[Federal Register Volume 65, Number 210 (Monday, October 30, 2000)]
[Rules and Regulations]
[Pages 64607-64619]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-27731]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 601

[Docket No. 99N-1852]


Postmarketing Studies for Approved Human Drug and Licensed 
Biological Products; Status Reports

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is revising the 
requirements for annual postmarketing status reports for approved human 
drug and biological products, and is requiring applicants to submit 
annual status reports for certain postmarketing studies of licensed 
biological products. This rule describes 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. This action will implement the Food 
and Drug Administration Modernization Act of 1997 (FDAMA).

DATES: This rule is effective February 27, 2001.

[[Page 64608]]


FOR FURTHER INFORMATION CONTACT:
    Sharon T. Risso, Center for Biologics Evaluation and Research (HFM-
500), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 
20852-1448, 301-827-5098; or
    James L. Cobbs, Center for Drug Evaluation and Research (HFD-102), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-827-5922.

SUPPLEMENTARY INFORMATION:

I. Background

A. Statutory Requirements

    Section 130(a) of FDAMA (Public Law 105-115) 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 applicants 
have made a commitment to conduct and requires the agency to make 
publicly available information that pertains to the status of these 
studies. The following summary describes the obligations of applicants 
and of FDA under section 506B of the act.
1. Submission of Annual Reports to FDA Under Section 506B of the Act
    Any applicant that has 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. The applicant must 
submit the report within a year after the approval of the product and 
annually thereafter on the anniversary of the product's U.S. approval 
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 commitments made before enactment of 
FDAMA.
2. Special One-Time Reporting Requirement Under Section 506B of the Act
    An applicant must submit an initial report to FDA for study 
commitments made before November 21, 1997, within 6 months after the 
effective date of the final rule. Subsequent to the initial report, an 
applicant must submit an annual report to the agency on the anniversary 
of the product's U.S. approval. For those applicants required to submit 
an annual report 7 to 12 months after the effective date of the final 
rule, the submission of the initial report to FDA within 6 months after 
the effective date of the final rule is an additional one-time burden.
3. FDA Obligations Under Section 506B(c) of the Act
    FDA must develop and publish annually in the Federal Register a 
report on the status of postmarketing study commitments.
4. FDA Obligation Under FDAMA (Section 130(b))
    FDA must submit a specific report to Congress by October 1, 2001, 
that contains the following:
    1. A summary of the status reports submitted under section 506B of 
the act;
    2. An evaluation of the performance of applicants in fulfilling 
their commitments to conduct postmarketing studies under this 
provision;
    3. FDA's timeliness in reviewing these postmarketing studies; and
    4. Any legislative recommendations regarding postmarketing studies.

B. Proposed Rule

    FDA published a proposed rule in the Federal Register of December 
1, 1999 (64 FR 67207), that would revise the requirements for annual 
postmarketing status reports for drug and biological products, and that 
would require applicants to submit annual status reports for certain 
postmarketing studies of licensed biological products. The proposed 
rule described 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 proposed this action to implement section 130 of 
FDAMA. In proposed Secs. 314.81(b)(2)(vii) and (b)(2)(viii), and 
601.70(b), FDA would require that a status report for a postmarketing 
study 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. New drug application (NDA) number, abbreviated new drug 
application (ANDA) number, biologics license application (BLA) 
reference number, or supplement number for 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, 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. 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 status 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 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.
    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).

[[Page 64609]]

If the schedule under section 7 of the status report has changed since 
the last annual report, this section would also include a revised 
schedule, as well as the reason(s) for the revision.
    FDA invited the public to submit written comments on the proposed 
rule by February 14, 2000, and on the information collection provisions 
by January 3, 2000. Comments received have been considered and are 
discussed in section III of this document. No comments were received on 
the information collection provisions.

C. Availability of Guidance

    To help applicants comply with the requirements of this final rule, 
the agency is developing a guidance for industry entitled ``Reports on 
the Status of Postmarketing Studies--Implementation of section 130 of 
the Food and Drug Administration Modernization Act of 1997.'' FDA 
intends to make a draft of this guidance available shortly after 
publication of this final rule.

II. Description of the Final Rule

    This final rule amends parts 314 and 601 (21 CFR parts 314 and 601) 
to revise the status reports section of postmarketing annual reports 
for drug and licensed biological products (Secs. 314.81(b)(2)(vii) and 
601.28). This final rule also amends part 601 to require applicants 
with licensed biological products to submit a separate annual report 
that describes the status of certain postmarketing studies 
(Sec. 601.70). The major provisions of the final rule are summarized 
below.
    Under Secs. 314.81(b)(2)(vii) and 601.70(a), the final rule defines 
postmarketing studies for which status reports must be submitted to FDA 
under section 506B of the act as those that concern: (1) Clinical 
safety; (2) clinical efficacy; (3) clinical pharmacology; and (4) 
nonclinical toxicology studies that are either required by FDA (e.g., 
accelerated approval clinical benefit studies, pediatric studies) or 
committed to by the applicant, in writing, at the time of approval of 
an application or a supplement or after approval of an application or 
supplement. FDA is including clinical safety and efficacy and clinical 
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 of an approved drug or 
licensed biological product. FDA also is including nonclinical 
toxicology studies within the scope of this rule, although such studies 
are not performed on human subjects, because they are important to the 
further evaluation of the safety of a marketed drug or biological 
product. For the purpose of this rule, clinical safety and clinical 
efficacy studies include human epidemiological studies. Clinical 
pharmacology studies include pharmacokinetic and pharmacodynamic 
studies.
    Under Secs. 314.81(b)(2)(vii) and 601.70, the final rule requires 
applicants to provide status reports to FDA regarding the progress of 
the postmarketing studies described above. In addition, under 
Sec. 314.81(b)(2)(viii), applicants with approved NDA's and ANDA's must 
provide status reports for any postmarketing study not reported under 
Sec. 314.81(b)(2)(vii) (e.g., chemistry, manufacturing, controls, 
product stability). These include postmarketing studies performed by, 
or on behalf of, the applicant on its own initiative. Section 
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 on postmarketing studies 
in annual reports. FDA is not requiring a similar reporting requirement 
for postmarketing studies of licensed biologicals in this rule. 
However, applicants with licensed biological products may voluntarily 
submit status reports to FDA for postmarketing studies that are not 
required to be reported under Sec. 601.70.
    The agency is committed to harmonizing its reporting requirements 
for drugs and biologics as much as possible. FDA considered amending 
its biologics regulations 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 also considered combining postmarketing annual 
reports required under Secs. 601.12(d), 601.28, and proposed 601.70 
into a single annual report that would 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 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.

