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Guidance for Industry
Reports on the Status of Postmarketing Study Commitments —
Implementation of Section 130 of the Food and Drug Administration
Modernization Act of 1997
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
February 2006
Procedural
Guidance for Industry
Reports on the Status of Postmarketing Study Commitments —
Implementation of Section 130 of the Food and Drug Administration
Modernization Act of 1997
Additional copies are available
from:
Office of Training and
Communications
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Training,
and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
(Tel) 800-835-4709 or 301-827-1800
http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
February 2006
Procedural
G. How the FDA Evaluates
Fulfillment of and Release from Postmarketing Study Commitments
Guidance for Industry
Reports on the Status of Postmarketing Study Commitments —
Implementation of Section 130 of the Food and Drug Administration
Modernization Act of 1997
This guidance represents the Food and Drug Administration’s
(FDA’s) current thinking on this topic. It does not create
or confer any rights for or on any person and does not
operate to bind FDA or the public. You can use an
alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations. If
you want to discuss an alternative approach, contact the FDA
staff responsible for implementing this guidance. If you
cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this
guidance.
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The purpose of this guidance is to assist
applicants in meeting the requirements of section 130 of the Food
and Drug Administration Modernization Act of 1997. This guidance
provides recommendations on procedures, content, and format for
submitting a postmarketing study commitment status report for an
approved human drug or licensed biological product. This guidance
also describes the FDA’s obligations to make certain information
about postmarketing study commitments public, including the type of
information that will be made public and the FDA’s time frames for
reviewing postmarketing study commitment final reports.
FDA’s guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
Section 130(a)
of Title I of the Food and Drug Administration Modernization Act of
1997 (the Modernization Act), signed into law on November 21, 1997,
added section 506B (Reports of Postmarketing Studies) to the Federal
Food, Drug, and Cosmetic Act (the “Act”) (21 U.S.C. 356b). Section
506B gives the FDA additional authority for monitoring the progress
of postmarketing studies that drug and biologics applicants (“you”)
have agreed to or are required to conduct. On October 30, 2000, the
FDA issued final regulations implementing that law (65 FR 64607).
The regulations went into effect on April 30, 2001 (66 FR 10815),
and FDA issued a draft guidance related to the rule in April 2001.
This final guidance complements the rule by describing in greater
detail the content, format, and timing of the postmarketing study
commitment reports required by section 506B. The guidance also
discusses reporting of other postmarketing studies not subject to
section 506B.
If you are required by the FDA, or if you have
entered into an agreement with the FDA, to conduct a postmarketing
study concerning clinical safety, clinical efficacy, clinical
pharmacology, or nonclinical toxicology, you are required to provide
the Agency with an annual report on the status of the study until
the FDA notifies you, in writing, that the Agency concurs with your
determination that the study commitment has been fulfilled or that
the study either is no longer feasible or would no longer provide
useful information. This annual report must address the progress of
the study or the reasons for your failure to conduct the study (21
U.S.C. 356b(a); 21 CFR 314.81(b)(2)(vii) and 601.70(b)).
Section 506B also requires the FDA to make
certain information available to the public about postmarketing
study commitments, and your progress in completing those studies.
More specifically, under section 506B(c), the FDA must develop and
publish annually in the Federal Register a report on the
status of postmarketing study commitments that you have agreed to or
are required to conduct and for which annual status reports have
been submitted (21 U.S.C. 356b(c)). Section 506B(b) indicates that
any information necessary to identify you as the applicant of a
study and establish the status of a study and the reasons, if any,
for any failure to carry out the study, is considered to be public
information (21 U.S.C. 356b(b)).
The regulations implementing section 506B of
the Act apply to both human drug products and licensed biological
products (21 CFR 314.81(b)(2)(vii) and 601.70). These regulations
are summarized as follows:
- Applicants are required to file
postmarketing study commitment status reports (506B reports) for
studies that the FDA has required an applicant to conduct or that
an applicant has agreed, in writing, to conduct, provided that the
study concerns a product’s clinical safety, clinical efficacy,
clinical pharmacology, or nonclinical toxicology (506B studies).
Information from 506B reports will be included in the Agency’s
annual Federal Register report and on the postmarketing
study commitments Web site.
- The regulations apply to 506B studies for
all approved applications, with no exception for products that are
not actively marketed.
- The regulations apply only to approved human
drug products and licensed biological products that meet the
definition of drug under the Act. The regulations do not
apply to biological products that meet the definition of device
under the Act. Such biological devices may be subject to the
device postmarket surveillance provisions in section 522 of the
Act (21 U.S.C. 360l). The rule does not apply to new animal
drugs.
