[Federal Register Volume 64, Number 230 (Wednesday, December 1, 1999)]
[Proposed Rules]
[Pages 67207-67216]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-31123]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 601

[Docket No. 99N-1852]
RIN 0910-AB83


Postmarketing Studies for Human Drugs and Licensed Biological 
Products; Status Reports

AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to revise 
the status reports section of the postmarketing annual reporting 
requirements for drug and biological products, and to require 
applicants to submit annual status reports for certain postmarketing 
studies of licensed biological products. This proposed rule would 
describe the types of postmarketing studies covered by these status 
reports, the information to be included in the reports, and the type of 
information that FDA would consider appropriate for public disclosure. 
The agency is taking this action to implement section 130 of the Food 
and Drug Administration Modernization Act of 1997 (FDAMA).

DATES: Submit written comments on the proposed rule by February 14, 
2000. Submit written comments on the information collection provisions 
by January 3, 2000.

ADDRESSES: Submit written comments to the Dockets Management Branch

[[Page 67208]]

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit 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., Washington, DC 20503, Attn: Wendy Taylor, Desk 
Officer for FDA.

FOR FURTHER INFORMATION CONTACT: 
    Paula S. McKeever, Center for Biologics Evaluation and Research 
(HFM-17), Food and Drug Administration, 1401 Rockville Pike, suite 
200N, Rockville, MD 20852-1448, 301-827-6344; or
    Audrey A. Thomas, Center for Drug Evaluation and Research (HFD-7), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-594-5625.

SUPPLEMENTARY INFORMATION: 

I. Introduction

    On November 21, 1997, the President signed the FDAMA into law 
(Public Law 105-115). Section 130(a) of the FDAMA amended the Federal 
Food, Drug, and Cosmetic Act (the act) by adding a new provision on 
reports of postmarketing studies) (section 506B of the act (21 U.S.C. 
356b)). Section 506B of the act provides FDA with additional authority 
for monitoring the progress of postmarketing studies that companies 
have made a commitment to conduct and also requires the agency to make 
information that pertains to the status of these studies publicly 
available.
    Under section 506B(a) of the act, applicants that have committed to 
conduct a postmarketing study for a drug or biological product that is 
approved for marketing must submit to FDA a report on the progress of 
the study or the reasons for the failure of the applicant to conduct 
the study. This provision directs FDA to issue regulations that 
prescribe the content of these reports.
    Section 506B(a) of the act also states that these reports must be 
submitted to FDA within 1 year after the approval of the product and 
annually thereafter until the study is completed or terminated. This 
provision applies to commitments for postmarketing studies that were 
made on or after enactment of FDAMA, as well as those made prior to 
enactment of FDAMA. For commitments made prior to enactment of FDAMA, 
the act requires that an initial report be submitted to FDA within 6 
months after the date of issuance of the final rule implementing 
section 506B of the act. Section 506B(b) of the act specifies which 
information in a status report may be considered public information. 
Under section 506B(b) of the act, FDA may publicly disclose any 
information pertaining to a status report under section 506B(a) to the 
extent that the information is necessary to identify the applicant, or 
to establish the status of a study and the reasons, if any, for failure 
to conduct, complete, and report the study.
    Section 506B(c) of the act directs FDA to develop and publish 
annually in the Federal Register a report concerning this activity. 
This report must provide information on the status of postmarketing 
studies that applicants have committed to conduct under this provision 
and for which reports have been submitted.
    FDAMA also directs FDA, under section 130(b), to submit a specific 
report to Congress by October 1, 2001. This report must contain a 
summary of the status reports submitted under section 506B of the act, 
an evaluation of the performance of applicants in fulfilling their 
commitments to conduct postmarketing studies under this provision and 
of FDA's timeliness in reviewing these postmarketing studies, and any 
legislative recommendations regarding postmarketing studies.
    Under the agency's existing postmarketing reporting regulations for 
human drug products, at Sec. 314.81(b)(2) (21 CFR 314.81(b)(2)), each 
applicant holding an approved new drug application (NDA) or abbreviated 
new drug application (ANDA) must submit an annual report to FDA for the 
drug product. This annual report is required to contain, among other 
information, a section on status reports that includes a statement on 
the current status of any postmarketing studies of the drug product 
performed by, or on behalf of, the applicant (Sec. 314.81(b)(2)(vii)). 
This section also permits applicants to include a list of any open 
regulatory business with FDA concerning the drug product. In the 
Federal Register of December 2, 1998 (63 FR 66632), FDA issued a final 
rule amending these postmarketing reporting regulations to require that 
annual reports contain, among other information, specific information 
about the status of postmarketing clinical studies in pediatric 
populations. In this proposed rule, FDA is proposing to amend these 
regulations, including the new provisions issued in the final rule of 
December 2, 1998, to implement the requirements of section 506B of the 
act for human drug products. In a separate rulemaking, FDA plans to 
propose additional amendments to the annual report requirements 
pertaining to the nonclinical laboratory studies and clinical data 
sections of the annual report. However, these amendments are beyond the 
scope of this proposed rule.
    Each applicant holding a biologics license application (BLA) must 
submit an annual report to FDA describing any minor changes that may 
relate to the safety or effectiveness of the product (Sec. 601.12(d) 
(21 CFR 601.12(d)) and must also submit a separate annual report, in 
accordance with the final rule of December 2, 1998 (63 FR 66632), 
regarding postmarketing pediatric studies (Sec. 601.37 (21 CFR 
601.37)). In this proposed rule, FDA is proposing to amend the 
biologics regulations at part 601 (21 CFR part 601) by revising the 
postmarketing annual reporting requirement at Sec. 601.37 and by adding 
a new postmarketing annual reporting requirement, Sec. 601.70, to 
implement the requirements of section 506B of the act for licensed 
biological products. Proposed Sec. 601.70 would only apply to licensed 
biological products that meet the definition of ``drug'' under the act; 
it would not apply to biological products that also meet the definition 
of ``medical device'' under the act, since section 506B does not cover 
medical devices.
    This proposed rule would only apply to human drug and biological 
products; it would not apply to animal drug products. FDA intends to 
amend its regulations to implement section 506B of the act for animal 
drug products in a separate rulemaking.
    In May 1996, the Office of Inspector General of the Department of 
Health and Human Services issued a report regarding FDA's oversight of 
postmarketing study commitments for prescription drugs (Ref. 1). This 
study found that the number of postmarketing study commitments was 
increasing and that the agency did not have formal standards or 
procedures for monitoring postmarketing studies or for establishing 
whether a postmarketing study commitment had been met. At the same 
time, FDA was developing formal procedures for tracking the progress of 
postmarketing study commitments, an effort that began in February 1995 
when the agency recognized the need for such procedures. These 
procedures were implemented in October 1996. The proposed revisions to 
the human drug and biologics regulations in this rule will facilitate 
FDA's current system for tracking postmarketing study commitments.
    In addition to the regulatory changes proposed in this rule, FDA 
will issue guidance regarding section 506B of the act. This guidance 
will describe in greater detail the type of information