III. Comments on the Proposed Rule and FDA Responses

    FDA received seven comments on the proposed rule from 
representatives of pharmaceutical companies and associations. While 
most comments agreed that the proposed rule appropriately implements 
section 130 of FDAMA, many comments expressed concern about what 
information should be included in the status reports and what 
information should be disclosed to the public.
    A discussion of the comments on the proposed rule and the agency's 
responses follows.

A. Status Reports

    (Comment 1) One comment claimed that the proposed content of status 
reports exceeds that necessary to determine, as stated in section 130 
of FDAMA, ``the progress of the study or the reasons for the failure of 
the sponsor to conduct the study.'' The comment said that the agency 
turns the simple reporting requirement contemplated by FDAMA into a 
potentially complicated and burdensome exercise. For example, the 
comment noted that applicants must provide detailed information on a 
postmarketing study commitment regarding the purpose of the study, the 
patient population addressed by the study, the indication and dosage(s) 
that are to be studied, the projected dates for initiation of the 
different phases of the study and completion of the study, the status 
of patient accrual, as well as an explanation of the study's status 
(which would be categorized separately). The comment recommended that 
the proposed rule be revised to require applicants to simply identify a 
pertinent postmarketing study commitment and report on its status using 
a standardized description. The comment added that additional details 
regarding the postmarketing study commitment should be provided at the 
discretion of the applicant.
    FDA has reviewed the proposed content for status reports and has 
decided to make several changes. In Secs. 314.81(b)(2)(vii)(a)(6) and 
601.70(b)(6), the agency is revising the requirements for the 
``Description of postmarketing study commitment'' section of status 
reports to permit an applicant to determine the type of information 
that is necessary to identify a postmarketing study commitment. Instead 
of specifying the elements that would be required to be included in 
this section, the provision now provides examples of the type of 
information that applicants may choose to use to describe a 
postmarketing study commitment. This section, as revised, now reads:

    The description must include sufficient information to uniquely 
describe the study. This information may include the purpose of the 
study, the type of study, the patient

[[Page 64610]]

population addressed by the study and the indication(s) and 
dosage(s) that are to be studied.

    The list of examples does not contain ``the number of patients and/
or subjects to be included in the study.'' However, an applicant is 
required to include patient accrual information (by providing the 
number of patients or subjects enrolled to date and the total planned 
enrollment) in the section requiring an explanation of the study's 
status.
    The agency recognizes that the extent of information necessary to 
identify various postmarketing study commitments will vary. In most 
cases, it will be sufficient to use the language provided in the FDA 
document describing the postmarketing study commitment (e.g., action 
letter). In other cases, such as when multiple studies are required to 
fulfill a postmarketing study commitment, additional information is 
likely to be needed to describe each of the studies.
    In Secs. 314.81(b)(2)(vii)(a)(7) and 601.70(b)(7), the agency is 
revising the ``Schedule of conduct, completion and reporting of the 
postmarketing study commitment'' section of the status report to 
require inclusion of only the information that is most important in 
determining the progress of a study and to clarify that information. 
FDA is replacing the phrase ``projected dates for initiation of the 
different phases of the study'' with the phrase ``actual or projected 
dates for submission of the study protocol to FDA, completion of 
patient accrual or initiation of an animal study'' and adding ``any 
additional milestones or submissions for which projected dates were 
specified as part of the commitment.'' FDA recognizes study phases may 
vary depending on the type of study and the study design. Because 
information on some phases of a study may not be meaningful in 
establishing study progress, FDA is limiting the information for this 
section to the projected, or actual, dates for the submission of the 
study protocol to FDA; for completion of patient accrual into a 
clinical study or initiation of an animal study; for completion of the 
study; and for submission of the final study report to FDA. In 
addition, FDA recognizes that some study commitments include an 
agreement to report important intermediate timepoints or early study 
endpoints (e.g., evaluation of surrogate endpoints in a study also 
measuring clinical benefit). If a study commitment includes reporting 
at such intermediate timepoints, these timepoints should be included in 
the projected schedule submitted under Secs. 314.81(b)(2)(vii)(a)(7) 
and 601.70(b)(7).
    FDA is requiring that the schedule in this section include actual 
dates, if they represent milestones that have already been reached, in 
addition to projected dates. This is particularly appropriate for 
studies that were started before the effective date of this final rule 
and for which a particular aspect of the study has already been 
completed by the effective date. Actual dates are also appropriate if a 
particular aspect of the study (e.g., submission of study protocol) was 
completed prior to approval of the drug or agreement on the 
postmarketing commitment.
    The agency is revising the section title ``Schedule for conduct, 
completion and reporting of the postmarketing study commitment'' by 
removing the word ``conduct'' from the section heading. FDA is making 
this revision because the word ``conduct'' is not necessary.
    FDA is modifying the section ``Current status of the postmarketing 
study commitment'' at Secs. 314.81(b)(2)(vii)(a)(8) and 601.70(b)(8), 
by removing from the paragraph ``Ongoing'' the requirement to include 
the date the study was completed, and removing from the paragraph 
``Submitted'' the requirement to provide the date the final study 
report was submitted to FDA. These date requirements have been added to 
the section ``Explanation of the study's status'' at 
Secs. 314.81(b)(2)(vii)(a)(9) and 601.70(b)(9) to consolidate under 
this section all information providing clarification of the status of 
individual studies. The paragraph ``Pending'' has been clarified to 
state that studies that have not been initiated will be categorized as 
delayed if the study is behind the original schedule for completion and 
reporting of the postmarketing commitment. FDA is modifying the 
paragraph ``Terminated'' to clarify that this category is to be used if 
a study has been terminated before completion, but a final study report 
has not yet been submitted to the agency.
    FDA is requiring, as proposed, that annual status reports include 
the applicant's name, product name, application (NDA, ANDA, BLA, and 
supplement) number, date of postmarketing commitment, and the product 
approval date. However, in Secs. 314.81(b)(2)(vii)(a)(4) and 
601.70(b)(4), the agency is replacing the ``Date of product's U.S. 
approval'' section heading with the heading ``Date of U.S. approval of 
NDA, ANDA, or BLA.'' This change is being made to clarify 
identification of the postmarketing commitment because the product may 
be included in more than one application.
    FDA is keeping all other sections of the status reports as 
proposed, because the agency believes that the information that is 
being requested in them is necessary to identify a postmarketing study 
commitment, to establish the progress of a postmarketing study 
commitment, or to identify the reasons for the failure of the applicant 
to conduct the study. The agency will use these status reports to 
review the progress of postmarketing study commitments and to meet its 
statutory reporting obligations (i.e., its report to Congress on this 
topic by October 1, 2001, and its annual report in the Federal Register 
on the status of postmarketing study commitments). FDA anticipates that 
preparation of a status report for a postmarketing study commitment 
will not be burdensome. Each status report should contain no more than 
one page of information that is readily available to the applicant.
    (Comment 2) One comment said that much of the information required 
to be submitted in an NDA annual report under the proposed rule must 
already be submitted to an investigational new drug application (IND). 
The comment noted that the risk of duplicative reporting burdens is 
exacerbated by the fact that NDA and IND anniversary dates may differ 
and applicants may be required to collect and reconcile information for 
the same postmarketing studies twice a year. The comment recommended 
that FDA scale back the scope of the information required to be 
submitted to the NDA annual report and also permit applicants to 
reference pertinent sections of an IND and IND annual report in an NDA 
annual report.
    FDA declines to permit applicants to reference their IND and IND 
annual reports in the status report section of NDA and BLA annual 
reports. Most of the information contained in these reports is 
different from the information submitted to the IND and is used by the 
agency for different purposes. FDA needs the information that is 
contained in a status report in the prescribed format to meet its 
statutory reporting obligations. FDA does not believe that preparation 
of status reports will be unduly burdensome for applicants, and the 
fact that no comments were submitted on the information collection 
provisions supports this conclusion.

