Federal Register, Volume 65 Issue 27 (Wednesday, February 9, 2000)

[Federal Register Volume 65, Number 27 (Wednesday, February 9, 2000)]
[Notices]
[Pages 6377-6380]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-2982]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 00D-0084]

Draft Guidance for Industry on Special Protocol Assessment;
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance for industry entitled ``Special
Protocol Assessment.'' This draft guidance is intended to provide
guidance for industry on procedures that will be adopted by the Center
for Drug Evaluation and Research (CDER) and the Center for Biologics
Evaluation and Research (CBER) to evaluate issues related to the
adequacy (e.g., design, conduct, analysis) of certain proposed studies.

DATES: Submit written comments on the draft guidance and the
collection of information provisions by April 10, 2000. General
comments on agency guidance documents are welcome at any time.

ADDRESSES: Copies of this draft guidance for industry are available on
the Internet at http://www.fda.gov/cder/guidance/index.htm or http://www.fda.gov/cber/guidelines.htm. Submit written requests for single
copies of the draft guidance to the Drug Information Branch (HFD-210),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857; or the Office of Communication,
Training, and Manufacturers Assistance (HFM-40), Center for Biologics
Evaluation and Research, 1401 Rockville Pike, Rockville, MD 20852-1448,
301-827-3844, FAX: 888-CBERFAX. Send two self-addressed adhesive labels
to assist the office in processing your requests. Submit written
comments to the Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Requests and comments should be identified with the docket number found
in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Murray M. Lumpkin, Center for Drug
Evaluation and Research (HFD-2), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5400; or Robert A. Yetter,
Center for Biologics Evaluation and Research (HFM-10), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-
0373.

SUPPLEMENTARY INFORMATION:

I. Description of the Guidance

FDA is announcing the availability of a draft guidance for industry
entitled ``Special Protocol Assessment.'' The draft guidance is
intended to provide guidance for industry on procedures that will be
adopted by CDER and CBER to evaluate issues related to the adequacy
(e.g., design, conduct, analysis) of certain proposed studies. This
draft guidance describes procedures for sponsors to request

[[Page 6378]]

special protocol assessment and for the agency to act on such requests.
The Prescription Drug User Fee Act of 1992 (PDUFA) (Public Law 102-
571) was reauthorized in November 1997 as part of the Food and Drug
Administration Modernization Act of 1997 (the Modernization Act)
(Public Law 105-115). In conjunction with the reauthorization of PDUFA,
FDA agreed to specific performance goals (PDUFA goals) for activities
associated with the development and review of products in human drug
applications as described in section 735(1) of the Federal Food, Drug,
and Cosmetic Act (the act) (21 U.S.C. 379g) (PDUFA products). The PDUFA
goals are summarized in ``PDUFA Reauthorization Performance Goals and
Procedures,'' an enclosure to a letter dated November 12, 1997, from
the Secretary of the U.S. Department of Health and Human Services,
Donna E. Shalala, to Senator James M. Jeffords. The PDUFA goals for
special protocol assessment and agreement provide that, upon request by
a sponsor, FDA will evaluate within 45 days of receipt certain
protocols and issues relating to the protocols to assess whether their
design is adequate to meet scientific and regulatory requirements
identified by the sponsor. Three types of protocols are eligible for
this special protocol assessment under the PDUFA goals: (1) Animal
carcinogenicity protocols, (2) final product stability protocols, and
(3) clinical protocols for phase 3 trials whose data will form the
primary basis for an efficacy claim if the trials had been the subject
of discussion at an end-of-phase 2/pre-phase 3 meeting with the review
division or if the division is otherwise aware of the developmental
context in which the protocol is being reviewed and the questions are
being answered. These protocols for phase 3 clinical trials may relate
to efficacy claims that will be part of an original new drug
application (NDA) or biologics license application (BLA) or that will
be part of an efficacy supplement to an approved NDA or BLA.
Section 119(a) of the Modernization Act amends section 505(b) of
the act (21 U.S.C. 355(b)). Section 505(b)(4)(B) of the act directs FDA
to meet with sponsors and applicants, provided certain conditions are
met, for the purpose of reaching agreement on the design and size of
clinical trials intended to form the primary basis of an effectiveness
claim in a marketing application submitted under section 505(b) of the
act or section 351 of the Public Health Service Act (42 U.S.C. 262)
(the PHS Act). Such marketing applications include NDA's, BLA's, and
efficacy supplements to approved NDA's and BLA's.
The procedures and policies described in this draft guidance are
designed to implement section 505(b)(4)(B) of the act and the PDUFA
goals for special protocol assessment and agreement.
This draft Level 1 guidance is being issued consistent with FDA's
good guidance practices (62 FR 8961, February 27, 1997). The draft
guidance represents the agency's current thinking on special protocol
assessment in CDER and CBER. 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 statute, regulations, or both.
Interested persons may submit to the Dockets Management Branch
(address above) written comments on the draft guidance. Two copies of
any comments are to be submitted, except that individuals may submit
one copy. Comments should be identified with the docket number found in
brackets in the heading of this document. The draft guidance and
received comments are available for public examination in the Dockets
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.