[[Page 67209]]

that applicants should submit to the agency in a status report for a 
postmarketing study of an approved drug or licensed biological product, 
the implementation schedule for submission of these status reports to 
the agency, how FDA will track information obtained for postmarketing 
studies, and the schedule for FDA review of status reports and final 
study reports for postmarketing studies. In accordance with the 
agency's Good Guidance Practices (62 FR 8961, February 27, 1997), FDA 
will make the guidance available in draft form for public comment 
before issuing a final guidance. FDA is also in the process of 
reviewing and revising, as necessary, its internal operating procedures 
related to tracking commitments made for the conduct of postmarketing 
studies under this provision for approved drug and licensed biological 
products.

II. Description of the Proposed Rule

A. Introduction

    The proposed rule would amend the postmarketing annual reporting 
requirements for human drug products under Sec. 314.81(b)(2) by 
reorganizing the status reports section, at Sec. 314.81(b)(2)(vii), to 
require that the information contained in this section be provided to 
FDA in a different format. FDA is proposing that this information be 
included in the annual report in three different sections. One section 
would contain, as described below (see section II.B of this document), 
status reports for those postmarketing studies of the drug product 
(i.e., clinical safety, clinical efficacy, clinical pharmacology and 
nonclinical toxicology) that are required by FDA (e.g., pediatric 
studies) or that an applicant has committed, in writing, to conduct 
either at the time of approval of an application or a supplement to an 
application, or after approval of an application or a supplement 
consistent with section 506B of the act (proposed 
Sec. 314.81(b)(2)(vii)). This section would also include, for pediatric 
studies, a statement that indicates whether postmarketing clinical 
studies in pediatric populations were required by FDA under Sec. 201.23 
(21 CFR 201.23). Another section would contain status reports for any 
other postmarketing studies of the drug product (proposed 
Sec. 314.81(b)(2)(viii)) (e.g., chemistry, manufacturing, and controls, 
stability of the product), and the third section would contain, at the 
applicant's discretion, a list of any open regulatory business with FDA 
concerning the drug product (proposed Sec. 314.81(b)(2)(ix)). FDA would 
use the information provided under proposed Sec. 314.81(b)(2)(vii) to 
meet its reporting obligations under section 506B of the act (annual 
report in the Federal Register) and section 130(b) of FDAMA (report to 
congressional committees by October 1, 2001). FDA does not intend to 
use information provided under proposed Sec. 314.81(b)(2)(viii) for 
this purpose. This proposed change in the structure of the annual 
report would facilitate FDA's preparation of its annual reports and its 
report to Congress without imposing a new reporting burden on 
applicants with approved NDA's and ANDA's because these applicants are 
currently required to report such information to FDA.
    The proposed rule would also create a new subpart G under part 601 
entitled ``Postmarketing Studies'' and a new Sec. 601.70 under subpart 
G. Proposed Sec. 601.70 would require, as described in section II.B of 
this document, annual reports of the status of postmarketing studies 
for licensed biological products (i.e., clinical safety, clinical 
efficacy, clinical pharmacology, and nonclinical toxicology) that are 
required by FDA (e.g., pediatric studies) or that an applicant has 
committed, in writing, to conduct either at the time of approval of an 
application or a supplement to an application, or after approval of an 
application or a supplement. Proposed Sec. 601.37(c) would require that 
the status of postmarketing pediatric studies that are covered under 
proposed Sec. 601.70 be reported to FDA under proposed Sec. 601.70 
rather than under Sec. 601.37. FDA notes that biological products 
previously approved under the product license application and 
establishment license application process are included wherever BLA, 
the new form of application for biological products, is used in this 
preamble.

B. Scope of Proposed Rule

    Postmarketing studies for marketed human drug and licensed 
biological products are conducted for a variety of purposes (e.g., new 
indication, safety, medication errors, pharmacokinetics, pharmacology, 
chemistry, marketing, stability, use in special populations such as 
children). Some of these postmarketing studies are conducted by an 
applicant on its own initiative. Other postmarketing studies are 
required by FDA to be conducted by applicants such as assessing the 
safety and effectiveness of new drugs and biologics in pediatric 
patients (Sec. 314.55 (21 CFR 314.55) and Sec. 601.27. Others result 
from an applicant's commitment, in writing, to the agency to conduct 
the study at the time of approval of an application (e.g, an NDA, ANDA, 
BLA, or supplement), after approval of an application (e.g., as a 
result of suspected adverse drug reaction reports), as a condition of 
accelerated approval of new drugs and biological products for serious 
or life-threatening illnesses (subpart H of part 314 (21 CFR part 314), 
and subpart E of part 601 respectively), or as a deferred submission of 
pediatric studies (Secs. 314.55(b) and 601.27(b)). Studies that 
applicants commit to conduct at the time of approval of an application 
are usually intended to address concerns about the risks, benefits, or 
optimal use of a drug or biological product that do not warrant 
delaying approval of the application.
    This proposed rule would define postmarketing studies for which 
status reports must be submitted under section 506B of the act as those 
that concern clinical safety, clinical efficacy, clinical pharmacology 
or nonclinical toxicology studies and that are required by FDA (e.g., 
pediatric studies) or that are committed to, in writing, either at the 
time of approval of an application or a supplement or after approval of 
an application or supplement. FDA is proposing to include clinical 
studies such as safety, efficacy, and pharmacology studies within the 
scope of this rule because these types of studies provide the most 
relevant and useful additional information about the risks, benefits, 
and optimal use to patients and consumers of an approved drug or 
licensed biological product. In addition, FDA is proposing to include 
nonclinical toxicology studies within the scope of this rule, although 
such studies typically cannot be performed on human subjects, because 
they are very useful to further evaluate the safety of a marketed drug 
or biological product.
    For the purpose of this rule, clinical safety and clinical efficacy 
studies would include human epidemiological studies. Examples of 
clinical pharmacology studies are pharmacokinetic and pharmacodynamic 
studies. For all of the postmarketing studies described previously, 
Secs. 314.81(b)(2)(vii) and 601.70 would require applicants to provide 
status reports to FDA regarding the progress of such studies.
    Postmarketing studies designed to evaluate other types of issues 
such as manufacturing and control issues (e.g., stability of the 
product, development of new tests or specifications) and medication 
errors (e.g., attributable to the labels, labeling and/or packaging of 
the product) would be reported for drug products, as described below, 
under proposed Sec. 314.81(b)(2)(viii) rather than under proposed 
Sec. 314.81(b)(2)(vii), and