B. Public Disclosure of Information

    New Secs. 314.81(b)(2)(vii)(b) and 601.70(e) require the agency to 
publicly disclose any information concerning a postmarketing study if 
the agency determines that the information is

[[Page 64611]]

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. The proposal stated that information necessary to 
establish the status of a postmarketing study would include the study 
protocol, patient accrual rates, reports of unexpected suspected 
adverse drug reactions, and study results. The proposal also specified 
that FDA would not publicly disclose trade secrets, as defined in 
Sec. 20.61 (21 CFR 20.61), or information, described in Sec. 20.63 (21 
CFR 20.63), the disclosure of which would constitute an unwarranted 
invasion of personal privacy.
    (Comment 3) Three comments strongly objected to the public 
disclosure provisions of the proposed rule contending that such 
disclosure could potentially result in release of confidential and 
highly sensitive commercial information. One comment said that the 
``proposed rule directly violates the limits set by FDAMA,'' when the 
proposed rule calls for the disclosure of the study protocol, patient 
accrual rates, reports of unexpected suspected adverse drug reactions, 
and study results. The comment claimed that the agency is incorrect 
when it asserts that this additional information is ``necessary to 
identify the applicant and to establish the status of a study.'' 
Another comment noted that there is an inconsistency in the content of 
the status reports section and the public disclosure sections of the 
proposed rule that needs clarification. The content of the status 
report section is limited to patient accrual and study status, whereas 
the public disclosure section states that the study protocol and study 
results will be made public.
    The comments recommended that study protocols, reports of 
unexpected suspected adverse drug reactions, and results of the study 
not be publicly disclosed. One comment said that clinical protocols are 
highly proprietary in terms of design and analytical plan and that 
applicants should only be required to provide a general description of 
the study for public disclosure. Another comment said that with regard 
to disclosure of study results in an orphan drug exclusivity situation, 
the publication of detailed study results may allow competitors to 
strategically redesign clinical trials in an effort to nullify another 
company's market exclusivity. The comment also said that detailed 
knowledge of study results could also lead to potential disputes 
between competitors via negative advertising. The comment recommended 
that applicants only be required to provide a brief summary of the 
study results for public disclosure. Another comment said that 
disclosure of study results represents bad science because it is 
generally not appropriate to ``peek'' at results from a study before 
its scheduled completion. Another comment said that annual public 
disclosure of all reports of unexpected adverse drug reactions are 
inappropriate for epidemiological studies because no scientifically-
based conclusions can be drawn when safety reports are reviewed out of 
context of the study population and without regard to the appropriate 
controls. However, the comment noted that if any new association is 
established between a product and a previously unknown adverse 
reaction, such information should be made public. Another comment noted 
that if a study is delayed because of low patient accrual rates, 
despite legitimate efforts to enroll subjects, information posted on a 
website could negatively affect the company and its ability to complete 
the commitment.
    FDA has considered these comments and agrees that disclosure of the 
study protocol, reports of unexpected suspected adverse drug reactions, 
and the results of studies reported under Secs. 314.81(b)(2)(vii) and 
601.70 are not necessary to achieve the purposes of the rule or section 
130 of FDAMA. Section 130 of FDAMA requires the agency to publicly 
disclose information pertaining to status reports if that information 
is necessary to identify the applicant and to establish the status of a 
study, including the reasons, if any, for failure to conduct, complete, 
and report the study. FDA has, therefore, decided to remove the 
following sentence from proposed Secs. 314.81(b)(2)(vii)(b) and 
601.70(e): ``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.''
    For purposes of public disclosure, the agency intends to release 
information that establishes the status of a study and that is 
contained in Secs. 314.81(b)(2)(vii)(a)(1) through (b)(2)(vii)(a)(9) 
and 601.70(b)(1) through (b)(9) of the final rule. These sections do 
not call for study results and FDA does not believe that any 
information provided by applicants in these sections of a status report 
would be considered confidential commercial information. However, even 
if an applicant considers certain information in these sections to be 
confidential commercial information, section 130(a) of FDAMA would 
authorize FDA to release such information if it were necessary to 
identify the applicant or to establish the status of a study, including 
the reasons, if any, for failure to conduct, complete, and report the 
study. The agency has decided that a study protocol, study results, and 
reports of unexpected suspected adverse drug reactions are not 
information necessary to establish the status of the study. However, 
the agency expects to continue to receive study protocols and study 
results since that information is necessary for FDA to determine 
whether a study commitment has been satisfied. The agency also expects 
to continue to receive reports of unexpected suspected adverse drug 
reactions, which are required reports. Other laws, such as the Freedom 
of Information Act (FOIA), would determine whether the agency would 
release to the public study protocols, study results, and reports of 
unexpected suspected adverse drug reactions.
    FDA believes that the number of patients who are enrolled in a 
postmarketing study is an important factor establishing the status of a 
study. Applicants would provide such information to FDA in status 
reports, and, under section 130 of FDAMA, patient accrual rates would 
be considered to be public information.
    (Comment 4) One comment claimed that the proposed rule is contrary 
to FOIA and the Trade Secrets Act. The comment said that FOIA 
specifically exempts confidential commercial information from public 
disclosure under 5 U.S.C. 552(b)(4) (so-called ``FOIA Exemption 4'') 
and that the Trade Secrets Act makes it a crime for a Federal employee 
to disclose any information within the scope of FOIA Exemption 4, 
including confidential commercial information to the extent that the 
disclosure is not authorized by law (18 U.S.C. 1905). The comment 
further asserted that there is nothing in the legislative history of 
FDAMA to suggest that Congress intended to make public information that 
would otherwise be exempt from disclosure under FOIA, except to the 
very narrow extent necessary to identify a sponsor and establish the 
status of a study. The comment said that the only information that 
should be required to be disclosed should be basic information to 
identify the study and sponsor, and the standardized information on the 
status of a study (or, if applicable, a brief explanation of why a 
study was not conducted). The comment said that this is the only 
information that should be posted on FDA's website.
    FDA disagrees with the comment because it does not believe that 
status reports would contain confidential commercial information. In 
any event,

