Guidance for Industry
Fast Track Drug Development Programs —Designation, Development, and
Application Review
(PDF
version of this document)
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)
July 2004
Procedural
Revision 1
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Research
Food and Drug Administration
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http://www.fda.gov/cder/guidance/index.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)
July 2004
Procedural
Revision 1
Guidance for Industry
Fast Track Drug Development Programs
– Designation, Development, and Application Review
This
draft guidance, when finalized, will represent the Food and Drug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. An alternative approach may be
used if such 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.
The fast track programs of the Food and Drug
Administration (FDA) are designed to facilitate the development and
expedite the review of new drugs that are intended to treat serious
or life-threatening conditions and that demonstrate the potential to
address unmet medical needs (fast track products). This document
provides guidance to industry on the regulations, policies, and
procedures related to the Agency's fast track programs. The
guidance also clarifies the criteria and processes for designating
fast track products.
This guidance revises the Fast Track
guidance that published September 1998. The revision is intended
to make it clear that a drug can be said to address an unmet medical
need if the only available treatments for the condition are approved
under the accelerated approval regulations (21 CFR. 314.500 and
601.40), either on the basis of an effect on a surrogate endpoint or
with restrictions on distribution. Minor editorial changes also
have been made to make this guidance consistent with the Agency's
good guidance practices (GGP) regulation (21 CFR 10.115).
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 112 of the Food and Drug Administration
Modernization Act of 1997 (the Modernization Act) (P.L. 105-115)
(Appendix 1) amended the Federal Food, Drug, and Cosmetic Act (the
Act) by adding new section 506 (21 U.S.C. 356). The Modernization
Act directed FDA to issue guidance describing its policies and
procedures pertaining to fast track products. Section 506
authorizes FDA to take actions appropriate to facilitate the
development and expedite the review of an application for such a
product. These actions are not limited to those specified in the
fast track provision but also encompass existing FDA programs to
facilitate development and review of products for serious and
life-threatening conditions. Such programs include (a) the
procedures described in the 1988 interim rule "Procedures for Drugs
Intended to Treat Life-Threatening and Severely Debilitating
Illnesses" (21 CFR 312.80 through 312.88 (Subpart E)), in which FDA
formalized certain procedures to facilitate the development of
promising therapies (Appendix 2), and (b) the priority review
procedures of the Center for Biologics Evaluation and Research and
the Center for Drug Evaluation and Research (CDER) (Appendix 3).
Under the Subpart E regulations for
investigational new drugs (Appendix 2), drug development is
considered a continuum from early preclinical and clinical studies
through submission of a marketing application. The regulations
emphasize the critical nature of close early communication between
the Agency and a sponsor, outline procedures such as pre-IND and end
of phase 1 meetings as methods to improve the efficiency of
preclinical and clinical development, and focus on efforts by the
Agency and the sponsor to reach early agreement on the design of the
major clinical efficacy studies that will be needed to support
approval.
CBER and CDER have longstanding policies that
describe criteria for review priority classification of marketing
applications. Products regulated by CBER are eligible for priority
review if they provide a significant improvement in the safety or
effectiveness of the treatment, diagnosis, or prevention of a
serious or life-threatening disease (see Appendix 3). Products
regulated by CDER are eligible for priority review if they provide a
significant improvement compared to marketed products in the
treatment, diagnosis, or prevention of a disease; eligibility is not
limited to drugs for a serious or life-threatening disease (see
Appendix 3). A fast track product would ordinarily meet either
Center's criteria for priority review. Note, however, that an NDA
or BLA sponsor need not seek fast track designation to be eligible
for priority review.
The Modernization Act specifically permits FDA
to:
1. Approve a marketing application under section 505(c) of
the Act or section 351 of the Public Health Service Act "upon a
determination that the product has an effect on a clinical endpoint
or on a surrogate endpoint that is reasonably likely to predict
clinical benefit." This, in effect, codifies in statute FDA's
Accelerated Approval Rule (Appendix 4), made final in 1992, which
allows expedited marketing of certain new drugs or biological
products intended to treat serious or life-threatening illnesses and
that appear to provide meaningful therapeutic benefits to patients
compared with existing treatments. Under this rule, "FDA may grant
marketing approval for a new drug [or biological] product on the
basis of adequate and well-controlled trials establishing that the
drug [or biological] product has an effect on a surrogate endpoint
that is reasonably likely, based on epidemiologic, therapeutic,
pathophysiologic, or other evidence, to predict clinical benefit or
on the basis of an effect on a clinical endpoint other than survival
or irreversible morbidity." Where an accelerated approval is based
upon a surrogate endpoint or on an effect on a clinical endpoint
other than survival or irreversible morbidity, postmarketing studies
are ordinarily required "to verify and describe the drug's clinical
benefit and to resolve remaining uncertainty as to the relation of
the surrogate endpoint upon which approval was based to clinical
benefit, or the observed clinical benefit to ultimate outcome" (57
FR 58942, December 11, 1992).