[[Page 67210]]

would not be required to be reported under Sec. 601.70 for licensed 
biological products.
    This proposed rule would require, as stated previously, status 
reports, under proposed Secs. 314.81(b)(2)(vii) and 601.70, for 
postmarketing studies that either are required by FDA (e.g., pediatric 
studies) or that applicants commit, in writing, to conduct either at 
the time of approval of an application or a supplement to an 
application, or after approval of an application or a supplement.
    Under proposed Sec. 314.81(b)(2)(viii), applicants with approved 
NDA's and ANDA's would be required to provide status reports for any 
postmarketing study not reported under proposed Sec. 314.81(b)(2)(vii) 
(e.g., chemistry, manufacturing, and controls, stability of the 
product, medication errors). These would include postmarketing studies 
performed by, or on behalf of, the applicant, whether or not the 
studies are required or subject to commitments. Proposed 
Sec. 314.81(b)(2)(viii) does not represent a new reporting burden for 
applicants with approved NDA's or ANDA's because these applicants are 
currently required to provide status reports for these studies in their 
postmarketing annual reports. FDA is not proposing a similar reporting 
requirement for postmarketing studies of licensed biological products 
in this proposed rule. Applicants with licensed biological products may 
voluntarily submit status reports to FDA for postmarketing studies that 
are not required to be reported under proposed Sec. 601.70.
    The agency is committed to harmonizing its reporting requirements 
for drugs and biologics as much as possible. Section 123(f) of FDAMA 
requires FDA to take measures to minimize differences in the review and 
approval of products required to have approved BLA's under section 351 
of the Public Health Service Act (42 U.S.C. 262) and products required 
to have approved NDA's under section 505(b)(1) of the act (21 U.S.C. 
355(b)(1)). At the present time, FDA is considering whether to amend 
its biologics regulations in a separate rulemaking to require the 
submission of information in postmarketing annual reports currently 
submitted to the agency by applicants with approved NDA's and ANDA's 
under Sec. 314.81(b)(2)(i) through (b)(2)(vi). FDA requests comment on 
whether the postmarketing annual report for licensed biological 
products under Sec. 601.12(d), (changes to an approved application), 
Sec. 601.37 (annual reports of postmarketing pediatric studies), and 
proposed Sec. 601.70 should be combined into a single annual report and 
whether such a report should include additional information as required 
in Sec. 314.81(b)(2)(i) through (b)(2)(vi). However, FDA has determined 
that requiring such additional information is beyond the scope of this 
proposed rulemaking and that it is appropriate, at this time, to 
harmonize only the drugs and biologics postmarketing annual reporting 
requirements as they relate to section 506B of the act.

C. Content of Status Reports

    Current regulations (Sec. 314.81(b)(2)(vii)) do not prescribe the 
content of status reports of postmarketing studies. In this proposed 
rule, FDA is proposing to set forth the format and content of these 
reports, as described in section 506B of the act, which requires 
sufficient information to identify the applicant of the postmarketing 
study, the specific study being conducted, the status of the study, and 
the reasons, if any, for the applicant's failure to complete the study. 
Under proposed Sec. 314.81(b)(2)(vii) and (b)(2)(viii) and 
Sec. 601.70(b), a status report for a postmarketing study would be 
required to contain the following information:
    1. Applicant's name.
    2. Product name. This would include the approved product's 
established/proper name and proprietary name, if applicable.
    3. NDA number, ANDA number, BLA/reference number, or supplement 
number of the approved product.
    4. Date of product's U.S. approval.
    5. Date of postmarketing study commitment. This date would be the 
same as the date of the product's U.S. approval for commitments made, 
in writing, at the time of U.S. approval of an application; would be 
the date of U.S. approval of the supplement for commitments made, in 
writing, at the time of U.S. approval of a supplement; and would be the 
date of written commitment for commitments made after U.S. approval of 
an application or supplement.
    6. Description of postmarketing study commitment. For clinical 
studies, this section would include the purpose of the postmarketing 
study, the patient population addressed by the study, the number of 
patients and/or subjects to be included in the study, and the 
indication and dosage(s) that are to be studied. For nonclinical 
studies, this section would include the type and purpose of the study 
(e.g., carcinogenicity study to determine effects of chronic dosing).
    7. Schedule for conduct, completion, and reporting of the 
postmarketing study commitment. This section would include projected 
dates for initiation of the different phases of the study, for 
completion of the study, and for submission of the final study report 
to FDA. This schedule should reflect a reasonable, but aggressive 
timetable for completing the postmarketing study commitment. Although 
some delays in a study may be unanticipated, it is expected that 
studies would progress as originally scheduled. If the original 
schedule is revised under section 9 of this status report, the revised 
schedule would also be reported in this section (i.e., section 7) in 
the next report with a note indicating that the schedule has been 
revised as reported in the previous status report.
    8. Current status of the postmarketing study commitment. Applicants 
would categorize the status of each postmarketing study using one of 
the following terms that describe the study's status on the U.S. 
anniversary date of approval of the application or other agreed upon 
date:
    a. Pending. The study has not been initiated (i.e., first patient 
has not been enrolled).
    b. Ongoing. The study is proceeding according to or ahead of the 
original schedule described in section 7 of the status report. If a 
study has been completed but the final study report has not been 
submitted to FDA, the date the study was completed would be provided.
    c. Delayed. The study is proceeding but is behind the original 
schedule described in section 7 of the status report. The original 
schedule would serve as the basis for defining a study as ``delayed,'' 
even if a revised schedule is provided.
    d. Terminated. The study was ended before completion.
    e.  Submitted. The study has been completed (i.e., last patient 
finished the protocol) or terminated and a final study report has been 
submitted to FDA. This category would include the date the final study 
report was submitted to FDA.
    9. Explanation of the study's status. This section would include a 
brief description of the status of the study, including the number of 
patients and/or subjects enrolled to date and an explanation of the 
study's status identified under section 8 of the status report (e.g., 
delayed due to difficulty in patient accrual, terminated because study 
would no longer provide useful information, terminated because study is 
no longer feasible, terminated because of adverse events or other 
safety issues associated with the use of the product). This section 
would also include a