[[Page 64612]]

section 130(a) of FDAMA requires the agency to disclose certain 
information from postmarketing study reports even if that information 
ordinarily would be considered confidential commercial information. 
Since section 130(a) of FDAMA requires disclosure, the disclosure would 
be authorized by law and not prohibited by the Trade Secrets Act. FDA 
will not disclose any information from postmarketing study reports that 
is considered a trade secret as defined in Sec. 20.61(a) and section 
301(j) of the act (21 U.S.C. 331(j)) or would constitute an unwarranted 
invasion of personal privacy as defined in Sec. 20.63.
    (Comment 5) Two comments wanted to know what information would be 
disclosed on FDA's website and what format would be used for this 
purpose. One of the comments asked if a company would have the 
opportunity to review information before it is posted on the website to 
ensure that confidential data are not disclosed. Another comment 
requested that an efficient procedure be established to identify the 
information that is disclosable. The comment said that applicants 
should be instructed to include a section in their postmarketing status 
reports that is specifically intended for public disclosure. The 
comment noted that this approach is consistent with that adopted 
recently by FDA for information provided by sponsors to advisory 
committees in connection with open advisory committee meetings. The 
comment also noted that if FDA disagrees with an applicant's 
designation of disclosable information, the agency could then consult 
with the applicant.
    FDA intends to include information on its webpage that is provided 
to FDA by applicants in their status reports. In the proposed rule, FDA 
stated that the website 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. At this time, FDA intends to include this information 
on FDA's webpage, as well as the date the final study report is 
received by the agency. In the future, FDA may decide to add or remove 
types of information from the website or to revise the format. FDA 
intends to provide a suggested format for postmarketing reports and an 
example of what information will appear on the agency website in the 
guidance the agency is developing or on which the agency will solicit 
public comment. (See section I.C of this document.)
    With regard to the submission of a publicly releasable version of 
the status report by applicants, the agency will not require such 
submissions at this time. FDA is considering recommending, in guidance, 
that applicants include with their status reports a publicly releasable 
version of the report. This version of the status report would 
facilitate FDA's transmission of information to its website.
    (Comment 6) One comment said that the agency needs to clarify that 
public disclosure does not apply to chemistry, manufacturing, and 
controls (CMC) studies. Another comment said that the agency needs to 
clarify that public disclosure does not apply to the log of outstanding 
regulatory business section of approved NDA annual reports.
    The rule has been clarified to require the status of CMC studies 
that the applicant has agreed to conduct to be reported under 
Sec. 314.81(b)(2)(viii). FDA would not publicly disclose in its annual 
Federal Register report or website information concerning postmarketing 
study commitments submitted in NDA annual reports under 
Secs. 314.81(b)(2)(viii) and 314.81(b)(2)(ix). FDA intends to limit 
information in the annual Federal Register report and website to 
information submitted in status reports under Secs. 314.81(b)(2)(vii) 
and 601.70.