2. Accept for review portions of a marketing application
prior to receipt of the complete application.
Fast track programs should be distinguished
from expanded access programs for investigational drugs such as the
treatment investigational new drug (IND) regulations (52 FR 19466,
May 22, 1987; codified as 21 CFR 312.34). Fast track is intended to
facilitate development and expedite review of drugs to treat serious
and life-threatening conditions so that an approved product can
reach the market expeditiously. Expanded access programs such as
the treatment IND are intended to facilitate access to
investigational drugs prior to approval for patients
with serious and life-threatening conditions and without therapeutic
alternatives.
Section 506(a)(1) of the Act states that a drug
designated as a fast track product is intended for the treatment of
a serious or life-threatening condition and demonstrates the
potential to address unmet medical needs for the condition. The
fast track classification thus does not apply to a product alone,
but applies to a combination of the product and specific indication
for which it is being studied. The indication, for the purposes of
this document, includes both the condition for which the drug is
intended (e.g., heart failure) and the anticipated or established
benefits of use (e.g., improved exercise tolerance, decreased
hospitalization, increased survival). It is therefore the
development program for a specific drug for a specific indication
that will receive fast track designation. Such a program is
referred to in this document as a fast track drug development
program and the criteria involved in designation are represented in
Figure 1. These criteria are more fully described below.
This section of the document provides specific
guidance regarding how the Agency intends to determine whether a
condition is serious and whether a drug is intended to treat a
serious condition. All conditions meeting the definition of
life-threatening as set forth at 21 CFR 312.81(a) would also be
serious conditions. Because the benefits of fast track designation
apply to products for serious conditions as well as to products for
life-threatening conditions, distinction between the two categories
of conditions with regard to eligibility for fast track programs is
unnecessary. Therefore, in the following discussion, all references
to serious conditions will include life-threatening conditions.
As discussed in the preamble to the proposed
accelerated approval rule (57 FR 13234, April 15, 1992),
determination of the seriousness of a condition:
... is a
matter of judgment, but generally is based on its impact on such
factors as survival, day-to-day functioning, or the likelihood that
the disease, if left untreated, will progress from a less severe
condition to a more serious one. Thus, acquired immunodeficiency
syndrome (AIDS), all other stages of human immunodeficiency virus
(HIV) infection, Alzheimer's dementia, angina pectoris, heart
failure, cancer, and many other diseases are clearly serious in
their full manifestations. Further, many chronic illnesses that are
generally well-managed by available therapy can have serious
outcomes [such as] ... inflammatory bowel disease, asthma,
rheumatoid arthritis, diabetes mellitus, systemic lupus
erythematosus, depression, psychoses, and many other diseases.
For a condition to be serious, the condition
should be associated with morbidity that has substantial impact on
day-to-day functioning. Short-lived and self-limiting morbidity
will usually not be sufficient but the morbidity need not be
irreversible, providing it is persistent or recurrent.
For a product to be in a fast track drug
development program, it must not only be used in patients with a
serious condition, it must be intended to treat a serious aspect of
that condition. Thus, in making a fast track determination, FDA
will assess whether the development program is designed to
demonstrate an effect on a serious aspect of the condition. The
following examples illustrate FDA's approach:
a. A therapeutic product directed at some aspect of a
serious condition would be considered to treat a serious condition
if it were being evaluated for effects on a serious manifestation(s)
or serious symptom(s) of the condition.
b. A diagnostic product would be considered to treat a
serious condition if it were being evaluated directly for its impact
on a serious aspect of the condition or if it were being evaluated
for its ability to improve diagnosis or detection of the condition
and scientific data provided a strong basis for a presumption that
the improvements in diagnosis or detection of the condition would
lead to improved outcome.
c. A preventive product would be considered to treat a
serious condition if (1) it were being evaluated for its ability to
prevent a serious manifestation(s) of the condition, or (2) it were
being studied for its ability to prevent the condition and it was
scientifically reasonable to assume that prevention of the condition
would prevent its serious consequences.
d. A product intended to ameliorate or prevent a side effect
of therapy of a condition would be considered to treat a serious
condition if the side effect were serious (e.g., serious infections
in patients receiving immunosuppressive therapy).
e. A product intended and being studied for its ability to
treat a condition while avoiding the side effects of currently
accepted treatments of the condition might be considered to treat a
serious condition if such side effects were serious (e.g., a less
myelosuppressive treatment for a tumor or an anti-inflammatory drug
that does not cause gastrointestinal bleeding). The potential for a
new drug to avoid the serious sequelae of existing drugs would
qualify that drug development program for fast track designation
only in limited circumstances. Many therapies, even those intended
to treat nonserious conditions, are associated with rare, serious,
adverse reactions, and new therapies, despite initial hopes, often
are associated with their own set of serious reactions.
