement on the major components for 
standardizing electronic transmission of certain safety reports, and 
worldwide implementation of this initiative has begun.

B. Postmarketing Safety Reports

    Under existing regulations, manufacturers, packers, distributors, 
applicants of approved new and abbreviated marketing applications for 
drugs, and licensed manufacturers of biological products must submit 
expedited individual case safety reports of postmarketing adverse drug 
experiences under Secs. 310.305, 314.80, 314.98, and 600.80 (21 CFR 
310.305, 314.80, 314.98, and 600.80). Applicants and licensed 
manufacturers must also submit periodic reports of postmarketing 
adverse drug experiences under Secs. 314.80, 314.98, and 600.80.
    Expedited individual case safety reports are required to be 
submitted for 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 
(Secs. 310.305(c)(1), 314.80(c)(1)(i), and 600.80(c)(1)(i)). Followup 
reports to these expedited reports are required to be submitted within 
15 calendar days of receipt of new information or as requested by FDA 
(Secs. 310.305(c)(2), 314.80(c)(1)(ii), and 600.80(c)(1)(ii)).
    Presently, periodic reports are required to be submitted at 
quarterly intervals for 3 years from the date of approval of the 
application and annually thereafter (Secs. 314.80(c)(2)(i) and 
600.80(c)(2)(i)). The periodic report is required to contain: (1) A 
narrative summary and analysis of the information in the report and an 
analysis of the expedited individual case safety reports submitted 
during the reporting interval, (2) individual case safety reports for 
each adverse drug experience not previously reported, and (3) a history 
of actions taken since the last periodic report (Secs. 314.80(c)(2)(ii) 
and 600.80(c)(2)(ii)).
    Each adverse drug experience is required to be submitted to the 
agency on an FDA Form 3500A (Secs. 310.305(d), 314.80(f), and 
600.80(f)). Foreign events may be submitted either on an FDA Form 3500A 
or, if preferred, on a CIOMS (Council for International Organizations 
of Medical Sciences) I form.
    FDA is in the process of revising these regulations to be 
consistent with safety reporting recommendations developed by ICH. In 
the Federal Register of October 27, 1994 (59 FR 54046), FDA published a 
proposed rule to amend its postmarketing expedited and periodic safety 
reporting requirements, as well as others, to implement international 
standards and to facilitate the reporting of adverse drug experiences. 
In the Federal Register of October 7, 1997 (62 FR 52237), FDA published 
a final rule amending its premarketing and postmarketing expedited 
safety reporting regulations to implement certain recommendations in 
the ICH E2A guidance on definitions and standards for expedited 
reporting. At this time, the agency is considering other 
recommendations in the ICH E2A guidance and plans to propose additional 
amendments to its postmarketing expedited safety reporting regulations. 
With regard to the amendments to the postmarketing periodic adverse 
drug experience reporting requirements proposed on October 27, 1994, 
FDA has decided to repropose these amendments based on recommendations 
in the ICH E2C guidance on postmarketing periodic safety update 
reports. In developing the reproposal, FDA will consider comments 
submitted in response to the proposed rule of October 27, 1994, 
regarding postmarketing periodic adverse experience reports.