C. Scope of Proposed Rule--FDAMA 130 Studies for Drug and Licensed 
Biological Products

    Annual reports submitted under Sec. 314.81(b)(2) apply to human 
drug products with an approved NDA or ANDA. New Sec. 601.70 applies to 
human licensed biological products that meet the definition of ``drug'' 
under the act; it would not apply to biological products that meet the 
definition of ``medical device'' under the act. Revised 
Sec. 314.81(b)(2)(vii) and new Sec. 601.70 require, under section 130 
of FDAMA, status reports of postmarketing studies concerning clinical 
safety, clinical efficacy, clinical pharmacology, and nonclinical 
toxicology that are required by FDA (e.g., accelerated approval 
clinical benefit studies and pediatric studies) or that the applicant 
committed to conduct, in writing, either at the time of approval of an 
application for the drug product or licensed biological product or of a 
supplement to an application, or after approval of an application or a 
supplement.
    (Comment 7) One comment requested that reporting on the status of 
nonclinical studies (e.g., preclinical) be made optional for 
Sec. 601.70.
    FDA disagrees with the comment. The agency is requiring that 
information be provided for postmarketing nonclinical toxicology 
studies because of their significance in assessing the safety of drug 
and licensed biological products.
    (Comment 8) One comment said that FDA should set some reasonable 
limit on how far back in time it will require applicants to report on 
studies that they committed to conduct years before enactment of 
section 130 of FDAMA but that still remain open. The comment suggested 
that the agency could remove the status report requirement for a study 
commitment that was entered into more than 3 years ago.
    FDA disagrees with the comment. Section 130 of FDAMA requires that 
the status of postmarketing study commitments, whether entered into 
before or after the date of enactment of FDAMA, be reported to FDA 
annually until the commitment is completed or terminated. Many clinical 
studies take several years to complete. Studies that applicants 
committed to conduct several years ago are only now coming to 
completion and will yield important information about the safety and 
effective use of the drug or biological product. The agency will 
monitor an applicant's submission of status reports under 
Secs. 314.81(b)(2)(vii) and 601.70 for any postmarketing study 
commitment that the agency has formally tracked in agency postmarketing 
commitment data bases.

D. Scope of Proposed Rule--Other Studies for Drug Products

    In Sec. 314.81(b)(2)(viii), FDA proposed to require that status 
reports be submitted for any postmarketing study not included under 
Sec. 314.81(b)(2)(vii) that is being performed by, or on behalf of, the 
applicant. The applicant was to provide the information prescribed 
under Sec. 314.81(b)(2)(vii) for each of the postmarketing studies 
subject to reporting.
    (Comment 9) Three comments requested that the agency remove this 
section from the regulations because section 130 of FDAMA only requires 
status reports for studies that a company has committed to FDA to 
perform. One of the comments said that, as an alternative, the agency 
could limit the studies in this section to those which the applicant 
committed to FDA that it would conduct.
    FDA disagrees with the comment. The agency currently requires that 
the status of any postmarketing studies performed by, or on behalf of, 
the applicant be provided in NDA annual reports and

[[Page 64613]]

FDA will continue to require status reports for these studies. It was 
not the intent of this rule, however, to expand current reporting 
requirements for postmarketing studies reported under 
Sec. 314.81(b)(2)(viii). In considering the comments received, FDA has 
decided that it is not necessary to prescribe the content and format 
for status reports under Sec. 314.81(b)(2)(viii) and has removed this 
requirement. Section 314.81(b)(2)(viii) and (b)(2)(ix) are retained in 
this rule due to the reorganization of Sec. 314.81(b)(2)(vii).
    (Comment 10) Two comments requested that CMC studies be exempt from 
inclusion in proposed Sec. 314.81(b)(2)(viii) because there is no 
purpose in providing such information in this section. One comment said 
that even though current Sec. 314.81(b)(2)(vii) requires status reports 
for ``any'' postmarketing study, existing regulation and guidance have 
previously established a more narrow definition of the CMC reporting 
requirement. The comment explained that current Sec. 314.81(b)(2)(iv) 
states that reports for CMC changes are only required for new 
information that may affect FDA's previous conclusions about the safety 
or effectiveness of the drug product and that the guidance for industry 
on ``Format and Content for the CMC section of an Annual Report'' 
specifies only the need to include stability data under current 
Sec. 314.81(b)(2)(vii). The comment recommended that CMC study 
information be provided under current Sec. 314.81(b)(2)(iv) so that all 
the information pertinent to the chemistry review would be consolidated 
into a single section. Another comment said that reporting the status 
of CMC studies is not pertinent and repeating this information under 
proposed Sec. 314.81(b)(2)(viii) is redundant and unnecessary.
    FDA disagrees in part with this comment. Section 314.81(b)(2)(vii) 
currently requires reporting of any postmarketing study. FDA's current 
guidance for industry states that data accumulated from ongoing 
stability studies should be included in Sec. 314.81(b)(2)(vii). 
Therefore, it is clear from existing regulations and guidance that 
stability studies are to be reported under existing 
Sec. 314.81(b)(2)(vii) (now Sec. 314.81(b)(2)(viii) of the rule). These 
reports provide FDA with valuable information regarding the safety and 
efficacy of products, and FDA has decided to retain this requirement in 
the final rule. However, FDA has decided to modify 
Sec. 314.81(b)(2)(viii) to clarify the reporting requirements for CMC 
studies. FDA will maintain a requirement for reporting data from all 
ongoing product stability studies including those that are being 
conducted without a postmarketing study commitment, (e.g., annual 
stability assessment performed in conformance with 21 CFR 211.166). For 
other types of CMC studies, FDA is revising Sec. 314.81(b)(2)(viii) to 
require a status report for only those studies which the applicant has 
agreed to perform. This section now reads as follows:
    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. A 
status report is to be included for any chemistry, manufacturing, and 
controls studies that the applicant has agreed to perform and for all 
product stability studies.
    Information from other CMC studies, experiences, investigations, or 
tests that are not stability studies or the subject of a specific 
commitment but that provide new information that may affect FDA's 
previous decisions about product safety and efficacy will continue to 
be reported under Sec. 314.81(b)(2)(iv).