Nonetheless, some adverse reactions are significant public health
problems, and the development of therapies that do not cause such
serious reactions would merit close attention. The Agency may
designate the development of such a therapy as a fast track drug
development program when (1) currently accepted therapy is widely
used despite an unavoidable serious risk, (2) serious outcomes are a
significant public health issue, and (3) the new therapy shows
significant potential to have a substantially improved overall
safety profile with at least similar efficacy.
Many conditions not generally considered to be
serious have rare or distant serious sequelae (e.g., urinary tract
infections or duodenal ulcers). Product development programs for
such conditions could be designated as fast track if the sponsor
specifically designs the development program to demonstrate an
effect on those serious sequelae. Conversely, some conditions that
are generally considered to be serious have nonserious
manifestations requiring symptomatic therapy (e.g., insomnia
associated with schizophrenia, skin discoloration from Addison's
disease, alopecia with lupus, subcutaneous nodules from rheumatoid
arthritis). The Agency will not generally designate as fast track a
development program for a product whose effect has been measured in
terms of nonserious manifestations unless the product's effect on
those manifestations is reasonably likely to predict benefit on a
serious manifestation.
Section 506(a) of the Act further requires that
the drug demonstrate the potential to address unmet medical needs.
Thus, in designating a fast track drug development program, the
Agency will determine whether the drug has a potential to address
unmet medical needs and whether the development program is designed
to evaluate this potential.
An unmet medical need is a medical need that is
not addressed adequately by an existing therapy.
a. Where there is no available therapy for the condition
If no therapy exists
for a serious condition, there is an obvious unmet medical need and
a new treatment effective in that condition would meet this aspect
of the criteria for fast track designation.
b. Where there is available therapy for the condition
When therapies exist
for a condition, the developmental program for the new agent would
address unmet medical needs if it evaluated any of the following:
i.
Improved effect(s) on serious outcomes of the condition that are
affected by alternate therapies (e.g., superiority of the new drug
used alone or in combination with other therapies in an active
controlled trial assessing an endpoint reflecting serious
morbidity).
ii. Effect(s) on serious outcomes of the condition not known
to be affected by the alternatives (e.g., progressive disability in
multiple sclerosis when the alternative treatments have shown an
effect on exacerbations but have not shown an effect on progressive
disability).
iii. Ability to provide benefit(s) in patients who are unable
to tolerate or are unresponsive to alternative agents (e.g., an
antipsychotic agent that is effective in people failing standard
therapy), or an ability to be used effectively in combination with
other critical agents that cannot be combined with available
therapy.
iv. Ability to provide benefit(s) similar to those of
alternatives while avoiding serious toxicity that is present in
existing therapies, or avoiding less serious toxicity that is common
and causes discontinuation of treatment of a serious disease.
v. Ability to provide benefit(s) similar to those of
alternatives but with improvement in some factor, such as compliance
or convenience, that is shown to lead to improved effects on serious
outcomes.
c. Where the only available
therapy is approved under the accelerated approval regulations
(either on the basis of an effect on a surrogate endpoint or for
restricted distribution)
A drug can be
said to address an unmet medical need if the only available
treatment(s) for the condition are approved under the accelerated
approval regulations (21 CFR 314.500 and 601.40), either on the
basis of an effect on a surrogate endpoint or with restrictions on
distribution.
FDA
recognizes that, as a general matter, it is preferable to have more
than one treatment approved under the accelerated approval
provisions because of the uncertainty inherent in an approval under
these provisions. For example, post-approval studies of a drug
product may fail to establish a relationship of the surrogate
endpoint to clinical benefit, or of the observed clinical benefit to
ultimate outcome. In these circumstances, it is important to
continue to expedite the development and review of important new
therapies for serious and life-threatening illnesses under the
accelerated approval provisions. Therefore, if the only therapies
that exist for a condition are approved under the accelerated
approval regulations on the basis of a surrogate endpoint or are
approved with restrictions on distribution necessary to ensure the
safe use of the drug, FDA may designate a product as fast track
notwithstanding the availability of other therapies approved under
the accelerated approval regulations.
The type of information needed to demonstrate
the potential of a drug to address unmet medical needs will depend
on the stage of drug development. Data that become available during
clinical development should support the drug's potential to address
unmet medical needs and the development plan should be designed to
assess this potential. The Agency will rely on summaries of
available data to determine whether the potential to address unmet
medical needs has been demonstrated.