[[Page 67211]]

revised schedule, as well as the reason(s) for the revision, if the 
schedule under section 7 of the status report has changed since the 
last annual report. This revised schedule would be included, as noted 
previously, under section 7 of the next report.
    FDA believes that the information proposed to be required in status 
reports would provide the agency with sufficient data for review of the 
progress of ongoing postmarketing studies under this section. These 
reports would also provide FDA with sufficient information to meet the 
agency's reporting obligations under section 130 of FDAMA (i.e., annual 
report in the Federal Register on the status of postmarketing studies, 
report to congressional committees by October 1, 2001).

D. Log of Outstanding Regulatory Business

    Current regulations (Sec. 314.81(b)(2)(vii)), as noted previously 
(see section I of this document), permit applicants with approved NDA's 
and ANDA's to include in the status reports section of annual reports a 
list of any open regulatory business with FDA concerning the drug 
product that is the subject of the annual report. FDA would continue to 
permit applicants to submit such information in annual reports under 
proposed Sec. 314.81(b)(2)(ix). For clarification, FDA is proposing to 
provide examples of the types of open regulatory business that would be 
reported under proposed Sec. 314.81(b)(2)(ix). These would include a 
list of the applicant's unanswered correspondence with the agency and a 
list of the agency's unanswered correspondence with the applicant.
    Proposed Sec. 601.70 does not contain a similar provision for 
outstanding regulatory business. However, as noted previously (see 
section II.B of this document), FDA is considering a separate 
rulemaking that would require the same postmarketing annual reporting 
requirements for drugs and biologics.

E. Report Submission Requirements

    Current regulations at Sec. 314.81(b), require applicants with 
approved drug products to submit two copies of an annual report to FDA. 
Under Sec. 314.81(b)(2), these annual reports are required to be 
submitted within 60 days of the anniversary date of U.S. approval of 
the application to the FDA division responsible for reviewing the 
application and these reports. Each annual report is required to be 
accompanied by a completed transmittal Form FDA-2252 (Transmittal of 
Periodic Reports for Drugs for Human Use) that includes all the 
information required under Sec. 314.81(b)(2) that the applicant 
received or otherwise obtained during the annual reporting interval, 
which ends on the U.S. anniversary date. FDA is proposing to amend 
these regulations by replacing the phrase ``Periodic Reports'' with the 
phrase ``Annual Reports'' to correct an error and by making other minor 
changes to provide clarity.
    Currently, applicants with licensed biological products must submit 
reports, under Sec. 601.12(d), describing certain minor changes to an 
approved BLA, and under Sec. 601.37, providing information on 
postmarketing pediatric studies, each year within 60 days of the 
anniversary date of approval of the application. Proposed 
Sec. 601.70(c) and (d) would require applicants with licensed 
biological products to submit a separate annual report to FDA 
describing the status of certain postmarketing studies using submission 
requirements similar to those required for drugs under 
Sec. 314.81(b)(2) and for licensed biologics under Secs. 601.12(d) and 
601.37. Applicants with licensed biological products would submit two 
copies of an annual progress report to FDA within 60 days of the 
anniversary date of the U.S. approval of the application for the 
product. Each annual progress report would be accompanied by a 
completed transmittal Form FDA-2252 that includes all the information 
required under proposed Sec. 601.70 that the applicant received or 
otherwise obtained during the annual reporting interval, which ends on 
the U.S. anniversary date. These annual progress reports would be 
submitted for all postmarketing studies of a licensed biological 
product covered under the scope of this proposed rule including those 
that are required by FDA (e.g., pediatric studies) and those that an 
applicant committed, in writing, to conduct on or after the effective 
date of any final rule that may issue based on this proposed rule and 
prior to the effective date.
    For drugs and biologics with approved NDA's, ANDA's, and BLA's, FDA 
intends, as noted previously (see section II.A of this document), to 
fulfill its annual reporting requirement mandated by section 506B(c) of 
the act by publishing in the Federal Register, the status of 
postmarketing study commitments reported under proposed 
Secs. 314.81(b)(2)(vii) and 601.70. Furthermore, FDA will post 
additional information on the agency's web page (see section G.2 of 
this document). This additional information will include an applicant's 
failure to submit a status report under proposed 
Secs. 314.81(b)(2)(vii) and 601.70 for any postmarketing study 
commitment that the agency has formally tracked (i.e., commitments 
included in agency databases which were made, in writing, at the time 
of approval or after approval of an application or a supplement to an 
application, and commitments made as a condition of accelerated 
approval, or required studies for assessing the safety and 
effectiveness of drugs and biologics in pediatric patients).
    A status report under proposed Secs. 314.81(b)(2)(vii) and 601.70 
would be submitted to FDA until the agency notifies the applicant, in 
writing, that the study commitment has been fulfilled or acknowledges 
that the study is either no longer feasible or would no longer provide 
useful information. Applicants may indicate in their status report that 
a study has been terminated because it is either no longer feasible or 
would no longer provide useful information. However, these applicants 
would be required to submit a final study report to FDA and continue to 
submit status reports for the study until the agency evaluates the 
final study report and concurs, in writing, with the applicant's 
determination. To expedite the process, FDA encourages applicants to 
submit a final study report to the agency as soon as they have 
determined that a postmarketing study commitment is to be terminated.