·
21 CFR 314.81(b)(2) provides that new drug application
(NDA) applicants will continue to report to the FDA on postmarketing
studies that are not 506B studies under another section of the
annual report requirements (21 CFR 314.81(b)(2)(viii)). These are
studies conducted without a commitment to the FDA (voluntary
studies); chemistry, manufacturing, and controls study commitments
that you have agreed with the FDA to conduct (CMC commitments); and
all product stability studies (stability studies). Reports on the
status of voluntary studies, CMC commitments, and stability studies
are not 506B reports. Accordingly, the 506B provisions concerning
public disclosure, including disclosure on the FDA’s Web site and in
the annual Federal Register reports, are not applicable to
these studies. Applicants for licensed biological products are not
required to submit reports of voluntary studies and CMC commitments
to the FDA under 21 CFR 601.70. If submitted voluntarily to the
FDA, such reports would not be 506B reports.
Applicants frequently perform studies after the
FDA approves a product for marketing. The studies are used to
gather additional information about product safety, efficacy, or
optimal use. Postmarketing studies are also used to evaluate CMC
issues, which are important for ensuring consistency and reliability
of product quality.
Generally, a postmarketing study would be
conducted in one of the following circumstances.
- The FDA can require you to conduct a
postmarketing study in certain situations. For example, the FDA
can require you to conduct studies to verify and describe clinical
benefit for a drug or biological product approved in accordance
with the accelerated approval provisions (21 U.S.C. 356(b)(2)(A);
21 CFR 314.510 and 601.41). For a drug or biological product
approved on the basis of animal efficacy data because human
efficacy studies are not ethical or feasible, an applicant must
conduct studies when ethical and feasible to verify and describe
clinical benefit and to assess the product’s safety
(21 CFR 314.610(b)(1) and 601.91(b)(1)).
Section 2 of the Pediatric Research Equity Act of 2003 (PREA)
authorized the FDA to require pediatric studies of marketed drugs
that are not adequately labeled for children. These studies may
be deferred if the drug is ready for approval in adults before
pediatric studies are completed or because of concerns about the
safety or effectiveness of the drug in pediatric populations (21
U.S.C. 355B(a); P.L. 108-155). The FDA may also issue an order or
regulation requiring an applicant to provide a study report that
is necessary and relevant to a determination concerning whether
there is or may be grounds for revoking approval of an approved
drug (21 U.S.C. 355(k)(1)). You must file 506B reports for all
postmarketing study commitments that you are required to
conduct provided that the study concerns a product’s clinical
safety, clinical efficacy, clinical pharmacology, or nonclinical
toxicology.
- A postmarketing study might be conducted
because you and the FDA agree, in writing, that one or more
such study should be conducted. These agreements can be made at
the time of approval or after the FDA grants marketing approval to
your drug. If you and the FDA agree at the time of drug approval
that a postmarketing study should be performed, the study will
likely be used to provide additional information about product
risks, benefits, and/or optimal use. If you and the FDA determine
after approval of the drug that a postmarketing study should be
performed, the study will generally be used to address a safety
concern that has been identified during the post-approval use of
the drug. You must file 506B reports for postmarketing study
commitments that you agreed, in writing, to conduct
provided that the study concerns a product’s clinical safety,
clinical efficacy, clinical pharmacology, or nonclinical
toxicology, and provided that the study commitment is not a CMC
commitment.
- Frequently, postmarketing CMC studies are
conducted because applicants agree, in writing, to conduct such
studies to ensure the consistency and reliability of product
quality (e.g., strength, purity, and potency). CMC commitments
are not subject to 506B’s reporting requirements, although 21 CFR
314.81(b)(2)(viii) requires you to advise the FDA on the status of
CMC commitments in another section of your annual report.
- Product stability studies are conducted to
determine the appropriate expiration date for drug products (21
CFR 211.166). Product stability studies are not subject to 506B’s
reporting requirements, although 21 CFR 314.81(b)(2)(viii)
requires you to advise the FDA on the status of all product
stability studies in another section of your annual report.
- A voluntary study can be conducted on an
applicant’s own initiative for a variety of reasons, such
as the evaluation of a new indication, a new delivery system for a
drug, a new container or closure system, or a new formulation.
Voluntary studies are not subject to 506B’s reporting
requirements, although 21 CFR 314.81(b)(2)(viii) requires you to
advise the FDA on the status of voluntary studies in another
section of your annual report.
1. Human Drug Products
The final rule
amended 21 CFR 314.81(b)(2)(vii) to implement section 506B. Under
this section, you must provide the FDA with annual 506B reports on
each 506B study annually until we notify you, in writing, that the
FDA concurs with your determination that the study commitment has
been fulfilled, or that the study is either no longer feasible or
would no longer provide useful information. This provision will
apply in rare cases to the holder of an abbreviated new drug
application (ANDA).
Under 21 CFR 314.81(b)(2)(viii), the final rule
requires you to provide the FDA with annual status reports on
voluntary studies that are being performed by you or on your behalf,
CMC commitments that you have agreed to perform, and for all
stability studies.