II. Proposed Policy

    FDA is considering preparing a proposed rule that would require 
that applicants, manufacturers, packers and distributors of marketed 
human drugs and licensed biological products submit postmarketing 
expedited individual case safety reports and individual case safety 
reports contained in periodic safety reports to the agency 
electronically rather than on paper. The proposed rule would require 
that the electronic submission of postmarketing expedited and periodic 
individual case safety reports be precoded in the standardized M1 
international medical terminology, use the E2B format, and be 
transmitted using M2 specifications. FDA may also propose requiring 
that textual materials contained within periodic safety reports (e.g., 
narrative summary and analyses, history of actions taken) be submitted 
electronically.
    In the Federal Register of March 20, 1997 (62 FR 13430), FDA 
published a final rule in part 11 (21 CFR part 11) providing the 
conditions under which the agency will accept electronic signatures, 
electronic records, and handwritten signatures executed to electronic 
records as equivalent to paper records and handwritten signatures 
executed to paper records. Part 11 applies to any required records 
submissions under the Federal Food, Drug, and Cosmetic Act, the Public 
Health Service Act, or Title 21 of the Code of Federal Regulations. 
Part 11 provides that for records required to be maintained but not 
submitted to the agency, electronic records and accompanying signatures 
may be used in lieu of traditional records and signatures provided 
certain requirements are met. Electronic records and accompanying 
signatures that are submitted to the agency must meet the requirements 
of part 11 and must also be identified in public docket number 92S-0251 
as the type of submission the agency is prepared to accept 
electronically. It is important to note that the use of electronic 
records, as well as their submission to FDA under part 11, is 
voluntary.
    However, for a number of reasons, FDA believes that it is essential 
to mandate the electronic submission of postmarketing expedited and 
periodic individual case safety reports as well as the use of 
international standards for electronic safety reporting.
    The rapid identification and dissemination of information about 
emerging problems with individual drugs or harmful drug interactions is 
central to the agency's mission to protect and promote public health 
and safety. First, receipt of safety information electronically will 
vastly increase FDA's ability to quickly analyze data and identify 
emerging safety problems. Second, the agency believes that use of 
international standards for electronic safety reporting will eliminate 
the costs to industry associated with maintaining multiple systems 
designed to meet the needs of different terminologies, data elements, 
and electronic transmission standards of different regulatory 
authorities, and would thereby greatly enhance the utility of the 
system. Third, electronic submissions will improve the speed and 
efficiency of industry and agency operations and enhance the quality of 
the safety data.

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III. Solicitation of Comments

    All interested persons are invited to submit to FDA their comments 
on any aspect of this advance notice of proposed rulemaking (ANPRM). In 
particular, FDA is seeking public comment on the following subjects:

1. Exemptions

    The agency believes that the electronic reporting of postmarketing 
individual case safety reports will be welcomed by most of industry. 
The agency is aware, however, that some entities may have difficulty 
adapting existing systems to the requirements of a mandatory 
standardized electronic reporting system. The agency seeks guidance on 
whether exemptions should be granted and, if so, what considerations 
should be used to determine whether requesting entities may continue 
submitting postmarketing individual case safety reports in a paper 
format and whether any such exemptions should continue indefinitely or 
be terminated after a certain period of time.
    In the Federal Register of October 30, 1997 (62 FR 58647), the 
Securities and Exchange Commission (SEC) published a final rule stating 
that it would no longer accept paper copies of filings and required 
filers to submit information electronically unless certain requirements 
for a temporary or continuing hardship were met. Filers may claim or 
request, as appropriate, hardship exemptions based on certain criteria, 
including: Technical difficulties in filing and undue burden and 
expense of conversion to electronic format. A temporary hardship 
exemption, generally for unanticipated technical difficulties, is 
available automatically, but submission of a paper copy of the filing 
must be followed, within 6 business days, by a confirming electronic 
copy. A continuing hardship exemption is also available but must be 
granted by the SEC. It may be granted for a specific period (after 
which a confirming electronic copy of the paper copy must be filed) or 
for an indefinite period.
    FDA is seeking specific comments on whether a similar exemption 
provision would be appropriate for electronic reporting for 
postmarketing individual case safety reports.

2. Cost Benefits and Burdens

    The agency is interested in comments on the impact of a mandatory 
standardized electronic reporting requirement on different segments of 
regulated industry. For example, how will such a requirement affect 
manufacturers of different type and size over the short term during 
implementation and over the long term once systems are established? FDA 
is also interested in information on the benefits that industry could 
derive from a mandatory standardized electronic reporting requirement 
(e.g., reduced paperwork burden, reduced errors, increased convenience 
and more timely receipt of information).

3. Timeframes for Implementation

    The SEC model, described in section III.1 of this document, phased 
companies into its electronic filing system over a 4-year period, with 
small business filers being the last to be required to file 
electronically. The agency is seeking comments on whether a similar 
implementation plan, based on the size of a firm, would be appropriate 
for electronic reporting of postmarketing individual case safety 
reports and, if not, how it should be modified, and what criteria 
should be used to define an implementation plan.