E. Fulfillment of Commitments

    FDA proposed at Secs. 314.81(b)(2)(vii) and 601.70(b) that the 
status of postmarketing studies be submitted to the agency 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.
    (Comment 11) Three comments requested that FDA specify the 
timeframe for agency review of a final study report and for notifying 
the applicant whether or not the postmarketing study commitment has 
been fulfilled or that a commitment is either no longer feasible to 
fulfill or would no longer provide useful information. One of the 
comments suggested a 90-day timeframe and another comment suggested a 
60-day timeframe.
    In general, FDA expects that final study reports for postmarketing 
study commitments will be submitted to the agency with a supplemental 
application to modify a product's labeling when the studies support 
such a change. When they are submitted in support of a supplement, FDA 
will review the submission under established review times for 
supplements. (For Prescription Drug User Fee Act (PDUFA) products, see 
letters from Secretary of Health and Human Services to the Chairman of 
the Committee on Commerce of the House of Representatives (143 
Congressional Record H10886, November 13, 1997), and the Chairman of 
the Committee on Labor and Human Resources of the Senate (143 
Congressional Record S12653, November 13, 1997)). If no supplemental 
application is submitted or a supplement is submitted for a product not 
covered by PDUFA, FDA will generally review the final study report and 
notify the applicant in writing within 1 year of receipt of the report 
regarding whether it considers the commitment to have been met.
    (Comment 12) One comment said that the requirement to continue to 
submit status reports on terminated postmarketing studies until FDA 
considers that the study commitments have been fulfilled is too vague. 
The comment requested clarification of the criteria that the agency 
would use to deem a study fulfilled.
    FDA will review final study reports and determine whether or not 
the study met the objectives of the commitment. Whether or not the 
objectives have been met will have to be determined on a case-by-case 
basis because of the variety of postmarketing study commitments. Once 
FDA completes its review of the final study report, it will notify the 
applicant, in writing, of the agency's conclusion. An applicant would 
be required to submit annual status reports to FDA until it receives 
written notification that the agency concludes that: (1) The study 
commitment has been met, or (2) the study is either no longer feasible 
or would no longer provide useful information.
    FDA may conclude that the study is no longer feasible but that the 
commitment's objectives remain important and can be addressed through a 
study of modified design. In this case, the original study may be 
terminated with no further reporting once a new postmarketing study 
commitment and schedule are agreed upon.
    FDA may conclude that even though a study was completed, it failed 
to meet the commitment objectives; or an applicant may terminate a 
study that FDA subsequently determines is feasible and would yield 
useful information. In these cases, the agency may ask the applicant to 
undertake another study to fulfill its commitment.
    (Comment 13) One comment said that FDA's confirmation in writing 
that a study commitment has been fulfilled could reasonably be 
accommodated through addition of a suitable field in the Form FDA 2252 
(Transmittal of Periodic Reports for Drugs for Human Use), which would 
be completed by FDA at the time that receipt of the annual report is 
acknowledged. From

[[Page 64614]]

that point on, the comment said that the status of the postmarketing 
commitment should be tracked under outstanding regulatory business. The 
comment noted that this suggestion, intended to reduce the 
administrative burden on FDA of acknowledging receipt of final study 
reports, would not remove the need for FDA to confirm in writing that 
they have evaluated the study report and concur with the applicant's 
conclusions or proposed action (e.g., submission and approval of a 
labeling supplement to accommodate study results).
    FDA disagrees with this suggestion. The agency will not acknowledge 
that the postmarketing study commitment has been fulfilled until it has 
reviewed the final study report and concurs that the commitment has 
been met. Applicants found to have fulfilled their commitments will be 
notified in writing. In addition, this information will be acknowledged 
in the agency's data bases and website.

F. Annual Report Submission Date

    Current Sec. 314.81(b)(2) requires that an applicant submit an 
annual report each year within 60 days of the anniversary date of U.S. 
approval of the application. FDA proposed to require the same 
submission times at Sec. 601.70(c) for annual progress reports of 
postmarketing study commitments entered into by applicants with 
licensed biological products.
    (Comment 14) One comment said that, for postmarketing studies that 
are already underway and for which annual reports are already provided, 
applicants should be permitted to continue to use the annual reporting 
cycles that are already established. The comment noted that it submits 
annual reports based on the anniversary date of the study initiation 
rather than the anniversary date of U.S. approval.
    Current Sec. 314.81(b)(2) requires that NDA annual reports be 
submitted to the agency within 60 days of the anniversary date of 
approval of the application. FDA will continue to require that NDA 
annual reports be submitted within the same timeframe. Applicants would 
not be permitted to submit NDA or BLA annual reports based on the 
anniversary date of a study's initiation.
    Many drug and licensed biological products have multiple 
postmarketing studies underway that were initiated on different dates. 
The submission of annual reports based on the date of study initiation 
would result in multiple reports in any given year, thereby 
unnecessarily increasing an applicant's reporting burden and 
complicating FDA's tracking and review of postmarketing study 
commitment reports. It is FDA's intent to minimize the reporting burden 
on industry by requiring only a single annual report for any NDA, ANDA, 
or BLA product. This single report allows applicants to submit status 
information on all studies and allows FDA reviewers to review and 
evaluate at one time the progress of all studies, some of which may be 
related.