F. Public Disclosure of Information

    Section 506B(b) of the act requires FDA to publicly disclose any 
information pertaining to a status report described in section 506B(a) 
of the act to the extent that such information is necessary to: (1) 
Identify the sponsor or (2) establish the status of the postmarketing 
study and the reasons, if any, for any failure to carry out the study. 
Therefore, FDA is proposing to state in the rule its authority to 
disclose any information contained within or relating to postmarketing 
studies under proposed Sec. 314.81(b)(2)(vii) or proposed Sec. 601.70, 
if the information is necessary to establish the identity of the 
applicant or the status of the study, including the reasons, if any, 
for the applicant's failure to conduct, complete, and report the study. 
However, FDA would not disclose trade secrets as defined in 21 CFR 
20.61(a) or information described in 21 CFR 20.63, the disclosure of 
which would constitute an unwarranted invasion of personal privacy. 
Information necessary to establish the status of a postmarketing study 
would include the study protocol, patient accrual rates, reports of 
unexpected (i.e., unlabeled) suspected adverse drug

[[Page 67212]]

reactions, and study results. Some of these types of information such 
as study protocols for certain postmarketing studies and adverse event 
reports for certain postmarketing studies are currently publicly 
available. Section 130(b) of FDAMA provides FDA with statutory 
authority to disclose data and information, including certain 
information that may be considered to constitute confidential 
commercial information. Section 130(b) of FDAMA constitutes 
authorization by law for the purposes of 18 U.S.C. 1905 to disclose 
certain information that could otherwise be considered nondisclosable 
confidential commercial information.

G. Proposed Implementation Scheme

1. Effective Dates
    FDA proposes that any final rule that may issue based on this 
proposed rule become effective 90 days after its date of publication in 
the Federal Register. Applicants with approved applications for human 
drug and licensed biological products (that are not medical devices) 
would be subject to the annual reporting requirements in this proposed 
rule. In addition, applicants that have entered into a commitment prior 
to November 21, 1997, to conduct a postmarketing study described under 
proposed Sec. 314.81(b)(2)(vii) or proposed Sec. 601.70 would be 
required, as mandated by FDAMA, to submit an initial report to FDA 
within 6 months after the effective date of any final rule that may 
issue based on this proposed rule. Thus, in some cases, an applicant 
would be required to submit two reports to FDA in the first year after 
the effective date of the final rule (i.e., an initial report 
containing only information required under proposed 
Sec. 314.80(b)(2)(vii) or proposed Sec. 601.70 due within 6 months 
after the effective date and a complete annual report based on the 
product's anniversary date of U.S. approval due in the 7th to 12th 
month after the effective date). After the first year, applicants would 
only be required to submit one annual report to FDA each year.
    This proposed rule does not affect the existing reporting 
requirements issued in the final rule of December 2, 1998 (63 FR 
66632). Any changes to the provisions in the final rule of December 2, 
1998, that are proposed in this rule would be in effect on the 
effective date of any final rule that may issue based on this proposed 
rule.
2. Annual Federal Register Report
    Consistent with section 506B(c) of the act, FDA will publish 
annually a report in the Federal Register. This report will provide a 
brief summary of the status of postmarketing study commitments for 
approved drugs and licensed biological products that applicants have 
submitted to FDA under proposed Secs. 314.81(b)(2)(vii) and 601.70. The 
report will include the number of pending, ongoing, delayed, and 
terminated postmarketing study commitments, as well as the number of 
final study reports that have been submitted to FDA, the number of 
study commitments that FDA has deemed fulfilled, and the number of 
applicants that failed to submit a status report to the agency for 
unfulfilled postmarketing study commitments. Detailed information 
regarding the status of these postmarketing studies will be posted on 
FDA's web page at ``http://www.fda.gov''. The web site will contain, at 
a minimum, the following information for each postmarketing study 
commitment: Name of the applicant, application number, product name, 
dosage form, product use category, type of study, commitment 
description, commitment date, projected study completion date, current 
status of commitment, applicant summary of status, annual report due 
date, and date annual report received.

III. Request for Comments

    Interested persons may, on or before February 14, 2000, submit to 
the Dockets Management Branch (address above) written comments 
regarding this proposal. 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.

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

    FDA has examined the impact of this proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
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 would have a significant economic impact on 
a substantial number of small entities, the 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 (2 
U.S.C. 1501 et seq.) requires that agencies prepare a written statement 
and economic analysis 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 (adjusted annually for 
inflation) in any 1 year.
    The agency believes that this rule is consistent with the 
principles set out in the Executive Order and in these two statutes. 
OMB has determined that the proposed rule is a significant regulatory 
action as defined by the Executive Order and so is subject to review. 
The rule would require applicants that have committed, in writing, to 
conduct a postmarketing study for an approved drug or biologic product 
to submit annual reports on the progress of the study or on the reasons 
for the failure of the applicant to conduct, complete, and report the 
study. The rule would permit FDA to publicly disclose information 
concerning these postmarketing studies, thereby providing patients, 
consumers, and the medical community with access to important and 
useful information.

A. Nature of Impact

    Currently, applicants holding approved NDA's or ANDA's are required 
to submit annual reports to the agency that include information on the 
current status of any postmarketing studies of the drug product 
performed by, or on the behalf of the applicant. Although the proposed 
rule prescribes the format for the required information, this 
requirement would add no new economic burden for the majority of NDA 
and ANDA applicants. About half of the applicants holding approved 
NDA's or ANDA's with outstanding postmarketing study commitments made 
prior to the enactment of FDAMA may incur a small cost the first year, 
if their annual report is due within the last 6 months after the 
effective date of issuance of the final rule and they must submit one 
initial report within the first 6 months after the effective date. FDA 
estimates that there will be approximately 116 such reports submitted, 
which will require about 16 hours per report to complete. Assuming an 
average wage rate of $35 per hour,

[[Page 67213]]

the estimated, one-time cost of this provision is $64,960.
    Applicants with licensed biological products are currently required 
to submit information on postmarketing studies in pediatric populations 
in annual reports to the agency. These applicants will incur additional 
costs to comply with the proposed requirements in this proposed rule. 
The agency estimates that about 33 applicants will submit approximately 
43 postmarketing status reports annually for approved licensed 
biological products. As the reporting requirements are not extensive 
and the information is readily accessible to the applicant, FDA 
estimates that establishments will require about 16 hours to complete 
the required information. Assuming an average wage rate of $35 per 
hour, the estimated incremental cost of the annual reporting 
requirement will be $560 per report, for an industry total of $24,080 
per year. As with applicants holding NDA's or ANDA's, a few applicants 
with licensed biological products with outstanding postmarketing study 
commitments may also incur an additional, one-time cost because they 
must submit their initial report within the first 6 months after the 
effective date of the final rule and an annual report within the last 6 
months of the year. FDA estimates there will be approximately seven 
such reports, for a total one-time cost of about $4,000.

