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)
October 2003
Procedural
Guidance for Industry
Continuous Marketing Applications:
Pilot 2 � Scientific Feedback and Interactions During Development of
Fast Track Products Under PDUFA
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http://www.fda.gov/cder/guidance/index.htm
or
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http://www.fda.gov/cber/guidelines.htm.
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For questions regarding the content of this document contact (CDER) John Jenkins
(301-594-3937) or (CBER) Robert A. Yetter (301-827-0373).
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)
October 2003
Procedural
Guidance for Industry
Continuous Marketing Applications:
Pilot 2 � Scientific Feedback and Interactions During Development
of Fast Track Products Under PDUFA
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 the FDA or the
public. You may 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. |
I. INTRODUCTION
This
document is intended to provide guidance to industry on how the Agency
will implement a pilot program (Pilot 2) to test the continuous
marketing application (CMA) concept during the IND (investigational new
drug application) phase of new drug and biological product development.
Pilot
2 provides for frequent scientific feedback and interactions based on a
prospectively defined agreement between the FDA and applicants.
Pilot 2 pertains only to new drug or biological products that have been
designated as Fast Track products pursuant to Section 112 of the FDA
Modernization Act of 1997 (Section 506 of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 356)
and have been selected to participate in the program. The pilot
program will be effective from the date that the Notice of Availability
for this guidance is published in the Federal Register
through September 30, 2007, and will include an evaluation component to
determine the added value and costs of the program and its impact on
the efficiency of the development process. Another pilot
program (Pilot 1), to test the CMA concept during the review of new
drug applications (NDAs) and biologic licensing applications (BLAs), is
the subject of a separate guidance, Continuous Marketing Applications: Pilot 1 � Reviewable Units for Fast Track Products Under PDUFA.
Applications that meet the relevant acceptance criteria may be included
in both Pilot 1 and Pilot 2. An application included in the
Pilots also may be subject to other special development or approval
programs (e.g., 21 CFR 314 Subpart H).
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.
In
conjunction with the June 2002 reauthorization of the Prescription Drug
User Fee Act of 1992 (PDUFA), the FDA agreed to meet specific
performance goals (PDUFA goals). The PDUFA goals are described in
PDUFA Reauthorization Performance Goals and Procedures, an enclosure to a letter dated June 4, 2002, from the Secretary of Health and Human Services to Congress. The PDUFA goals outline the basic elements of two pilot programs to explore the CMA concept.
The
CMA concept builds on the current practice of interaction between the
FDA and applicants during drug development and application review and
proposes improvements. Under PDUFA, two exploratory pilot
programs will be conducted to allow for a comprehensive assessment of
the added value, costs, and impact of more extensive feedback during
drug development and early review of parts of marketing
applications. These pilot programs will provide the Agency with
important information regarding whether such activity can improve the
efficiency of the drug development and review process and shorten
review time.
For many years, the FDA has
engaged in early review of parts of marketing applications prior to
submission of the entire application. For example, under section
112 of the FDA Modernization Act of 1997, the FDA has conducted for the
past several years rolling reviews of some presubmitted
portions of Fast Track marketing applications on a resource-available
basis. Although such Agency activities are believed to improve
the efficiency of the drug development and approval process for Fast
Track products, no formal program to assess the value, costs, and
impact of such activities has been undertaken.
Under
the first CMA pilot program, Pilot 1, the subject of a separate
guidance, applicants submitting NDAs or BLAs for products designated as
Fast Track products may be eligible, based on the terms and conditions
agreed upon by the applicant and the FDA, to submit portions of their
marketing applications (reviewable units) before submitting
the complete marketing application. The FDA has agreed to
complete reviews of such reviewable units within a specified period of
time and to provide early feedback for the presubmissions in the form
of discipline review letters. Pilot 1 also will evaluate the benefits and costs of providing applicants with such early review feedback.
Under
the second CMA pilot program, Pilot 2, the subject of this guidance,
the FDA and applicants of eligible Fast Track drug and biological
products can enter into an agreement to engage in frequent scientific
feedback and interactions during the IND phase of product
development. Pilot 2 will evaluate the cost of such enhanced
interaction between the FDA and applicants and whether it improves the
efficiency and effectiveness of development programs.
This
section of the guidance describes the application and selection process
for participating in Pilot 2 and the process of forming an agreement
with the review division on feedback and interactions. This
section also outlines the timelines and evaluation process for Pilot 2.
Many requirements for the Pilot 2 program are
detailed in the PDUFA goals. The FDA�s objective in designing the
details of implementation is to maximize the potential public health
impact of the resources invested in this exploratory program.
1. Eligible Drug and Biological Products
Under
the PDUFA goals, eligibility for participation in Pilot 2 is limited to
drug and biological products that (1) have been designated Fast Track,
(2) have been the subject of an end-of-phase 1, or equivalent, meeting,
and (3) are not on clinical hold. An equivalent meeting may, in
some cases, be a pre-IND meeting for a product that has been previously
developed outside of the U.S. The FDA retains the authority to
determine whether a pre-IND meeting is adequate to initiate the Pilot 2
process for a particular product.