Under 21 CFR 314.81(b)(2)(ix), you may list any
open regulatory business with the 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).
The FDA provides in its annual Federal
Register report and on its Web site information submitted in
annual status reports under 21 CFR 314.81(b)(2)(vii). The FDA does
not disclose under the public disclosure provisions of 506B
information about voluntary studies, CMC commitments, stability
studies, or any open regulatory business submitted in NDA annual
reports under 21 CFR 314.81(b)(2)(viii) or 314.81(b)(2)(ix).
A summary of the requirements for postmarketing
study commitment status reports of human drug products, as stated in
the rule, is depicted in the following flow chart.
To implement section 506B of the Act, the final
rule required annual 506B reports, and revised existing requirements
for reports of postmarket pediatric studies to require 506B reports
to be filed under 21 CFR 601.70.
Under new 21 CFR 601.70, you must provide the
FDA with 506B reports on each 506B study annually until we notify
you, in writing, that the FDA concurs with your determination that
the study commitment has been fulfilled, or that the study is either
no longer feasible or would no longer provide useful information.
Status reports on voluntary studies, CMC commitments, and stability
studies should not be reported under 21 CFR 601.70. The status of
these studies should be reported according to your agreement, if
any, with the FDA, and you may report them voluntarily.
A summary of the requirements for postmarketing
study commitment status reports of licensed biological products, as
stated in the rule, is depicted in the following flow chart.
The type of study and the agreements you
reached with the Agency before product approval — or
post-approval, in some cases — will influence when the protocol
for a postmarketing study commitment should be submitted. The
time frame for submitting the study protocol should be
negotiated between you and the review division as a part of your
commitment. However, it is generally expected that you will
submit the protocol for required studies (e.g., accelerated
approval clinical benefit studies, animal efficacy clinical
benefit and safety studies) before approval of your
application. The FDA intends to undertake timely review of the
submitted protocol.
Protocols for clinical studies requiring an
investigational new drug application (IND) should be submitted
to the appropriate IND with a copy of the cover letter to the
NDA, ANDA, or biologics license application (BLA). Protocols
for studies not requiring an IND (e.g., toxicology or CMC
studies) should be submitted to the NDA, ANDA, or BLA. If you
have specific questions for the FDA regarding the protocol
design, study conduct, study goals, and/or data analysis, you
should include those focused questions as part of the cover
letter in the submission. All submissions should be clearly
labeled Postmarketing Study Commitment Protocol.
For each
506B study, you must develop a schedule for completing that
commitment (21 CFR 314.81(b)(2)(vii)(a)(7) and
601.70(b)(7)). Often, the study schedule is established at the
time of approval and documented in the Agency’s approval letter
for the application, and you would report that schedule in your
initial 506B report. Otherwise, you must establish that
schedule in your initial 506B report. The study schedule
included in your 506B report should provide, for each
commitment, dates for submission of the study protocol to the
FDA, dates for completion of patient accrual (or initiation of
an animal study, if applicable), dates for completion of the
study, dates for submission of the final study report to the
FDA, and any additional dates, if the commitment specifies
projected dates for any additional milestones or submissions.
Study schedules are sometimes developed
with reference to the date that you and the FDA agree on the
protocol (protocol agreement date). If you request and obtain
FDA review of and agreement to a proposed study protocol,
establish subsequent dates in your schedule with reference to
the protocol agreement date. In most cases, you and the FDA
will have concurred on a protocol before you are required to
file your first annual postmarketing study commitment status
report for that commitment, and you will be able to use actual
dates for each entry in the schedule (e.g., Projected Final
Study Report Submission Date: June 1, 2006). For instances
when you and the FDA have not reached concurrence on a protocol
before you file your first annual postmarketing study commitment
status report (e.g., your annual report for a drug is due
shortly after you entered into a commitment), you can describe
your schedule dates by reference to a period of time from a
protocol agreement date (e.g., completion of patient
accrual: 6 months after protocol agreement; completion of the
study: 12 months after protocol agreement).
If you choose not to request FDA review of
and agreement to the study protocol, you should establish a
schedule for study completion, including dates for completing
all study milestones, without reference to a protocol agreement
date. We note that if you proceed without Agency review of the
study protocol, it is possible that, when the study is
concluded, the FDA may not agree that the completed study
satisfies your commitment.
You do not need to provide schedules for
studies conducted on your own initiative (e.g., without a
commitment to, or requirement by, the FDA).