B. Small Business Impacts

    The requirements in this proposed rule will not have a significant 
economic impact on a substantial number of small entities. Although it 
is possible that some firms may feel added pressure to honor the agreed 
upon commitments, the agency does not expect the proposed rule to 
result in an increased number of completed postmarketing studies. Nor 
does it believe that applicants will incur significantly increased 
costs from completing studies earlier than intended, as a result of the 
reporting, tracking, and disclosure activities implemented by the 
agency. Because affected applicants holding NDA's and ANDA's must 
currently submit annual reports to the agency, they already have 
procedures in place to monitor their postmarketing studies. The 
additional reporting requirement for applicants holding approved BLA's 
and the reformatting of the annual reports for applicants holding NDA's 
and ANDA's would be minimal. To simplify the reporting requirement 
further, however, the agency will publish a guidance for industry to 
aid applicants in preparing reports in the proper format.

C. Conclusion

    The previous cost estimates demonstrate that this rule is not 
economically significant under Executive Order 12866. The Unfunded 
Mandates Reform Act does not require a cost-benefit analysis of this 
rule, because the rule will not result in an expenditure by State, 
local, or tribal governments, in the aggregate, or by the private 
sector of $100 million in any 1 year. Finally, the agency certifies 
that the proposed rule will not have a significant economic impact on a 
substantial number of small entities.

VI. The Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3520). A description of these provisions is shown below 
with an estimate of the annual reporting burden. Included in the 
estimate is the time for reviewing the instructions, searching existing 
data sources, gathering and maintaining the data needed, and completing 
and reviewing each collection of information.
    FDA invites comments on: (1) Whether the proposed collection of 
information is necessary for the 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 on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Reporting the Status of Postmarketing Studies for Human 
Drugs and Licensed Biological Products.
    Description: Section 506B of the act provides FDA with additional 
authority for monitoring the progress of postmarketing studies that 
companies have made a commitment to conduct and also requires the 
agency to make the status of these studies publicly available.
    Under section 506B(a) of the act, applicants that have committed to 
conduct a postmarketing study for an approved human drug or biological 
product must submit to FDA a report of the progress of the study or the 
reasons for the failure of the applicant to conduct the study. This 
report must be submitted within 1 year after the U.S. approval of the 
product and annually thereafter until the study is completed or 
terminated. Under Secs. 314.81(b)(2)(vii) and (b)(2)(viii), and 
601.70(b), information submitted in a status report would be limited to 
that which is needed to sufficiently identify each applicant that has 
committed to conduct a postmarketing study, the status of the study 
that is being reported, and the reasons, if any, for the applicant's 
failure to conduct, complete, and report the study.
    Currently under Sec. 314.81(b)(2), applicants holding an NDA or an 
ANDA must submit status reports on postmarketing studies for the 
approved human drug product as part of an annual report to FDA. The 
agency is proposing to amend Sec. 314.81(b)(2)(vii) to specify 
information that must be included in status reports submitted under 
section 506B of the act (studies of clinical safety, clinical efficacy, 
clinical pharmacology, and nonclinical toxicology that are required by 
FDA or that an applicant commits, in writing, to conduct either at the 
time of approval of an application or a supplement to an application or 
after approval of an application or supplement). Proposed 
Sec. 314.81(b)(2) also adds paragraph (b)(2)(viii) which would require 
status information on any postmarketing study commitments not reported 
under paragraph (b)(2)(vii) that are being performed by, or on behalf 
of, the applicant; and paragraph (b)(2)(ix) which would allow the 
applicant to list any open regulatory business with FDA concerning the 
drug product subject to the application. For licensed biological 
products, FDA proposes to create Sec. 601.70 to require postmarketing 
status reports for studies of clinical safety, clinical efficacy, 
clinical pharmacology, and nonclinical toxicology that are required by 
FDA or that an applicant of a BLA commits to conduct, in writing, at 
the time of approval of an application or a supplement to an 
application or after approval of an application or a supplement. FDA is 
also proposing to revise Sec. 601.37(c) to require that the status of 
postmarketing pediatric studies described in proposed Sec. 601.70 be 
reported under proposed Sec. 601.70 rather than Sec. 601.37.
    This proposed rule is intended to provide FDA with specific 
procedures for monitoring the progress of postmarketing studies that 
companies have made a commitment, in writing, to conduct and also to 
permit the agency to make the status of these studies publicly 
available.
    Description of Respondents: Applicants holding approved

[[Page 67214]]

applications for human drugs and biological products that have 
committed to conduct postmarketing studies.
    Under current Sec. 314.81(b)(2), applicants with approved NDA's and 
ANDA's for human drugs are required to submit to the agency two copies 
of the annual reports that must include information on the current 
status of any postmarketing study (OMB No. 0910-0001).
    Proposed Sec. 314.81(b)(2)(vii), (b)(2)(viii), and (b)(2)(ix) would 
expressly require status information to be provided in a specific 
format as part of the status reports of postmarketing study commitments 
(clinical safety, clinical efficacy, clinical pharmacology, and 
nonclinical toxicology), a subpart of the annual report. Based on past 
experience, the agency estimates that each applicant holding an 
approved NDA or ANDA would expend an additional 8 hours, to reformat 
the annual report. This is a one-time burden required under proposed 
Sec. 314.81(b)(2)(vii). Based on the number of drug applicants in past 
years who have committed to conduct postmarketing studies, the agency 
estimates that this provision would apply to approximately 183 
applicants and approximately 462 postmarketing studies.
    Based upon information obtained from the Center for Biologics 
Evaluation and Research's computerized application and license tracking 
database, the agency estimates that approximately 33 applicants with 43 
approved BLA's have committed to conduct approximately 86 postmarketing 
studies (clinical safety, clinical efficacy, clinical pharmacology, and 
nonclinical toxicology) and would be required to submit an annual 
progress report on those postmarketing studies under proposed 
Sec. 601.70. Proposed Sec. 601.70 requires postmarketing studies status 
reports for the first time for biological products. Based on past 
experience with reporting under Sec. 314.81(b)(2), the agency estimates 
that approximately 8 hours annually is required for an applicant to 
gather, complete, and submit the appropriate information for each 
report (approximately two studies per report). Included in these 8 
hours is the time necessary to initially format the status report.
    Applicants holding NDA's, ANDA's, and BLA's whose anniversary date 
of U.S. approval of the application falls within the latter half of the 
year after the effective date of any final rule that may issue based on 
this proposed rule are required under section 506B of the act to submit 
an initial report to FDA for postmarketing studies committed to be 
conducted prior to November 21, 1997, within 6 months after the 
effective date of any final rule in addition to the reports required by 
the final rule. This information collection is a statutory requirement 
for which the proposed regulations add no additional burden other than 
prescribing the format. The burden of setting up the format is 
calculated under Secs. 314.81(b)(2)(vii) and 601.70(b).