Before human studies begin, the potential for a
drug to address unmet medical needs will be based on pharmacologic
and animal model data. At this stage, there may be little evidence
of effectiveness of the drug in humans and the potential will be
largely theoretical. For later fast track designation, but still
prior to the completion of the principal controlled trials,
available clinical data should begin to confirm or be consistent
with the potential to address unmet medical needs. Still later in
the development of a drug, the Agency will normally consider whether
the clinical data from controlled and uncontrolled trials, as
summarized by the sponsor, support the potential of the drug to
address unmet medical needs. At this later stage in development,
when an alternate therapy is available, the Agency's determination
will also be based on whether the new therapy has been evaluated by
comparison with the existing therapy, usually by direct comparison
in clinical trials. As noted above, if the only existing
therapy is approved under the accelerated approval regulations, the
relevant comparisons are to conventionally approved drugs (i.e.,
drugs approved under 21 CFR 314.105, 314.125, or 601.2), or drugs
approved without restrictions, if there are any in either category.
Evidence that a new therapy was less safe than a drug approved
under the accelerated approval regulations could, however, be
relevant.
The general procedures applicable to the
submission and review of fast track designation requests are
described below.
A sponsor may submit a request for fast track
designation at the time of original submission of its IND, or at any
time thereafter prior to receiving marketing approval of its BLA or
NDA. Note that the IND and potential fast track designation may be
discussed prior to an IND submission in a pre-IND meeting, but a
decision on designation would await submission of the IND. Although
benefits associated with fast track designation may occur throughout
the drug development process, from the early IND submission to
evaluation of a marketing application, as a practical matter,
requests should ordinarily occur no later than the sponsor's pre-BLA/NDA
meeting with the Agency, as many of the benefits of fast track
designation will no longer be applicable after that time.
A request for fast track designation should be
submitted as an amendment to the sponsor's IND in triplicate with
Form FDA 1571 attached or, if the request is simultaneous with
submission of the original IND, should accompany the IND. The
request for fast track designation should identify the sponsor's
contact person, including the person's address, telephone number,
and fax number. The IND or amendment should be submitted to the
attention of the appropriate division in CBER or CDER and should
clearly identify the submission as a "Request for Fast Track
Designation." In the unusual situation where a request is made
after the filing of a BLA or NDA, the request should be submitted to
the BLA or NDA with a Form FDA 356h.
The submission in support of a request for fast
track designation should establish that the criteria necessary for
designation are met: (1) that the drug is intended to treat a
serious or life threatening condition (see section III.A. above),
and (2) that the drug has the potential to address unmet medical
needs and this potential is being evaluated in the planned drug
development program (see section III.B. above). The sponsor should
identify the serious condition and the unmet medical needs, provide
a plausible basis for the assertion that the drug has the potential
to address such unmet medical needs, and include in the development
plan (at a level of detail appropriate to the stage of development)
trials designed to evaluate this potential.
To facilitate FDA review, a submission for fast
track designation should contain all discussion and supporting
documentation necessary to permit a reviewer to assess whether the
criteria for fast track designation are met without having to refer
to information located elsewhere, yet should also not be voluminous.
The amount of discussion and supporting documentation that shows
that the criteria are met will vary. For example, little
explanation or supporting documentation may be needed to establish
that studying the drug in the treatment of a fatal condition with no
approved treatment would qualify if the endpoint were mortality.
More extensive explanation and supporting documentation would likely
be submitted to show that for a nonfatal condition, serious or
life-threatening aspects of the condition will be studied. Where
acceptable therapy for the condition already exists, still more
extensive discussion and supporting documentation would probably be
submitted to establish that the new therapy has the potential to
fill a medical need not met by existing therapy.
Any data or published reports that support
assertions made in the discussion section of the fast track
submission and that have not previously been submitted to the
sponsor's IND should be included in the submission. Supporting data
already contained in the sponsor's IND generally need only be
summarized in the fast track submission with reference to its
location in the IND. For assertions made in the submission that are
consistent with accepted medical knowledge, the sponsor does not
need to include references to clinical data or other external
sources. If a sponsor references a large number of sources, a list
of those references should be included.
FDA will respond to a request for fast track
designation within 60 calendar days of receipt of the request.
If the Agency determines that the criteria for
designation as a fast track drug development program have been met,
the designation letter will (1) state that fast track designation is
granted for development of the product for use in treating the
specific serious or life-threatening condition, (2) point out that
the sponsor should design and perform studies that can show whether
the product fulfills unmet medical needs, and (3) alert the sponsor
that the drug development program is expected to continue to meet
the criteria for fast track designation (see section IV.E. below).
A nondesignation letter would reflect a
determination that the request was incomplete or that the drug
development program failed to meet the criteria for fast track
designation. The nondesignation letter will explain the reasons for
the Agency's decision. FDA will respond to a subsequent request for
fast track designation after a nondesignation determination within
60 calendar days of receiving the subsequent request.