G. Implementation Scheme--Effective Dates

    FDA proposed that any final rule that may issue based on the 
proposed rule become effective 90 days after its date of publication in 
the Federal Register. Applicants that have entered into a commitment 
prior to November 21, 1997, to conduct a postmarketing study under 
proposed Sec. 314.81(b)(2)(vii) or 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 issued based on the 
proposed rule.
    (Comment 15) One comment requested that FDA provide that the 
effective date of any final rule be 120 days after the date of 
publication of the rule in the Federal Register. The comment noted 
that, with the proposed 90-day effective date, an applicant could be 
required to submit an initial report 5 months following publication of 
the final rule, depending on the anniversary date of their products. 
The comment claimed that the 90-day effective date is not consistent 
with section 130 of FDAMA which indicates that applicants should have 6 
months following the issuance of final regulations to submit initial 
reports on postmarketing study commitments. The comment recommended 
that the effective date be modified to ensure that all applicants will 
have at least 6 months to file reports under the new requirements.
    FDA does not believe that section 130 of FDAMA requires the agency 
to give a period of 6 months after issuing a final rule for applicants 
to prepare a postmarketing study status report. Rather, section 130(a) 
of FDAMA requires all applicants, regardless of the anniversary date of 
the approval of their drug, to submit status information for 
postmarketing study commitments made prior to November 21, 1997, within 
6 months of the final rule's issuance. This timely submission of 
information is necessary to allow FDA to meet its reporting obligation 
in providing Congress with an evaluation of industry's performance in 
meeting postmarketing commitment obligations and FDA's performance in 
reviewing those postmarketing study reports.
    However, FDA has considered the comment and is revising the 
effective date to 120 days after the date of publication of the rule in 
the Federal Register. Although FDA anticipates the information required 
to complete an inital report on the progress of postmarketing studies 
is readily available to the applicant, the agency understands that some 
applicants may have a greater reporting burden than other applicants 
due to a larger number of postmarketing commitments. Revision of the 
effective date will give all applicants a minimum of 4 months to 
prepare an initial report on their postmarketing commitments. If an 
applicant chooses to submit the report up to 60 days after the 
anniversary date of the approval of the drug, the applicant will have 6 
months in which to file an initial report.
    Once the rule goes into effect, annual reports due on or after the 
effective date must meet the format and content requirements of this 
final rule. An applicant who has annual reports due on or after August 
27, 2001, will be required to submit a special 6-month report for all 
commitments made prior to November 21, 1997. This one-time additional 
report is required if:
    (1) The drug or biological product was approved before November 21, 
1997;
    (2) Postmarketing study commitments were made before November 21, 
1997; and
    (3) The next annual report is not due until August 27, 2001, or 
later.
    (Comment 16) One comment requested that FDA remove the requirement 
to submit a separate initial report within 6 months of the effective 
date of the final rule for pre-FDAMA commitments. The comment asserted 
that these reports would contain data from a time interval of less than 
1 year and that significant resources would be required to prepare such 
a report as well as for FDA to review the report, which, due to the 
limited data, would be of minimal value. Another comment said that 
there is little value in requiring submission of these separate reports 
and that the requirement should be fulfilled in the next annual report 
due for each product. The comment claimed that this would also be more 
compatible with collation and publication of the planned Annual Federal 
Register Report.
    FDA does not accept this suggestion. Section 130(a) of FDAMA 
requires that an initial report on the progress of postmarketing 
commitments made prior to November 21, 1997, be submitted to FDA within 
6 months of the agency issuing a final rule. Although some information 
on postmarketing studies may be included in annual reports for

[[Page 64615]]

new drugs submitted before the effective date of the final rule, these 
reports may not include all information necessary for FDA to evaluate a 
study's progress. Also, applicants of approved biological products may 
not have previously submitted study status information. FDA 
acknowledges that the special 6-month report may contain limited new 
data. However, the submission of that data, in the format required by 
Secs. 314.81(b)(2)(vii) and 601.70(b), is necessary to allow FDA to 
respond in a timely manner to Congress as required in section 130(b) of 
FDAMA. Therefore, FDA maintains this one-time reporting requirement.

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 final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1966 (Public Law 104-121)), and the Unfunded Mandates Reform Act of 
1995 (Public Law 104-4). 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). The Regulatory Flexibility Act requires agencies to 
analyze whether a rule may have a significant impact on a substantial 
number of small entities and, if it does, to analyze regulatory options 
that would minimize the impact. Section 202 of the Unfunded Mandates 
Reform Act requires that agencies prepare a written statement of 
anticipated costs and benefits and 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 one year.
    The agency has determined that the final rule is not a significant 
action as defined in the Unfunded Mandates Reform Act, and will not 
have an effect on the economy that exceeds $100 million in any one 
year. The analysis below details FDA's estimate of the potential cost 
and the potential benefit of the rule. Based on FDA's analysis using 
available data, the agency does not anticipate that the rule will 
result in a significant impact on a substantial number of small 
entities.

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 final 
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: (1) There will be approximately 116 such reports 
submitted; (2) each report will report on two postmarketing studies, on 
average; and (3) each report will require about 16 hours (or 8 hours 
per study) to complete. Assuming an average wage rate of $35 per hour, 
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 requirements in this final rule. The agency 
estimates that about 33 applicants will submit postmarketing status 
reports (reporting on two postmarketing studies, on average) on 
approximately 43 approved BLA's annually. 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 for each report (or 8 hours 
for each study). 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 final rule will not have a significant 
economic impact on a substantial number of small entities. The agency 
neither expects the final rule to result in an increased number of 
completed postmarketing studies nor believes 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 (see section I.C of this document).

C. Federalism

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

VI. The Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that 
were reviewed by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-3520), and 
that FDA invited the public to send comments to OMB. No comments were 
received by OMB on these provisions. A description of these provisions 
is shown below with an estimate of the annual reporting burden. 
Included in the estimate is the

[[Page 64616]]

time for reviewing the instructions, searching existing data sources, 
gathering and maintaining the data needed, and completing and reviewing 
each collection of information.
    Title: Reporting the Status of Postmarketing Studies for Approved 
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 
application and then annually until the study is completed or 
terminated. Under Secs. 314.81(b)(2)(vii) 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 amending 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). New Sec. 314.81(b)(2)(viii) 
of the final rule requires 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) permits the applicant to list any open regulatory business 
with FDA concerning the drug product subject to the application. For 
licensed biological products, FDA is requiring applicants under 
Sec. 601.70 to submit 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 revising Sec. 601.28(c) to require 
that the status of postmarketing pediatric studies described in new 
Sec. 601.70 be reported under Sec. 601.70 rather than Sec. 601.28. This 
final 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 
applications for human drugs and biological products that have 
committed to conduct postmarketing studies.
    As required by section 3506(c)(2)(B) of the PRA, FDA provided an 
opportunity for public comment on the information collection 
requirements of the proposed rule (64 FR 67207). In accordance with the 
PRA, OMB reserved approval of the information collection burden in the 
proposed rule stating ``FDA shall assess comments received regarding 
information collection requirements contained in the proposed rule. 
These comments shall be addressed in the preamble to the final rule.'' 
No letters of comment on the information collection requirements were 
submitted to OMB.
    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 control No. 0910-0001).
    New Sec. 314.81(b)(2)(vii) expressly requires 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 new 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 
data base, 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 
Sec. 601.70. Section 601.70 requires postmarketing studies status 
reports for the first time for all biological products. Previously, 
status reports were required only for postmarketing studies in 
pediatric populations. Based on past experience with reporting under 
Sec. 314.81(b)(2), the agency estimates that approximately 8 hours 
annually are required for an applicant to gather, complete, and submit 
the appropriate information for each study (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 this final 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 the final rule in 
addition to the reports required by the final rule. This information 
collection is a statutory requirement for which the final rule adds 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).