If it becomes necessary for any reason to
revise the projected dates for study milestones, submit a
revised study schedule, along with the reasons for the revision,
in your next 506B report
(21 CFR 314.81(b)(2)(vii)(a)(9) and
601.70(b)(9)). Although schedule revisions are sometimes
necessary, we will use the original study schedule to
determine the study progress and to designate its status as
pending, ongoing, or delayed (21 CFR 314.81(b)(2)(vii)(a)(8)
and 601.70(b)(8)). If the schedule has been previously revised,
you must include a copy of the original study schedule and the
most recently revised schedule in your annual status report (21
CFR 314.81(b)(2)(vii)(a)(7),(9) and
601.70(b)(7),(9)) (see section IV).
You must submit 506B reports for both human
drugs and biological products annually until we notify you, in
writing, that the FDA concurs with your determination that the
study commitment has been fulfilled, or that the study is either
no longer feasible or would no longer provide useful information
(21 CFR 314.81 (b)(2)(vii) and 601.70(b)) (see section III.G.).
Your 506B report must be submitted to the FDA each year within
60 days of the anniversary of the FDA’s approval of your NDA,
ANDA, or BLA (21 CFR 314.81(b)(2) and 601.70(c)).
1. Human Drug Products
Your annual report should clearly
distinguish 506B reports from reports on the status of voluntary
studies, CMC commitments, and stability studies, with separate
headings for each section. However, it is useful to list or
cross-reference the CMC study commitments
that you have agreed, in writing, to conduct and whose statuses
are reported under 21 CFR 314.81(b)(2)(viii) in the “Status
Reports of Postmarketing Study Commitments” section of the
annual report. The cover letter should clearly identify the
annual report submission as including an Annual Status Report
of Postmarketing Study Commitments. The annual report must
be accompanied by one copy of Form FDA-2252 (Transmittal of
Annual Reports for Drugs and Biologics for Human Use) (21 CFR
314.81(b)(2)).
Two copies of your annual reports for human
drug products must be sent to the review division responsible
for reviewing the application (21 CFR 314.81(b)(2)). We
encourage the electronic submission of annual reports, including
506B reports, submitted according to the electronic records
requirements described under 21 CFR part 11.
2. Licensed Biological
Products
The cover letter for annual 506B reports
filed under 21 CFR 601.70 should clearly identify the submission
as an Annual Status Report of Postmarketing Study Commitments.
The annual report must be accompanied by one copy of Form
FDA-2252 (Transmittal of Annual Reports for Drugs and Biologics
for Human Use) (21 CFR 601.70(b)). Submit two copies of the
report to the CBER Document Control Center, HFM-99, 1401
Rockville Pike, Rockville, MD 20852-1448. We encourage the
electronic submission of 506B reports submitted according to the
electronic records requirements described under 21 CFR part 11.
You should submit 506B reports separately for each licensed
product, but if you are performing multiple 506B studies for the
same biological product, all 506B studies should be included in
a single postmarketing study commitment annual status report.
Do not include other notifications or
submissions in your 506B report. Other notifications, such as
manufacturing changes reported under 21 CFR 601.12, should be
identified clearly and submitted in a separate report.
When a postmarketing study commitment has
been completed or terminated early, you should submit a final
report as a separate submission or as a supplement to the NDA,
ANDA, or BLA. If you submit a final report as a separate
submission, the cover letter should prominently identify the
submission as POSTMARKETING STUDY COMMITMENT — FINAL STUDY
REPORT in bold, capital letters at the top of the letter and
should clearly identify the commitment being addressed by
referring to the commitment wording and number, if any, used in
the approval letter, as well as the date of the approval
letter. Similarly, if you submit a final report as a
supplement, the top of the cover letter should state
SUPPLEMENT CONTAINS POSTMARKETING STUDY COMMITMENT — FINAL STUDY
REPORT and clearly identify the commitment being addressed.
If you do not designate a submission as a final study report,
the Agency might not recognize it as such. You should submit
the final study report as soon as possible after completing the
study.
If a postmarketing study commitment
includes multiple studies, the cover letter for the submission
of the final completed study should identify the submission
dates of reports on all previously concluded and submitted
studies. If the final study report is the first report
submitted for multiple studies described within a single
commitment, the cover letter should indicate that the final
study report only partially addresses the commitment.
After a postmarketing study commitment has
been completed (i.e., the study has been conducted), you are
expected to submit a final study report that describes the study
and its results and explain, if necessary, how the study
fulfills the requirement or commitment. If the study does not
fulfill the requirement or commitment, you should explain why
the study was unable to do so and describe your future plans to
meet the objective of the commitment.
The Agency will review the final study
report and determine whether the commitment has been satisfied.
We will notify you, in writing, of our conclusion.
- If we conclude that the study commitment
has been met, we will consider the commitment satisfied and
will notify you, in writing, that the commitment is considered
fulfilled. You will no longer need to report the status of
the study commitment in your annual status report.