It is foreseeable that, for certain products in
fast track drug development programs, it will become apparent over
the course of drug development that the development programs do not
continue to meet the criteria for fast track designation. A product
in a fast track development program may not continue to meet the
criteria if the drug no longer (1) demonstrates a potential to
address unmet medical needs, or (2) is being studied in a manner
that would show the product is able to treat a serious or
life-threatening condition and fulfills unmet medical needs. It may
no longer demonstrate a potential to address unmet needs, for
example, if a new product were approved under a conventional
approval that addressed the same needs, or if emerging clinical data
failed to show that the product in a fast track development program
had the anticipated advantage over existing therapy. For products
in fast track drug development programs, the Agency expects that the
appropriateness of considering particular drug development plans as
part of the fast track program will be discussed and evaluated
during the drug development process, including at the end of phase 2
meeting and the pre-BLA/NDA meeting. If the sponsor recognizes that
the fast track drug development program will no longer be pursued,
the sponsor should inform the Agency of this change in plans.
When fast track designation is no longer
supported by emerging data or the designated drug development
program is no longer being pursued, the Agency may choose to send a
letter notifying the sponsor that the program is no longer
classified as a fast track drug development program.
It is important to distinguish between fast
track designation itself and the specific programs that are
available to a sponsor or applicant of a product in a fast track
drug development program under section 506(a) of the Act. A sponsor
or applicant may apply for fast track designation at any time in the
development process from the original submission of an IND until the
BLA or NDA is approved by the Agency (see section IV.A.). A product
that is in a fast track drug development program would be eligible
for consideration for some or all of the programs outlined below.
It is also important to recognize that, with
the exception of the submission of portions of a BLA/NDA before
submission of the entire application, the programs described below
have been established in regulations under authority separate from
section 506 of the Act. Therefore, products that are not in fast
track drug development programs may also be able to take advantage
of these programs.
Appropriately timed meetings between the
regulated industry and FDA are a critical aspect of efficient drug
development. Sponsors of products in fast track drug development
programs should be in regular contact with the appropriate reviewing
division to ensure that the evidence necessary to support marketing
approval will be developed and presented in a format conducive to an
efficient review. Specifically, the following are strongly
recommended:
1. Pre-IND consultation so that (1)
appropriate preclinical studies can be performed to demonstrate the
potential to address unmet medical needs and to support introduction
of the product into human trials, (2) phase 1 studies can be
optimally designed to support further product development, (3)
overall development strategy can be considered, and (4) issues
regarding the potential for fast track designation may be discussed.
2. An end of phase 1 meeting because, as
discussed in 21 CFR 312.82 (see Appendix 3), the first phase 2
controlled trials in life-threatening or severely debilitating
illnesses may provide sufficient data on safety and effectiveness to
support approval, with later development of more extensive safety
data, dose response information, and other information in
postmarketing studies. It is critical that early trials with
mortality/major morbidity endpoints be discussed before
implementation to reach agreement on study design, including the
statistical plan.
3. An end of phase 2 meeting to ensure that
agreement between FDA and the sponsor has been reached on the design
of the principal controlled trials intended to provide evidence of
safety and efficacy. As noted in the paragraph above (section
A.2.), for some fast track drug development programs, a meeting with
much the same purpose will occur at the end of early clinical
testing and may be referred to as end of phase 1/2 meeting.
Note that the standard of evidence applicable to principal
controlled trials is set forth at 21 CFR 314.126 (see also the FDA
guidance document, Providing Clinical Evidence of Effectiveness
for Human Drug and Biological Products).
4. A pre-BLA/NDA meeting to discuss and
achieve agreement on critical issues including:
·
Whether preliminary evidence of effectiveness was seen
in the principal controlled trials intended to provide evidence of
effectiveness
·
Structure, content, and timing of submission of the
BLA or NDA
·
Structure and content of any electronic submissions
·
Structure, content, and timing of submission of
portions of an application for marketing approval, if such
submission is appropriate
·
Readiness for, and proposed timing of, preapproval
inspections
·
Potential for, and proposed timing of, advisory
committee presentation if applicable
5. A meeting may be scheduled to discuss
labeling issues as early in the review process as appropriate
In addition to meeting minutes,
the FDA should provide the sponsor with the following:
·
Timely comments on the design of the proposed
principal controlled clinical trials that are to provide the basis
for the Agency's determination of the safety and effectiveness of
the product.