4. OMB Circular A-130

     Section 8a(3) of OMB circular A-130 cites a policy to encourage 
agencies to explore the use of automated techniques for the collection 
of information and conditions conducive to the use of those techniques. 
Section 8a(3) reads as follows:
    Electronic Information Collection. Agencies shall use electronic 
collection techniques where such techniques reduce burden on the 
public, increase efficiency of government programs, reduce costs to 
the government and the public, and/or provide better service to the 
public. Conditions favorable to electronic collection include:
    (a) The information collection seeks a large volume of data and/
or reaches a large proportion of the public;
    (b) The information collection recurs frequently;
    (c) The structure, format, and/or definition of the information 
sought by the information collection does not change significantly 
over several years;
    (d) The agency routinely converts the information collected into 
electronic format;
    (e) A substantial number of the affected public are known to 
have ready access to the necessary information technology and to 
maintain the information in electronic form;
    (f) Conversion to electronic reporting, if mandatory, will not 
impose substantial costs or other adverse effects on the public, 
especially State and local governments and small business entities.
    FDA is soliciting comments on whether a proposed rule consistent 
with the objectives discussed in this ANPRM would advance the 
objectives of the policy stated in the OMB circular.
    If FDA develops a proposed rule for electronic reporting of 
postmarketing individual case safety reports, it will take into 
consideration comments submitted in response to this ANPRM.

IV. Executive Order 12866 Analysis

    In any rulemaking proposed as a result of comments received on this 
ANPRM, FDA will examine the economic implications of the proposed rule 
as required by Executive Order 12866, which directs agencies to assess 
all costs and benefits of available regulatory alternatives. Executive 
Order 12866 classifies a rule as significant if it meets any one of a 
number of specified conditions, including having an annual effect on 
the economy of $100 million or adversely affecting in a material way a 
sector of the economy, competition, or jobs, or if it raises novel 
legal or policy issues. In any rulemaking, the agency will examine the 
potential costs and potential benefits of the proposed rule. FDA 
requests information that would aid the agency in responding to the 
Executive Order.

V. Regulatory Flexibility Analysis

    If a rule has a significant economic impact on a substantial number 
of small entities, the Regulatory Flexibility Act (5 U.S.C. 601-612) 
requires agencies to analyze options that would minimize the economic 
impact of that rule on small entities. FDA requests information 
regarding the impact on small entities of the three subjects identified 
in section III of this document.

VI. Comments

    Interested persons may on or before February 3, 1999, submit to the 
Dockets Management Branch (address above) written comments regarding 
this ANPRM. Two copies of any comments are to be submitted, except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document. 
Received comments may be seen in the office above between 9 a.m. and 4 
p.m., Monday through Friday.

VII. Appendices

A. Appendix A: M1 Medical Terminology

     Most organizations currently process their regulatory data using 
an international adverse drug reaction (ADR) terminology in combination 
with a morbidity terminology. In Europe, many users combine the World 
Health Organization's Adverse Reaction Terminology with the ninth 
revision of the International Classification of Diseases (ICD-9). In 
the United States, Coding Symbols for a Thesaurus of Adverse Reaction 
Terms with Clinical Modification of ICD-9 (ICD-9-CM) is

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very commonly used, and Japan has developed its own version of these 
ADR terminologies, J-Art and MEDIS.
    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.
    A medical terminology designed for regulatory purposes was 
recognized as necessary by industry and regulatory authorities to 
support the computerization and transmission of information related to 
many aspects of the regulation of medical products. In October 1994, 
the ICH Steering Committee introduced a multidisciplinary communication 
initiative to establish an international medical terminology for 
regulatory purposes (M1).
    In November 1994, the ICH Steering Committee released a draft (or 
alpha) version of the M1 terminology for review and evaluation. The 
alpha version was made available free of charge to all national 
regulatory entities participating in the WHO International Drug 
Monitoring Program and, on request, to pharmaceutical companies and 
contract research organizations. More than 600 electronic copies were 
distributed with a testing guide which provided suggestions on how the 
terminology could be evaluated.
    In March 1995, the M1 ICH working group met to evaluate the results 
of the alpha test, review proposals submitted by potential users 
participating in the alpha test, and evaluate suggested changes. Since 
1995, the working group has: (1) Refined and documented the definitions 
of the levels in the structural hierarchy; (2) reviewed and established 
the scope of the terminology; (3) reviewed terms and codes of the 
established terminologies, made necessary linkages and deletions, and 
included the most recent versions of the current terminologies to 
facilitate the transfer of historical data; (4) reviewed the results of 
the extensive and systematic Organ Class reviews performed in the 
United States and Japan; and (5) made necessary changes to facilitate 
data analysis and presentation.
    Over time, it is essential that the M1 medical terminology be 
maintained and updated in response to medical/scientific advances and 
regulatory changes. An international maintenance and service 
organization (MSSO) is being established to provide this function as 
well as serve as the licensing agent for the distribution of the M1 
medical terminology. It is anticipated that the MSSO will begin 
licensing the M1 medical terminology in the near future.