- If a study was completed but failed to
satisfy the purpose of the requirement or commitment, but
would still provide useful information and can be addressed
through a study of modified design, the Agency may release the
original commitment and establish a new postmarketing study
commitment and schedule. If the FDA agrees that the failed
study is no longer feasible or would not provide useful
information, the FDA may release the commitment, and you will
no longer need to report the status of the study commitment in
your annual status report.
- If you terminate a study early, you
should submit the final study report for that study commitment
for FDA review to determine whether the commitment has been
satisfied. If you terminate a study that the FDA determines
is still feasible, would yield useful information, and can be
addressed through a study of modified design, the Agency may
release the original commitment and establish a new
postmarketing study commitment and schedule. If you terminate
a study that the FDA agrees is no longer
feasible or would not provide useful information, the FDA
may release the commitment, and you will no longer need to
report the status of the study commitment in your annual
status report. You are encouraged to contact the FDA if you
are contemplating the early termination of a postmarketing
study commitment.
If you have not undertaken the
postmarketing study commitment and we determine the study is no
longer feasible or would not provide useful information, we will
notify you, in writing, that the commitment is released. You
will no longer need to report the status of the study commitment
in your annual status report.
The rule implementing section 506B sets
forth the required format and content of the postmarketing study
commitment status reports that must be submitted under 21 CFR
314.81(b)(2)(vii) and 601.70(b). These requirements are
intended to ensure that the reports you submit contain enough
information for the FDA to identify you (the applicant), the
product being studied, the specific study being conducted, the
status of the study commitment, and the reasons, if any, for
your failure to complete the study commitment.
Section 506B requires you to report the
status of 506B studies. A postmarketing study commitment
ideally consists of one study (i.e., the completion of a single
study is expected to fulfill the commitment). In some cases,
postmarketing study commitments made before the enactment of
section 506B involve conducting multiple studies. When
reporting on the progress of multiple studies being conducted
under a single postmarketing study commitment, the annual status
report should list separately the appropriate information for
each study.
You must provide the following information
for each postmarketing study commitment submitted under 21 CFR
314.81(b)(2)(vii) or 601.70(b) (see Appendix A for examples).
- Applicant: The name of the
individual or entity holding the approved NDA, ANDA, or BLA.
- Product: The approved product’s
established or proper name and proprietary name, if any. If
the product is distributed under more than one proprietary
name, you should include all proprietary names.
- Application Number: The NDA,
ANDA, or BLA number and supplement number, if any, for which
the postmarketing study commitment was made.
- NDA, ANDA, or BLA Approval Date:
The date the NDA, ANDA, or BLA was first approved for
marketing in the United States. This date will appear on the
approval letter for the original application.
- Date of Postmarketing Study
Commitment: The date of the letter that details the
postmarketing study commitment. For study commitments made
before or at the time of approval of an original application
or supplemental application, the commitment date is the same
as the date of the FDA’s approval of the original application
or supplemental application, as applicable. For commitments
made after approval, the commitment date is the date of the
FDA’s letter confirming the commitment.
- Commitment Description: The
description must include sufficient information to uniquely
describe the study. You should provide the number assigned to
each postmarketing study commitment as it appears in the
application’s approval letter or postmarketing study
commitment letter. Your commitment description 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 (21 CFR 314.81(b)(2)(vii)(a)(6)
and 601.70(b)(6)). Generally, the description of the
postmarketing study commitment as it appears in the
application’s approval or postmarketing study commitment
letter will provide an adequate description. However, in
cases where multiple studies are being conducted, the
following information may be needed:
-
Purpose of the study, including study goals,
objectives, and endpoints
-
Patient population being studied, including the
specific illness or condition, and whether the study targets
subpopulations such as pediatric or geriatric subjects
-
Drug dosage or delivery system
-
Specific study protocol number, if applicable
- Study Schedule: The original and
most recent (if revised) study schedule for conducting,
completing, and reporting on the postmarketing study
commitment. If more than one study is being conducted under a
single commitment, provide a schedule for each study. If the
original schedule has been previously revised, provide both
the original schedule and the most recently revised schedule
in this section of each annual status report (see section
III.D.). You should describe the following elements in your
schedule:
-
Actual/projected date for submission of study
protocol to the FDA
-
Date of completion of patient accrual into the
study (or date of first animal dosed)
-
Completion date of the study
-
Submission date of the final study report to the
FDA
You may also have
an agreement to report important intermediate milestones (e.g.,
date of initiation of patient accrual, evaluation of surrogate
endpoints in a study that also measures clinical benefit). If
your study commitment includes a commitment to report at these
intermediate milestones, you should include the milestones in
the study schedule (21 CFR 314.81(b)(2)(vii)(a)(7)
and 601.70(b)(7)). For any milestones that have been met at the
time the commitment is made (e.g., submission of the final study
protocol), you should report the actual date that the milestone
was met in the study schedule.