·
End of phase 1 and/or end of phase 2 letters
commenting on the adequacy of phase 2/3 development plans
In addition to the usual information contained
in premeeting packages described in the guidance for industry on
Formal Meetings with Sponsors and Applicants for PDUFA Products,
the sponsor should provide the following to FDA:
·
Responses to FDA questions about any clinical trials
that are to form the basis for the Agency's determination of the
safety and effectiveness of the product
·
At the earliest possible time, protocols of any
clinical trials that are not being carried out under an IND (i.e.,
foreign studies) and that will form the basis for the Agency's
determination of the safety and effectiveness of the product
·
In meeting packages for meetings held after initial
fast track designation, a discussion of how accumulated data and
study plans continue to demonstrate that the product and the
development plan meet the criteria for fast track designation
·
If submission of portions of an incomplete application
is sought, a written request for this kind of submission and a
proposed schedule for submission (see V.C.2. below)
·
As soon as possible, if there are plans to study a
surrogate endpoint suitable for review under the accelerated
approval provisions, a discussion of and support for the proposed
endpoint
Sponsors of products in fast track drug
development programs may be considered for one or more of the
following procedures regarding marketing applications.
Because fast track products are intended to
treat serious or life-threatening conditions and must demonstrate
the potential to address unmet medical needs for such conditions, a
BLA or NDA for a product in a fast track drug development program
ordinarily will be eligible for priority review (see CBER and CDER
procedures in Appendix 3).
a. BLAs
and NDAs
Section 506(c) of the Act provides that FDA may
consider for review portions of a marketing application before the
complete BLA or NDA is submitted. Filing may only occur if the
applicant provides a schedule for submission of information
necessary to make the application complete and pays any fees that
may be required under section 736 of the Act (i.e., user fees).
After the sponsor submits to the IND a
preliminary evaluation of data from the clinical trials, the Agency
may consider accepting portions of an application if (1) the
clinical trials that would form the basis for the Agency's
determination of the safety and effectiveness of the product and
that would support drug labeling are nearing completion or have been
completed, (2) the Agency agrees that the product continues to meet
the criteria for fast track designation, and (3) the Agency agrees
that preliminary evaluation of the clinical data supports a
determination that the product may be effective.
A sponsor seeking to submit portions of an
application should (1) provide a schedule for submission of the
portions of the BLA or NDA and receive FDA agreement to accept
portions of the application and agreement that the schedule is
acceptable before making any submission under the schedule, and (2)
pay any applicable user fee to the Agency at the time the first
portion of the BLA or NDA is submitted. The pre-BLA/NDA meeting
should be used to obtain preliminary Agency agreement on the
proposal. At the meeting, the sponsor and the reviewing division
should discuss the data that will be used to support effectiveness,
the schedule for submission of each portion of the BLA or NDA, and a
description of portions of the application to be submitted
separately. A request to submit portions of an application
ordinarily should be included in the information package for the
pre-BLA/NDA meeting. If a sponsor seeks to submit portions of an
application under these procedures after the pre-BLA/NDA meeting,
the sponsor should request submission and submit a proposed schedule
for submission of portions of an application to the IND as soon as
possible.
A request for submission of portions of an
application should be submitted as an amendment to the IND for the
product in a fast track drug development program in triplicate with
Form FDA 1571 attached. The amendment should be clearly identified
a "Request for Submission of Portions of an Application." A sponsor
may apply for fast track designation and submission of portions of a
BLA or NDA at the same time. These requests should be submitted as
one amendment to the IND.
FDA will respond to a request for submission of
portions of an application by letter to the sponsor. Any changes in
an agreement to accept portions of an application will also be in
writing.
b.
Portions of an application eligible for early submission
Generally, the Agency will accept for
submission only a complete section of a BLA or NDA, such as the
entire CMC section, toxicology section, or clinical section (Form
FDA 356h may be a useful guide to items in a BLA or NDA). It is
expected that a section submitted for review will be in a form
adequate to have been included in a complete BLA or NDA submission.
Drafts should not be included in a submission; if final reports need
to be updated, the applicant should submit a formal amendment to the
BLA or NDA with the revised information. Occasionally, the Agency
may, in its discretion, accept less than a complete section (e.g., a
CMC section lacking final consistency lot data and long term
stability data; an acute toxicology section lacking chronic
toxicology data; or final study reports for some or all of the
principal controlled trials without integrated summaries) if it
determines that such a subsection would constitute a reviewable unit
and would be useful in making the review process more efficient
overall. The company should confirm that these subsections are
final reports. The Agency and the sponsor should work together at
the time of the pre-BLA/NDA meeting to clearly define the parameters
of accepting an incomplete section and to determine whether FDA
could conduct a meaningful review of the submission prior to
receiving the missing information.
c.
Submission of the user fee
Section 506(c)(1) of the Act requires a sponsor
to pay any fee that may be required under section 736 of the Act
before FDA may commence review of any portion of an application.
The applicant should submit Form FDA 3397 with any applicable user
fee and should follow the same procedures as those followed when a
complete application is submitted.
d.