Pilot 2 will be
limited to no more than one Fast Track product for each CDER and CBER
review division over the course of the pilot program.
The review division and applicant can discuss at the initiation of the
IND process the potential for an eligible product to benefit from
participation in Pilot 2.
The
selection of products for Pilot 2 will be based on FDA review of a
Pilot 2 application. In the Pilot 2 application, the applicant
should describe how the Fast Track product could significantly benefit
the public health and how the proposed development program could be
significantly enhanced by frequent communications with the FDA.
Each Pilot 2 application should include the following information:
- Cover letter prominently labeled Pilot 2 application
- IND number
- Date of Fast Track designation
- Date of the end-of-phase 1, or equivalent, meeting and summary of the outcome
- A
timeline of past and projected milestones from the drug or biological
product development program, including projected date of NDA/BLA
submission
- Overview of the proposed product
development program for a specified disease and indication(s),
providing information about each of the review disciplines (e.g., CMC,
pharmacology/toxicology, clinical, clinical microbiology, clinical
pharmacology, and biopharmaceutics)
- Rationale
for participation in Pilot 2, specifying the ways in which development
of the subject drug or biological product would be improved by frequent
scientific feedback and interactions with the FDA and the potential for
such communication to benefit public health by improving the efficiency
of the drug development program
- Draft agreement for proposed feedback and interactions with the FDA (see section III.B. below)
Pilot
2 applications should be submitted in triplicate to the attention of
the appropriate review division in CDER or CBER as an amendment to the
applicant�s IND with Form FDA 1571 attached.
Pilot
2 applications will be evaluated based on FDA�s overall assessment of
(1) the potential value of enhanced interaction, emphasizing the
potential public health benefit resulting from development of the
product, (2) the likelihood that concentrated scientific dialogue will
facilitate the availability of a promising novel therapy, and (3) the
applicant�s demonstration of commitment to product development as
evidenced by a thorough consideration of the rationale for
participation in Pilot 2.
As noted above, a
maximum of one Pilot 2 application for each CDER and CBER review
division will be selected to participate in the pilot program.
Each selected Pilot 2 product will remain in the pilot program until
the program�s completion date, unless (1) an NDA or BLA is submitted
for the product, (2) the applicant withdraws the product from the pilot
program, or (3) the FDA terminates the agreement for the product (see
Section B, below). If a Pilot 2 product is withdrawn or
terminated from the pilot program before the agreement
between the review division and applicant is finalized, the review
division will replace it with an alternate selection from among the
Pilot 2 applications. Pilot 2 products that are withdrawn or
terminated from the pilot program after an agreement between
the FDA and applicant is finalized may be replaced at the discretion of
the division based on the availability of other eligible applications
and the remaining duration of Pilot 2.
The implementation for Pilot 2 will begin on the date that the Notice
of Availability for this guidance is published in the Federal Register.
Pilot 2 applications will be accepted between that date and December 8,
2003. A single Pilot 2 application for each CDER and CBER review
division will be selected from the Pilot 2 applications that are
received by December 8, 2003. Those selection decisions will be
made by February 9, 2004, and the appropriate FDA review division will
notify the applicant of the selected Pilot 2 application in
writing. The Agency will inform applicants individually about
applications that are not selected.
Divisions
that have not received any acceptable Pilot 2 applications by December
8, 2003, will continue to accept applications through September 30,
2004. For each of these divisions, the first application received
that meets the evaluation criteria will be accepted into Pilot 2, and
the applicant will be informed within 3 months of application
submission.
A notice will be made
available on the FDA web site to identify the CDER and CBER divisions
that have selected a participant application.
Once an application is selected for Pilot 2, and prior to engaging in
any subsequent Pilot 2 activity, the review division and the applicant
will finalize an agreement on the nature of and timelines for feedback
and interactions between the applicant and the FDA. The initial
basis for this agreement will be the draft agreement submitted by the
applicant in the Pilot 2 application. However, the FDA will
retain full discretion to determine the contents of the final agreement
or to determine that no final agreement can be reached. The final
agreement between the review division and the applicant will outline
clearly the types of feedback and interactions that are expected to
occur along with a tentative timeline. The final agreement will
be written to provide reasonable flexibility in implementing and
adjusting the agreement as warranted during the drug development
program. The final agreement will be shared with the applicant in
writing (e.g., in meeting minutes, facsimile, letter). Changes to
the agreement can be made by subsequent agreement between the review
division and the applicant and should be documented for the record
(e.g., in meeting minutes). If after reasonable attempts to
negotiate, the review division and the applicant are unable to finalize
the agreement, the review division may notify the applicant in writing
that the product will not be entered into Pilot 2, and the review
division may select another application for Pilot 2.