B. Appendix B: Electronic Transmission Standards

    The ICH Steering Committee recognized the need for rapid 
communication of regulatory information between pharmaceutical 
manufacturers and regulatory authorities and, in particular, the need 
for the electronic communication of safety information. The ICH 
Steering Committee also noted that rapid communication required 
universal standards and that separate, uncoordinated initiatives 
launched in various countries could compromise the benefits of 
electronic communication and jeopardize the harmonization process. As a 
result, the ICH Multidisciplinary Group 2 (M2) Expert Working Group 
(EWG) was established in October 1994 to recommend electronic standards 
and provide solutions to facilitate international electronic 
communication in the three ICH regions.
    The M2 EWG recommended various open international standards that 
allow for the worldwide transmission of information regardless of the 
technical infrastructure. The electronic standards for the transfer of 
regulatory information (ESTRI) gateway is designed to ensure reliable 
regulatory communications by using certain common electronic elements. 
The M2 EWG recommended the following:
1. Physical Media
    Use of 3.5 inch floppy disk (ISO 8860) (1 and 2) and CD-ROM 640 MB 
(ISO 9660) as standard media for physical data storage and 
transferability across heterogenous computer platforms.
2. Network Messaging
    Use of the Internet (STP/MIME) and X400 as network messaging 
standards that will provide for the efficient transport of heterogenous 
data formats and complex documents among the three ICH regions.
3. Electronic Document Format
    Use of the Portable Document Format (PDF) as the interchange format 
for the transfer of certain types of documents.
4. Secure Electronic Data Interchange (EDI) Over the Internet
    Use of Templar, a standards-based solution that facilitates the 
transmission of secure EDI over the Internet in all three ICH regions.
    In addition, the M2 EWG facilitated the implementation of E2B data 
elements by defining an attribute list and deriving a relational view 
that allows for transmission of all types of individual case safety 
reports, regardless of source and destination. The E2B/M2 attribute 
list will form the basis for defining E2B data elements in various 
structured formats such as standard generalized markup language (SGML).

C. Appendix C: E2B Data Elements for Transmission of Individual Case 
Safety Reports

    In the Federal Register of October 1, 1996 (61 FR 51287), FDA 
published a draft guidance entitled ``Data Elements for Transmission of 
Individual Case Safety Reports.'' The notice gave interested parties an 
opportunity to submit comments by December 30, 1996. After 
consideration of the comments received and revisions to the guidance, a 
final draft was submitted to the ICH Steering Committee and endorsed by 
the three participating regulatory parties on July 17, 1997. The final 
guidance entitled ``E2B Data Elements for Transmission of Individual 
Case Safety Reports'' (ICH E2B guidance) was published in the Federal 
Register of January 15, 1998.
    The guidance is intended to facilitate the standardization of data 
elements for transmission of individual case safety reports. The format 
for individual case safety reports includes provisions for transmitting 
all the relevant data elements useful to assess an individual ADR or 
adverse event report. The data elements are sufficiently comprehensive 
to cover complex reports from most sources, different data sets, and 
transmission situations or requirements. In many, if not most, 
instances a

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substantial number of the data elements will not be known, but as much 
information as possible should be provided. The minimum information for 
the transmission of a safety report should include an identifiable 
patient, an identifiable reporter, a reaction/event, and a suspect drug 
or biological product.

    Dated: October 6, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-29564 Filed 11-4-98; 8:45 am]
BILLING CODE 4160-01-F