Commencement of review
Acceptance of a portion of an application by
the Agency does not necessarily mean that review will commence or
proceed prior to the receipt of a complete application. Actual
commencement and scheduling of review will depend on many factors,
including staffing, workload, competing priorities, time line for
completion of applications, and the perceived efficiency of
commencing review before the complete submission.
e.
Calculation of review time
The review clock will not begin until the
applicant informs the Agency that a complete BLA or NDA has been
submitted. Following notification that the application is complete,
the Agency will make a filing determination within the usual time
(see 21 CFR 314.101).
Applicants whose products are in fast track
drug development programs may seek traditional approval based on
data demonstrating an effect on clinically meaningful endpoints or
well-established surrogate endpoints. Alternatively, they may seek
approval under the accelerated approval regulations (Appendix 4).
If an applicant seeks approval of a product in a fast track drug
development program based on evidence of an effect on a less than
well-established surrogate endpoint, FDA may grant accelerated
approval based on a determination that the effect on the surrogate
endpoint is reasonably likely to predict clinical benefit (21 CFR
314.510 and 601.41). Drug approval under the accelerated approval
regulations may also be based on demonstrated clinical effects that
are not the desired ultimate benefit but are reasonably likely to
predict such benefit (e.g., improved exercise tolerance in
refractory heart failure might be considered reasonably likely to
predict ultimate benefit) (21 CFR 314.510 and 601.41).
Section 506(b) essentially codifies in statute
FDA's accelerated approval regulations. A surrogate endpoint was
defined in the preamble to the accelerated approval rule (57 FR
13234 at 13235, April 15, 1992) as "a laboratory or physical sign
that is used in therapeutic trials as a substitute for a clinically
meaningful endpoint that is a direct measure of how a patient feels,
functions, or survives and that is expected to predict the effect of
the therapy." Although some surrogate endpoints are recognized as
well-established and have long been a basis for approval (e.g.,
change in blood pressure or cholesterol), the accelerated approval
rule allows reliance in specific circumstances on a "surrogate
endpoint that, while 'reasonably likely' to predict clinical
benefit, is not so well-established as the surrogates ordinarily
used as bases of approval in the past" (57 FR 58942 at 58944,
December 11, 1992). To meet the statutory standard for approval,
which requires the submission of "substantial evidence" to
demonstrate effectiveness, "there must be evidence from adequate
and well-controlled studies showing that the drug will have [its
claimed] effect... That effect will, in this case, be an effect on
a surrogate endpoint...." (57 FR 58943-44).
With respect to approval based on clinical
endpoints other than survival or irreversible morbidity, the
preamble to the final accelerated approval rule pointed out that
such approval would usually be considered (like other approvals
based on a clinical finding) under traditional procedures (i.e., not
under accelerated approval). Approval based on clinical endpoints
other than survival or irreversible morbidity would "be considered
under the accelerated approval regulations only when it is essential
to determine effects on survival or irreversible morbidity in order
to confirm the favorable risk/benefit judgment that led to approval"
(57 FR 58946). The following examples illustrate types of clinical
endpoints that could be a basis for approval with a requirement for
further studies under the provisions of the Modernization Act and
the accelerated approval rule:
·
Clinical endpoints measuring short-term benefit in a
chronic condition where short-term benefit per se does not outweigh
risk and where durability of benefit is uncertain but expected.
·
Clinical endpoints measuring lesser symptoms or signs
of a serious disease (e.g., weight loss, appearance) when the
resulting benefits do not per se outweigh risks but are expected to
lead to a favorable effect on ultimate outcome, which would outweigh
risks.
·
Clinical endpoints measuring substantial benefits
otherwise suitable for ordinary approval but where there exists a
significant but limited concern that the treatment may adversely
affect ultimate outcome. Where such concerns are minimal, ordinary
approval would be used. Where the concerns are substantial, data
regarding ultimate outcome would be required preapproval. Between
these extremes, accelerated approval may be considered.
An FDA determination under the fast track
program may be appealed to the reviewing division. If the sponsor
is not satisfied with the response provided by the FDA component,
the sponsor may elect to pursue the Agency's procedures for internal
review or dispute resolution (see 21 CFR 10.75, 312.48, and
314.103).
SEC. 112. EXPEDITING STUDY AND APPROVAL OF FAST
TRACK DRUGS.
(a) IN GENERAL- Chapter V (21 U.S.C.
351 et seq.), as amended by section 125, is amended by inserting
before section 508 the following:
`SEC. 506. FAST TRACK PRODUCTS.
`(a) DESIGNATION OF DRUG AS A FAST
TRACK PRODUCT-
`(1) IN GENERAL- The
Secretary shall, at the request of the sponsor of a new drug,
facilitate the development and expedite the review of such drug if
it is intended for the treatment of a serious or life-threatening
condition and it demonstrates the potential to address unmet medical
needs for such a condition. (In this section, such a drug is
referred to as a `fast track product'.)