                                 Table 1.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
                             No. of       Annual Frequency    Total Annual        Hours per
    21 CFR Section         Respondents      per Response        Responses         Response         Total Hours
----------------------------------------------------------------------------------------------------------------
314.81(b)(2)(vii),            183                 2.5             462                 8             3,696
 (b)(2)(viii),
 (b)(2)(ix)\2\
601.70(b) and (d)              33                 2.6              86                 8               688
Total                                                                                               4,384
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs with this collection of information.
\2\ One-time burden for reformatting annual report.

    In compliance with section 3507(d) of the Paperwork Reduction Act 
of 1995 (44 U.S.C. 3507(d)), the agency has submitted the information 
collection provisions of this proposed rule to OMB for review. 
Interested persons are requested to send comments regarding this 
information collection by January 3, 2000, to the Office of Information 
and Regulatory Affairs, OMB, New Executive Office Bldg., 725 17th St. 
NW., rm. 10235, Washington, DC 20503, Attn: Desk Officer for FDA.

VII. Reference

    The following reference has 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. ``Postmarketing Studies of Prescription Drugs,'' Department 
of Health and Human Services, Office of the Inspector General Final 
Report, May 1996.

List of Subjects

21 CFR Part 314
    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.
21 CFR Part 601
    Administrative practice and procedure, Biologics, Confidential 
business information.
    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 314 
and 601 be amended as follows:

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

    1. The authority citation for 21 CFR part 314 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356b, 371, 
374, 379e.
    2. Section 314.81 is amended by revising the introductory text of 
paragraph (b)(2), by revising paragraph (b)(2)(vii), and by adding 
paragraphs (b)(2)(viii) and (b)(2)(ix) to read as follows:


Sec. 314.81  Other postmarketing reports.

* * * * *
    (b) * * *
    (2) Annual report. The applicant shall submit the following 
information each year within 60 days of the anniversary date of U.S. 
approval of the application. The applicant shall submit two copies of 
the report to the FDA division responsible for reviewing the 
application. Each annual report is required to be accompanied by a 
completed transmittal Form FDA-2252 (Transmittal of Annual Reports for 
Drugs for Human Use), which may be obtained from the PHS Forms and 
Publications Distribution Center, 12100 Parklawn Dr., Rockville, MD 
20857, and is required to include all the information required under 
this section that the applicant received or otherwise obtained during 
the annual reporting interval, which ends on the U.S. anniversary date. 
The report is required to contain in the order listed:
* * * * *
    (vii) Status reports of postmarketing study commitments. A status 
report of each postmarketing study of the drug product concerning 
clinical safety, clinical efficacy, clinical pharmacology,

[[Page 67215]]

and nonclinical toxicology that is required by FDA (e.g., pediatric 
studies) or that the applicant has committed, in writing, to conduct 
either at the time of approval of an application for the drug product 
or a supplement to an application, or after approval of an application 
or a supplement. For pediatric studies, the status report shall include 
a statement indicating whether postmarketing clinical studies in 
pediatric populations were required by FDA under Sec. 201.23 of this 
chapter. The status of these postmarketing studies shall be reported 
annually until FDA notifies the applicant, in writing, that the agency 
concurs with the applicant's determination that the study commitment 
has been fulfilled or that the study is either no longer feasible or 
would no longer provide useful information.
    (a) Content of status report. The following information shall be 
provided for each postmarketing study reported under this paragraph:
    (1) Applicant's name.
    (2) Product name. Include the approved drug product's established 
name and proprietary name, if applicable.
    (3) NDA, ANDA (abbreviated new drug application), or supplement 
number.
    (4) Date of product's U.S. approval.
    (5) Date of postmarketing study commitment.
    (6) Description of postmarketing study commitment. For clinical 
studies, include the purpose of the postmarketing study, the patient 
population addressed by the study, the number of patients and/or 
subjects to be included in the study, and the indication and dosage(s) 
that are to be studied. For nonclinical studies, include the type and 
purpose of the study.
    (7) Schedule for conduct, completion, and reporting of the 
postmarketing study commitment. Include projected dates for initiation 
of the different phases of the study, for completion of the study, and 
for submission of the final study report to FDA. Provide a revised 
schedule, in addition to the original schedule, if the original 
schedule was revised in the previous report.
    (8) Current status of the postmarketing study commitment. 
Categorize the status of each postmarketing study using one of the 
following terms that describes the study's status on the anniversary 
date of U.S. approval of the application or other agreed upon date:
    (i) Pending. The study has not been initiated.
    (ii) Ongoing. The study is proceeding according to or ahead of the 
original schedule described under paragraph (b)(2)(vii)(a)(7) of this 
section. Include the date the study was completed, if a study has been 
completed but the final study report has not been submitted to FDA.
    (iii) Delayed. The study is proceeding but is behind the original 
schedule described under paragraph (b)(2)(vii)(a)(7) of this section.
    (iv) Terminated. The study was ended before completion.
    (v) Submitted. The study has been completed or terminated and a 
final study report has been submitted to FDA. Include the date the 
final study report was submitted to FDA.
    (9) Explanation of the study's status. Provide a brief description 
of the status of the study, including the number of patients and/or 
subjects enrolled to date and an explanation of the study's status 
identified under paragraph (b)(2)(vii)(a)(8) of this section. Provide a 
revised schedule, as well as the reason(s) for the revision, if the 
schedule under paragraph (b)(2)(vii)(a)(7) of this section has changed 
since the last report.
    (b) Public disclosure of information. Except for the information 
described in this paragraph, FDA may publicly disclose any information 
concerning a postmarketing study, within the meaning of paragraph 
(b)(2)(vii) of this section, if the agency determines that the 
information is necessary to identify the applicant or to establish the 
status of the study including the reasons, if any, for failure to 
conduct, complete, and report the study. Information necessary to 
establish the status of a postmarketing study includes the study 
protocol, patient accrual rates, reports of unexpected suspected 
adverse drug reactions, and study results. Under this section, FDA will 
not publicly disclose trade secrets, as defined in Sec. 20.61 of this 
chapter, or information, described in Sec. 20.63 of this chapter, the 
disclosure of which would constitute an unwarranted invasion of 
personal privacy.
    (viii) Status of other postmarketing studies. A status report of 
any postmarketing study not included under paragraph (b)(2)(vii) of 
this section that is being performed by, or on behalf of, the 
applicant. The applicant shall provide information as prescribed under 
paragraphs (b)(2)(vii)(a)(1) through (b)(2)(vii)(a)(9) of this section 
for each of the postmarketing studies required to be reported under 
this paragraph.
    (ix) Log of outstanding regulatory business. To facilitate 
communications between FDA and the applicant, the report may, at the 
applicant's discretion, also contain a list of any open regulatory 
business with FDA concerning the drug product subject to the 
application (e.g., a list of the applicant's unanswered correspondence 
with the agency, a list of the agency's unanswered correspondence with 
the applicant).