- Current Status: A description of
the status of the 506B study. Describe the status of each
postmarketing study commitment against the original
projected study schedule, regardless of whether you have
submitted a revised schedule to the FDA. You should describe
the status using only one of the following terms (21
CFR 314.81(b)(2)(vii)(a)(8) and 601.70(b)(8)):
Pending:
The study has not been initiated (i.e., no subjects have been
enrolled or animals dosed), but does not meet the criterion for
delayed (i.e., the original projected date for
initiation of patient accrual or initiation of animal dosing has
not passed).
Ongoing:
The study is proceeding according to, or is ahead of, the
original schedule. The FDA considers a study to be
ongoing until a final study report is submitted to the FDA,
as long as the activities are proceeding according to the
original study schedule. If patient accrual or animal dosing
has started but is not complete, and the projected date for
completion of that milestone has passed, the study should be
categorized as delayed.
Delayed:
The progression of the study is behind the original study
schedule. Delays can occur in any phase of the study, including
patient enrollment, analysis of study results, or submission of
the final study report to the FDA. While the original
study schedule — not a revised schedule — serves as the basis
for defining a study as delayed, each phase of the study
will be considered in its own right. If you have one delayed
phase, but get back on schedule during the next phase, the
delayed status will no longer apply.
Terminated:
You ended the study before completion, and you have not yet
submitted a final study report to the FDA.
Submitted:
You have concluded or terminated the study and have submitted a
final study report to the FDA, but we have not yet notified you
in writing that the study commitment has been fulfilled or that
the commitment has been released.
If more than one
study is being conducted under a commitment, the status of the
overall commitment will be based on the status of the
least-progressed study. For example, if you are conducting two
studies, and both are progressing according to original
projected schedules, you should categorize the commitment as
ongoing. If one study is progressing according to the
original projected schedule but the other is behind
schedule, you should categorize the commitment as delayed.
You can provide information in the “Explanation of Status”
section of the report to explain the status of each study under
a commitment in an effort to demonstrate progress in that
commitment.
- Explanation of Status: A brief
explanation about how the study is progressing in reference to
the original projected study schedule (21 CFR 314.81(b)(2)(vii)(a)(9)
and 601.70(b)(9)). This information will be displayed on the
Agency Web site for delayed and terminated
studies; therefore, it should be concise and should not
include personal privacy information or trade secret
information (see example in Appendix A). Provide the
following information:
-
A brief description of the status of the study,
including the patient accrual or animal dosing rate. Express
the patient accrual or animal dosing rate by providing the
number of patients/animals you have enrolled/dosed to date and
the total number of patients/animals you plan to enroll/dose for
the study. To the extent necessary, the particular status
described under 21 CFR 314.81(b)(2)(vii)(a)(8) or
601.70(b)(8) should be explained.
-
If you are unable to meet the original
study schedule or any revised schedule (submitted under the
study schedule section), provide a revised schedule and the
reasons for the revision.
The FDA intends
to review postmarketing study commitment annual status reports
and final study reports according to the following time frames.
Generally, the FDA will review annual
status reports within 3 months of receipt. If we do not agree
with your categorization of the status of the study and/or your
explanation of status, we will contact you for clarification.
We will change the reported study categorization if we find that
the status category is not supported.
Final study reports are often submitted as
a supplemental application to modify product labeling. When this
occurs, the FDA will review the submission under established
review times for supplements (e.g., for Prescription Drug User
Fee Act (PDUFA) products). In some cases, a postmarketing study
commitment will not yield information that affects product
labeling, and the final study report will be submitted without a
supplemental filing. In such cases, we will generally review
the final study report within 1 year of receipt.
Section 506B of the Act states that “[a]ny
information pertaining to a [postmarketing status] report shall
be considered to be public information to the extent that the
information is necessary (1) to identify the sponsor; and (2) to
establish the status of [the] study and the reasons, if any, for
any failure to carry out the study” (21 U.S.C. 356b(b)). This
provision is applicable to all 506B reports. Section 506B
provides the FDA with statutory authority to disclose
information, including certain information that may be
considered to constitute confidential commercial information.
However, the FDA will not make public any trade secrets,
or any information that, if disclosed, might cause an
unwarranted invasion of personal privacy.
The FDA will publish an annual Federal
Register report on the status of postmarketing study
commitments and will maintain information about postmarketing
study commitments on an Agency Web site. The information in the
Federal Register report and on the Web site will be based
on the verification of information submitted in your annual
status reports and information from the Agency’s outgoing
approval and postmarketing study commitment letters. Although
you may wish to submit interim information about a study (e.g.,
the date patient accrual was actually completed), such interim
information will not be used to change the status of a study
commitment. We will update the status of a study commitment
when we complete our review of the final study report and issue
our determination regarding whether the commitment has been
fulfilled or you have been released from the commitment, or
after verification of the information submitted in your annual
status report.