`(2) REQUEST FOR
DESIGNATION- The sponsor of a new drug may request the Secretary to
designate the drug as a fast track product. A request for the
designation may be made concurrently with, or at any time after,
submission of an application for the investigation of the drug under
section 505(i) or section 351(a)(3) of the Public Health Service
Act.
`(3) DESIGNATION-
Within 60 calendar days after the receipt of a request under
paragraph (2), the Secretary shall determine whether the drug that
is the subject of the request meets the criteria described in
paragraph (1). If the Secretary finds that the drug meets the
criteria, the Secretary shall designate the drug as a fast track
product and shall take such actions as are appropriate to expedite
the development and review of the application for approval of such
product.
‘(b) APPROVAL OF APPLICATION FOR A
FAST TRACK PRODUCT-
`(1) IN GENERAL- The
Secretary may approve an application for approval of a fast track
product under section 505(c) or section 351 of the Public Health
Service Act upon a determination that the product has an effect on a
clinical endpoint or on a surrogate endpoint that is reasonably
likely to predict clinical benefit.
`(2) LIMITATION-
Approval of a fast track product under this subsection may be
subject to the requirements--
`(A) that
the sponsor conduct appropriate post-approval studies to validate
the surrogate endpoint or otherwise confirm the effect on the
clinical endpoint; and
`(B) that
the sponsor submit copies of all promotional materials related to
the fast track product during the preapproval review period and,
following approval and for such period thereafter as the Secretary
determines to be appropriate, at least 30 days prior to
dissemination of the materials.
`(3) EXPEDITED
WITHDRAWAL OF APPROVAL- The Secretary may withdraw approval of a
fast track product using expedited procedures (as prescribed by the
Secretary in regulations which shall include an opportunity for an
informal hearing) if--
`(A) the
sponsor fails to conduct any required post-approval study of the
fast track drug with due diligence;
`(B) a
post-approval study of the fast track product fails to verify
clinical benefit of the product;
`(C) other
evidence demonstrates that the fast track product is not safe or
effective under the conditions of use; or
`(D) the
sponsor disseminates false or misleading promotional materials with
respect to the product.
‘(c) REVIEW OF INCOMPLETE
APPLICATIONS FOR APPROVAL OF A FAST TRACK PRODUCT-
`(1) IN GENERAL- If the
Secretary determines, after preliminary evaluation of clinical data
submitted by the sponsor, that a fast track product may be
effective, the Secretary shall evaluate for filing, and may commence
review of portions of, an application for the approval of the
product before the sponsor submits a complete application. The
Secretary shall commence such review only if the applicant--
`(A)
provides a schedule for submission of information necessary to make
the application complete; and
`(B) pays
any fee that may be required under section 736.
`(2) EXCEPTION- Any
time period for review of human drug applications that has been
agreed to by the Secretary and that has been set forth in goals
identified in letters of the Secretary (relating to the use of fees
collected under section 736 to expedite the drug development process
and the review of human drug applications) shall not apply to an
application submitted under paragraph (1) until the date on which
the application is complete.
‘(d) AWARENESS EFFORTS- The
Secretary shall--
`(1) develop and
disseminate to physicians, patient organizations, pharmaceutical and
biotechnology companies, and other appropriate persons a description
of the provisions of this section applicable to fast track products;
and
`(2) establish a
program to encourage the development of surrogate endpoints that are
reasonably likely to predict clinical benefit for serious or
life-threatening conditions for which there exist significant unmet
medical needs.'.
(b) GUIDANCE- Within 1 year after
the date of enactment of this Act, the Secretary of Health and Human
Services shall issue guidance for fast track products (as defined in
section 506(a)(1) of the Federal Food, Drug, and Cosmetic Act) that
describes the policies and procedures that pertain to section 506 of
such Act.
21 CFR Parts 312 and 314
Investigational New Drug, Antibiotic and
Biological Drug Product Regulations;
Procedures for Drugs Intended to Treat
Life-Threatening
and Severely Debilitating Illnesses; Interim
Rule
(53 Federal Register 41516, October 21, 1998)
(Attachment provided separately)
Center for Biologics Evaluation and Research
Manual of Standard Operating Procedures and
Policies
SOPP 8405, Complete Review and Issuance of
Action Letters, June 11, 1998
Center for Drug Evaluation and Research
Manual of Policies and Procedures
MaPP 6020.3, Priority Review Policy, April 22,
1996
(Attachment provided separately)
21 CFR 314 and 601
New Drug, Antibiotic, and Biological Drug
Product Regulations;
Accelerated Approval; Final Rule
(57 Federal Register 58942, December 11, 1992)
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Date created: August 11, 2004 |