[[Page 64617]]



                                 Table 1.--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                      Annually
          21 CFR Section               No. of      Frequency per    Total Annual     Hours per      Total Hours
                                    Respondents      Response        Response        Response
----------------------------------------------------------------------------------------------------------------
314.81(b)(2)(vii), (b)(2)(viii),      183               2.5           462               8           3,696
 and
(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 asociated with this collection of information.
 
\2\ One-time burden for reformatting annual report.

    The information collection requirements of the final rule have been 
submitted to OMB for review. Prior to the effective date of the final 
rule, FDA will publish a document in the Federal Register announcing 
OMB's decision to approve, modify, or disapprove the information 
collection requirements in the final rule. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.

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, 21 CFR parts 314 and 601 are 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, 355a, 356, 
356a, 356b, 356c, 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 each year within 60 
days of the anniversary date of U.S. approval of the application, 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 Periodic Reports 
for Drugs for Human Use), and must include all the information required 
under this section that the applicant received or otherwise obtained 
during the annual reporting interval that 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, and 
nonclinical toxicology that is required by FDA (e.g., accelerated 
approval clinical benefit studies, 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 the 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 must 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 any.
    (3) NDA, ANDA, and supplement number.
    (4) Date of U.S. approval of NDA or ANDA.
    (5) Date of postmarketing study commitment.
    (6) Description of postmarketing study commitment. The description 
must include sufficient information to uniquely describe the study. 
This information may include the purpose of the study, the type of 
study, the patient population addressed by the study and the 
indication(s) and dosage(s) that are to be studied.
    (7) Schedule for completion and reporting of the postmarketing 
study commitment. The schedule should include the actual or projected 
dates for submission of the study protocol to FDA, completion of 
patient accrual or initiation of an animal study, completion of the 
study, submission of the final study report to FDA, and any additional 
milestones or submissions for which projected dates were specified as 
part of the commitment. In addition, it should include a revised 
schedule, as appropriate. If the schedule has been previously revised, 
provide both the original schedule and the most recent, previously 
submitted revision.
    (8) Current status of the postmarketing study commitment. The 
status of each postmarketing study should be categorized 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, but does not meet 
the criterion for delayed.
    (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.
    (iii) Delayed. The study is behind the original schedule described 
under paragraph (b)(2)(vii)(a)(7) of this section.
    (iv) Terminated. The study was ended before completion but a final 
study report has not been submitted to FDA.
    (v) Submitted. The study has been completed or terminated and a 
final study report has been submitted to FDA.

[[Page 64618]]

    (9) Explanation of the study's status. Provide a brief description 
of the status of the study, including the patient accrual rate 
(expressed by providing the number of patients or subjects enrolled to 
date, and the total planned enrollment), and an explanation of the 
study's status identified under paragraph (b)(2)(vii)(a)(8) of this 
section. If the study has been completed, include the date the study 
was completed and the date the final study report was submitted to FDA, 
as applicable. 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 
described in paragraph (b)(2)(vii) of this section, concerning a 
postmarketing study, 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. 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. A status report is to be included for any chemistry, 
manufacturing, and controls studies that the applicant has agreed to 
perform and for all product stability studies.
    (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 601.28 is amended by revising the second sentence in 
paragraph (c) to read as follows:


Sec. 601.28  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., accelerated approval clinical benefit 
studies, 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 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. Each annual progress report shall be accompanied by a 
completed transmittal Form FDA-2252, 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 must 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 any.
    (3) Biologics license application (BLA) and supplement number.
    (4) Date of U.S. approval of BLA.
    (5) Date of postmarketing study commitment.
    (6) Description of postmarketing study commitment. The description 
must include sufficient information to uniquely describe the study. 
This information may include the purpose of the study, the type of 
study, the patient population addressed by the study and the 
indication(s) and dosage(s) that are to be studied.
    (7) Schedule for completion and reporting of the postmarketing 
study commitment. The schedule should include the actual or projected 
dates for submission of the study protocol to FDA, completion of 
patient accrual or initiation of an animal study, completion of the 
study, submission of the final study report to FDA, and any additional 
milestones or submissions for which projected dates were specified as 
part of the commitment. In addition, it should include a revised 
schedule, as appropriate. If the schedule has been previously revised, 
provide both the original schedule and the most recent, previously 
submitted revision.
    (8) Current status of the postmarketing study commitment. The 
status of each postmarketing study should be categorized 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, but does not meet 
the criterion for delayed.
    (ii) Ongoing. The study is proceeding according to or ahead of the 
original schedule described under paragraph (b)(7) of this section.
    (iii) Delayed. The study is behind the original schedule described 
under paragraph (b)(7) of this section.
    (iv) Terminated. The study was ended before completion but a final 
study report has not been submitted to FDA.
    (v) Submitted. The study has been completed or terminated and a 
final study report has been submitted to FDA.
    (9) Explanation of the study's status. Provide a brief description 
of the status of the study, including the patient accrual rate 
(expressed by providing the number of patients or subjects enrolled to 
date, and the total planned enrollment), and an explanation of the 
study's status identified under paragraph (b)(8) of this section. If 
the study has been completed, include the date the study was completed 
and the date the final study report was submitted to FDA, as 
applicable. Provide a revised schedule, as well as the reason(s) for 
the revision, if the schedule under paragraph (b)(7) of this

[[Page 64619]]

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), 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. 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: October 13, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-27731 Filed 10-26-00; 8:45 am]
BILLING CODE 4160-01-F