Federal Register report. As
previously discussed, section 506B(c) also requires that the FDA
publish annually in the Federal Register a report on the
status of postmarketing studies that are required or that you
have agreed to conduct and for which you have submitted status
reports. The information that the FDA publishes in the
Federal Register report will include the following:
- The number of applicants with open
postmarketing study commitments
- The number of open postmarketing study
commitments
- The number of applications with open
study commitments for which annual reports were due but not
submitted by the sponsor within 60 days of the anniversary
date of the product’s U.S. approval
- The number of concluded postmarketing
study commitments:
-
That fulfilled the terms of the commitment
-
For which a study was completed but failed to
satisfy an applicant’s commitment
-
For which a study was not done and the FDA deemed
it was no longer feasible or would no longer provide useful
information and released the commitment
Agency Web site (http://www.fda.gov/cder/pmc).
To provide public access to certain information on the status of
specific postmarketing studies, the FDA displays detailed
information on an Agency Web site. The information included on
the Web site (see Appendix B) comes from our review of annual
506B reports and the Agency’s outgoing approval and
postmarketing study commitment letters. This information allows
the public to follow the progress of 506B studies of specific
interest. The Web site includes the following information:
Applicant:
Product:
NDA/BLA/ANDA Number:
Supplement Number:
NDA/BLA Approval Date:
Annual Report Due Date:
Annual Report Received Date:
Commitment Number:
Commitment Required Under: [if the commitment is a required
study]
Original Projected Completion Date: [if available]
Commitment Description:
Current Status:
Explanation of Status: [for delayed and
terminated studies only]
In establishing the FDA Web site, both CDER
and CBER use data from their electronic databases to identify
postmarketing study commitments for which an annual status
report was expected, but not submitted.
The FDA posts study schedule information on
the Web site to the extent necessary to explain the status of a
study. If a commitment did not have a schedule, and the Agency
did not receive an annual postmarketing study commitment status
report, the commitment is categorized according to the most
recent information available to the Agency.
There may be instances when you disagree
with the FDA’s categorization of the status of
a study as it appears on the Web site. If this happens, you may
contact us by e-mail at
pmcweb@cder.fda.gov so that we
can explain the displayed status or update it accordingly.
The FDA Web site will continue to list
postmarketing study commitments for no more than 1 year from the
date of the FDA’s letter confirming that the commitment was
fulfilled or released. After that time has passed, all
references to the study will be removed from the Web site. The
information on the FDA Web site is updated quarterly in January,
April, July, and October.
In reporting the status of postmarketing
study commitments, you should know and understand the following
terms:
506B Report: A status
report, submitted annually by applicants within 60 days of the
anniversary of the FDA’s approval of the product, reporting on
the progress of 506B studies (21 CFR 314.81(b)(2)(vii) and
601.70). A 506B report is required until the FDA notifies the
applicant, in writing, that the Agency concurs that the study
commitment has been fulfilled or that the study either is no
longer feasible or would no longer provide useful information.
506B Study: A study
conducted after approval that the FDA has required you to
conduct or that you have agreed, in writing, to conduct, and
that concerns a product’s clinical safety, clinical efficacy,
clinical pharmacology, or nonclinical toxicology.
Final Study Report: A final
report providing information to complete part or all of a
postmarketing study commitment. When a commitment includes
multiple studies, a single final study report may or may not
complete all parts of the commitment.
Postmarketing Study: A trial
or other investigation, conducted after marketing approval under
a single protocol, to gather specific information about an
approved drug or biological product.
Postmarketing Study Commitment:
An agreement between you and the FDA, confirmed in
writing, for you to conduct one or more 506B or CMC studies.
Also includes 506B studies that are required by the FDA
(e.g., accelerated approval clinical benefit studies, animal
efficacy clinical benefit and safety studies, deferred pediatric
studies under PREA).
Projected Final Study Report
Submission Date: The projected date by which the final
study report will be submitted to the FDA. When a commitment
includes multiple studies, the projected final study report
submission date is the date by which the final study report will
be submitted to address the last outstanding study in the
commitment.
Projected Protocol Submission Date:
The projected submission date by which the final protocol for
the postmarketing study will be submitted.
Projected Study Initiation Date:
The projected date by which patients will begin enrollment in a
clinical study, or the date the first animal will be dosed in a
nonclinical toxicology study.
(Submitted by the Applicant)
Note: Certain information from this
report will be displayed on the FDA Web site,
http://www.fda.gov/cder/pmc
Postmarketing Study Commitments Annual
Status Report: Submitted 02/01/2000.
Applicant: AABBCC Pharmaceuticals,
Inc.