PART 601--LICENSING

    3. The authority citation for 21 CFR part 601 is revised 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).
    4. Section 601.37 is amended by revising the second sentence in 
paragraph (c) to read as follows:


Sec. 601.37  Annual reports of postmarketing pediatric studies.

* * * * *
    (c) * * * The statement shall include whether postmarketing 
clinical studies in pediatric populations were required or agreed to, 
and, if so, the status of these studies shall be reported to FDA in 
annual progress reports of postmarketing studies under Sec. 601.70 
rather than under this section.
    5. Subpart G, consisting of Sec. 601.70, is added to part 601 to 
read as follows:

Subpart G--Postmarketing Studies


Sec. 601.70  Annual progress reports of postmarketing studies

    (a) General requirements. This section applies to all required 
postmarketing studies (e.g., pediatric studies) and postmarketing 
studies that an applicant has committed, in writing, to conduct either 
at the time of approval of an application or a supplement to an 
application, or after approval of an application or a supplement. 
Postmarketing studies within the meaning of this section are those that 
concern:
    (1) Clinical safety;
    (2) Clinical efficacy;
    (3) Clinical pharmacology; and
    (4) Nonclinical toxicology.
    (b) What to report. Each applicant of a licensed biological product 
shall submit a report to FDA on the status of postmarketing studies for 
each approved product application. The report shall include the status 
of each study which is required by FDA (e.g., pediatric studies) or 
which the applicant has committed, in writing, to conduct, including 
any reasons for the applicant's failure to conduct or to progress with 
the study. The status of these postmarketing studies shall be

[[Page 67216]]

reported annually until FDA notifies the applicant, in writing, that 
the agency concurs with the applicant's determination that the study 
commitment has been fulfilled, or that the study is either no longer 
feasible or would no longer provide useful information. Each annual 
progress report shall be accompanied by a completed transmittal Form 
FDA-2252, which may be obtained from the PHS Forms and Publications 
Distribution Center, 12100 Parklawn Dr., Rockville, MD 20857, and shall 
include all the information required under this section that the 
applicant received or otherwise obtained during the annual reporting 
interval, which ends on the U.S. anniversary date. The report shall 
provide the following information for each postmarketing study:
    (1) Applicant's name.
    (2) Product name. Include the approved product's proper name and 
the proprietary name, if applicable.
    (3) Biologics license application (BLA)/reference or supplement 
number. The biologics license application number, reference number, or 
supplement number of the approved product.
    (4) Date of product's U.S. approval.
    (5) Date of postmarketing study commitment.
    (6) Description of postmarketing study commitment. For clinical 
studies, include the purpose of the postmarketing study, the patient 
population addressed by the postmarketing study, the number of patients 
and/or subjects to be included in the study, and the indication and 
dosage(s) that are to be studied. For nonclinical studies, include the 
type and purpose of the study.
    (7) Schedule for conduct, completion, and reporting of the 
postmarketing study commitment. Include projected dates for initiation 
of the different phases of the study, for completion of the study, and 
for submission of the final study report to FDA. Provide a revised 
schedule, in addition to the original schedule, if the original 
schedule was revised in the previous report.
    (8) Current status of the postmarketing study commitment. 
Categorize the status of each postmarketing study using one of the 
following terms that describes the study's status on the anniversary 
date of the U.S. approval of the application or other agreed date:
     (i) Pending. The study has not been initiated.
     (ii) Ongoing. The study is proceeding according to or ahead of the 
original schedule described under paragraph (b)(7) of this section. 
Include the date the study was completed, if a study has been completed 
but the final study report has not been submitted to FDA.
     (iii) Delayed. The study is proceeding but is behind the original 
schedule described under paragraph (b)(7) of this section.
     (iv) Terminated. The study was ended before completion.
     (v) Submitted. The study has been completed or terminated, and a 
final study report has been submitted to FDA. Include the date the 
final study report was submitted to FDA.
    (9) Explanation of the study's status. Provide a brief description 
of the status of the study, including the number of patients and/or 
subjects enrolled to date and an explanation of the study's status 
identified under paragraph (b)(8) of this section. Provide a revised 
schedule, as well as the reason(s) for the revision, if the schedule 
under paragraph (b)(7) of this section has changed since the previous 
report.
    (c) When to report. Annual progress reports for postmarketing study 
commitments entered into by applicants shall be reported to FDA within 
60 days of the anniversary date of the U.S. approval of the application 
for the product.
    (d) Where to report. Submit two copies of the annual progress 
report of postmarketing studies to the Food and Drug Administration, 
Center for Biologics Evaluations and Research, Document Control Center 
(HFM-99), suite 200N, 1401 Rockville Pike, Rockville, MD 20852-1448.
    (e) Public disclosure of information. Except for the information 
described in this paragraph, FDA may publicly disclose any information 
concerning a postmarketing study, within the meaning of this section, 
if the agency determines that the information is necessary to identify 
an applicant or to establish the status of the study including the 
reasons, if any, for failure to conduct, complete, and report the 
study. Information necessary to establish the status of a postmarketing 
study includes the study protocol, patient accrual rates, reports of 
unexpected suspected adverse drug experiences, and study results. Under 
this section, FDA will not publicly disclose trade secrets, as defined 
in Sec. 20.61 of this chapter, or information described in Sec. 20.63 
of this chapter, the disclosure of which would constitute an 
unwarranted invasion of personal privacy.

    Dated: August 9, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-31123 Filed 11-30-99; 8:45 am]
BILLING CODE 4160-01-F