The following aspects of interaction between the FDA and the applicant will be addressed as part of the agreement:
- Frequency of Contact
� This provision in the agreement will outline the timing and/or
triggering events that will prompt interaction between the applicant
and the FDA review division. The agreement may provide for
regular interactions at appropriate times during the development
process and/or feedback from the FDA following applicant submission of
new information, such as a product development plan, important new
protocols, study summaries, or complete study reports.
- Applicant Submissions
� The applicant and the FDA will agree on the general types of
submissions that will stimulate feedback and interactions.
Examples include requests for evaluation of proposed preclinical or
clinical protocols, product development plans, special protocol
assessments, selected study summaries, draft study reports, and final
study reports. The Agency expects that study summaries and draft
reports, rather than final study reports, will be submitted routinely
during the IND process. Applicants should be aware, however, that
the FDA cannot anticipate important differences between draft and final
study reports. Feedback on development programs will be affected
by the quality and completeness of the information available to the FDA
at the time of its assessment.
- Feedback and Interaction from the FDA
� The review division and applicant will agree on the forms of
communication (e.g., regular face-to-face meetings, intermittent
telephone interactions, written communications, secure e-mail) to use
in response to each type of applicant submission. The review
division and applicant will also agree on general timelines for
responses, providing adequate time for FDA review and anticipating the
need of applicants for timely input to their development
processes. For submissions subject to PDUFA goals (e.g. requests
for special protocol assessment, see FDA guidance Special Protocol Assessment), an applicant and review division may negotiate shorter review schedules.
Review
divisions will undertake an annual evaluation of each agreement to
determine whether the agreement continues to promote the goals of Pilot
2. An agreement may be modified to refine the feedback and
interaction process based on applicant needs and other experience with
the ongoing program. Certain conditions may require termination
of a Pilot 2 agreement and removal of an application from Pilot 2
(e.g., if a development program changes so that it no longer tests the
ability of enhanced FDA feedback and interaction with the applicant to
promote the development of a highly beneficial product). Such
changes in a development program could include failure of an applicant
to actively pursue development of the drug or biological product
(either with or without termination or withdrawal of the IND), failure
of the product to demonstrate a potential ability to meet an important
medical need, loss of Fast Track status, significant disagreements in
approach to product development between the applicant and review
division, or significant deviation by the applicant from the
development plan negotiated with the review division.
Determination of the need to terminate Pilot 2 agreements will be made
by the review division in consultation with the appropriate office
director.
Pilot
2 agreements and activities for each application will continue through
September 30, 2007, the pilot program completion date, unless (1) an
NDA\BLA is submitted, (2) the applicant withdraws the product from the
pilot program, or (3) the agreement is terminated by the FDA for any of
the reasons described above.
An independent,
expert consultant will be engaged under a contract with the FDA to
evaluate Pilot 2. The consultant will, with input from the FDA,
develop an evaluation study design that identifies key questions, data
requirements, and a data collection plan, while maintaining applicants
confidentiality. The consultant will then conduct a comprehensive
study of Pilot 2 to help assess the value, costs, and effects of this
program in relation to the product development and review
process. Data collection and evaluation is expected to inform and
refine the conduct of the program and will begin on the date that the
Notice of Availability for this guidance is published in the Federal Register.
To
evaluate Pilot 2 fully, the independent expert consultant will need
access to applicants� feedback. Accordingly, applicants engaged
in Pilot 2 will be expected to cooperate with the consultant throughout
the program as a mandatory condition for continued participation.
The
independent consultant will provide a preliminary report on the
evaluation of Pilot 2 to the Commissioner of Food and Drugs by
September 30, 2006, with a final report due after September 30,
2007. A version of both the preliminary and final reports,
redacted to remove confidential commercial information or other
information exempt from disclosure, will be made available to the
public. At the conclusion of the pilot program and after review
of the preliminary and final reports, the FDA will determine the
appropriate plan to handle participating Pilot 2 applications.
This guidance has been prepared by the Office of New Drugs in the
Center for Drug Evaluation and Research (CDER) in cooperation with the
Center for Biologics Evaluation and Research (CBER) at the Food and
Drug Administration.
Additional information regarding Fast Track products (i.e., those
products intended to treat a serious and/or life-threatening disease
for which there is an unmet medical need) and the Fast Track program,
including product designation and the program associated with such
designation, is available in the FDA guidance Fast Track Drug Development Programs � Designation, Development and Application Review.
3
The letter was sent to Congress with identical copies addressed to the
Chairman and Ranking Minority Members of the Committee on Health,
Education, Labor and Pensions, United States Senate and Committee on
Energy and Commerce, United States House of Representatives. The
PDUFA Goals can be found at http://www.fda.gov/oc/pdufa/PDUFAIIIGoals.html.
The comments included in the discipline review letter are considered
preliminary by the FDA and do not represent final Agency conclusions
regarding the application. Additional information regarding
discipline review letters is available in the FDA guidance Information Request and Discipline Review Letters Under the Prescription Drug User Fee Act.
Sixteen divisions in CDER and four divisions in CBER will participate in Pilot 2.