Product: Efficacymycin
(Curritt)/Oral, chewable tablets (25 mg; 50 mg)
NDA/BLA/ANDA Number: 12-345
NDA/BLA/ANDA Approval Date:
12/31/97
Commitment Date: 12/31/97
Commitment Number: 1
Description of Study Commitment:
Evaluate the safety and efficacy of Curritt in pediatric
patients. Study is an open-label, randomized comparison to
amoxicillin in cohort ages 2-4 and 6-12 years. Study will
include approximately 400 patients with confirmed urinary tract
infection. Dosage: 25 mg oral chewable tablets.
Original Schedule for Conduct
and Reporting of Study: Final protocol will be submitted to
the FDA for review by 02/01/98. Study enrollment will begin by
06/01/98, with enrollment concluded by 12/01/99. Last patients
should complete evaluations by 04/01/00. Study final report
will be submitted to the FDA by 10/01/00.
Current Status: Ongoing
Explanation of Status:
Study completed enrollment of 408 patients on schedule and all
patient evaluations were concluded 01/15/00. Study is closed.
Clinical monitors are in the process of verifying data. Study
final report should be submitted on schedule.
Supplement Number: 005
Commitment Date: 02/23/99 (NDA
supplement 12-345/S-005: 50 mg oral chewable tablets)
Commitment Number: 1
Description of Study
Commitment: Evaluation of 50 mg Curritt in patients with
impaired liver function. Study to include approximately 100
patients (30 with normal liver and renal function).
Original Schedule for Conduct
and Reporting of Study: Protocol was approved at time of
study commitment (02/23/99). Study enrollment to begin 08/01/99
with enrollment to be concluded by 05/01/00. Last patients
should complete evaluations by 10/01/00. Study final report
will be submitted to the FDA by 02/01/01.
Revised Schedule for Conduct
and Reporting of Study: [Revised 02/01/2000]. A revised
protocol will be submitted to the FDA by 06/01/00. Study
enrollment will conclude by 12/03/00. Current study completion
date is now anticipated by 06/01/01 with a study final report to
the FDA by 11/24/01.
Current Status: Delayed
Explanation of Status: No
patients have been enrolled. Two IRBs have raised issues that
must be addressed by revising the study protocol.
Commitment Number: 2
Commitment Date: 02/23/99 (NDA
supplement 12-345/S-005: 50 mg oral chewable tablets)
Description of Study Commitment:
Evaluation of 50 mg Curritt in patients with impaired renal
function. Study to include approximately 60 patients (15
normal).
Original Schedule for Conduct
and Reporting of Study: Protocol was approved at time of
study commitment (02/23/99). Study enrollment started 08/01/99
with enrollment to be concluded by 05/01/00. Last patients
should complete evaluations by 10/01/00. Study final report
will be submitted to the FDA by 02/01/01.
Current Status: Ongoing
Explanation of Status: A
total of 57 patients completed the study. Study report in
preparation. The study final report will be submitted to the FDA
by 02/01/01.
[To be displayed on the FDA Web site]
Applicant: AABBCC Pharmaceuticals,
Inc.
Product: Efficacymycin (Curritt)/Oral,
chewable tablets (25 mg; 50 mg)
NDA/BLA/ANDA
Number: 12-345
NDA/BLA Approval Date: 12/31/97
Annual Report Due
Date: 12/31/99
Annual Report
Received: 02/01/00
Commitment Number: 1
Original Projected Completion
Date: 10/01/00
Commitment Description:
Evaluate the safety and efficacy of Curritt in pediatric
patients. Study is an open-label, randomized comparison to
amoxicillin in cohort ages 2-4 and 6-12 years. Study will include
approximately 400 patients with confirmed urinary tract
infection. Dosage: 25 mg oral gelatin capsules.
Current Status: Ongoing
Applicant: AABBCC Pharmaceuticals,
Inc.
Product: Efficacymycin (Curritt)/Oral,
chewable tablets (25 mg; 50 mg)
NDA/BLA/ANDA Number: 12-345
Supplement Number: 005
NDA/BLA Approval Date: 12/31/97
Annual Report Due Date: 12/31/99
Annual Report Received: 02/01/00
Commitment Number: 1
Original Projected Completion
Date: 02/01/01
Commitment Description:
Evaluation of 50 mg Curritt in patients with impaired liver
function. Study to include approximately 100 patients (30 with
normal liver and renal function).
Current Status: Delayed
Explanation of Status: No
patients have been enrolled. Two IRBs have raised issues that
must be addressed by revising the study protocol.
Commitment Number: 2
Original Projected Completion
Date: 02/01/01
Description of Study Commitment:
Evaluation of 50 mg Curritt in patients with impaired renal
function. Study to include approximately 60 patients (15 normal).
Current Status: Ongoing
[Note:
Postmarketing study commitment information is displayed on the
Web site as one application per page. Thus, in this example, the
information for Commitment Number 1 established under the original
application would display on a separate Web page from the
postmarketing study commitment information for Commitment Numbers
1 and 2 established under supplement application number 005, as
shown above.]
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