II. The Paperwork Reduction Act of 1995

Under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C.
3501-3520), Federal agencies must obtain approval from the Office of
Management and Budget (OMB) for each collection of information they
conduct or sponsor. ``Collection of information'' is defined in 44
U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes agency requests or
requirements that members of the public submit reports, keep records,
or provide information to a third party. Section 3506(c)(2)(A) of the
PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal agencies to provide a
60-day notice in the Federal Register concerning each proposed
collection of information before submitting the collection to OMB for
approval. To comply with this requirement, FDA is publishing notice of
the proposed collection of information set forth in this document.
With respect to the following collection of information, FDA
invites comment on: (1) Whether the proposed collection of information
is necessary for the proper performance of FDA's functions, including
whether the information will have practical utility; (2) the accuracy
of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection on respondents, including through the use of automated
collection techniques, when appropriate, and other forms of information
technology.
Title: Draft Guidance for Industry on Special Protocol Assessment
Description: FDA is issuing a draft guidance on agency procedures
to evaluate issues related to the adequacy of certain proposed studies.
The draft guidance describes procedures for sponsors to request special
protocol assessment and for the agency to act on such requests. The
draft guidance provides information on how the agency will interpret
and apply provisions of the Modernization Act and the specific PDUFA
goals for special protocol assessment associated with the development
and review of PDUFA products.
The draft guidance describes two collections of information: (1)
The submission of a notice of intent to request special protocol
assessment of a carcinogenicity protocol, and (2) the submission of a
request for special protocol assessment.

A. Notification for a Carcinogenicity Protocol

As described in the draft guidance, a sponsor interested in agency
assessment of a carcinogenicity protocol should notify the appropriate
division in CDER or CBER of an intent to request special protocol
assessment at least 30 days prior to submitting the request. With such
notification, the sponsor should submit relevant background information
so that the agency may review reference material related to
carcinogenicity protocol design prior to receiving the carcinogenicity
protocol. The agency is currently drafting a separate guidance
describing the type of information that would be appropriate to submit
before requesting carcinogenicity protocol assessment.

B. Request for Special Protocol Assessment

In the draft guidance, CDER and CBER ask that a request for special
protocol assessment be submitted as an amendment to the investigational
new drug application (IND) for the underlying product and that it be
submitted to the agency in triplicate with Form FDA 1571 attached. The
agency also suggests that the sponsor submit the cover letter to a
request for special protocol assessment via

[[Page 6379]]

facsimile to the appropriate division in CDER or CBER. Agency
regulations (21 CFR 312.23(d)) state that information provided to the
agency as part of an IND is to be submitted in triplicate and with the
appropriate cover form, Form FDA 1571. An IND is submitted to FDA under
existing regulations in part 312 (21 CFR part 312), which specifies the
information that manufacturers must submit so that FDA may properly
evaluate the safety and effectiveness of investigational drugs and
biological products. The information collection requirements resulting
from the preparation and submission of an IND under part 312 have been
estimated by FDA and the reporting and recordkeeping burden has been
approved by OMB until December 31, 1999, under OMB control number 0910-
0014. In the Federal Register of May 6, 1999 (64 FR 24402), FDA
published a notice requesting comments on the burden estimates for the
information collection requirements in part 312. The notice also
requested an extension of OMB approval for this information collection.
FDA suggests that the cover letter to the request for special
protocol assessment be submitted via facsimile to the appropriate
division in CDER or CBER to enable agency staff to prepare for the
arrival of the protocol for assessment. The agency recommends that a
request for special protocol assessment be submitted as an amendment to
an IND for two reasons: (1) To ensure that each request is kept in the
administrative file with the entire IND, and (2) to ensure that
pertinent information about the request is entered into the appropriate
tracking data bases. Use of the information in the agency's tracking
data bases enables the appropriate agency official to monitor progress
on the evaluation of the protocol and to ensure that appropriate steps
will be taken in a timely manner.
CDER and CBER have determined and the draft guidance recommends
that the following information should be submitted to the appropriate
Center with each request for special protocol assessment so that the
Center may quickly and efficiently respond to the request:
1. Questions to the agency concerning specific issues regarding the
protocol; and
2. All data, assumptions, and information needed to permit an
adequate evaluation of the protocol, including: (1) The role of the
study in the overall development of the drug; (2) information
supporting the proposed trial, including power calculations, the choice
of study endpoints, and other critical design features; (3) regulatory
outcomes that could be supported by the results of the study; (4) final
labeling that could be supported by the results of the study; and (5)
for a stability protocol, product characterization and relevant
manufacturing data.
1. Description of Respondents
A sponsor, applicant, or manufacturer of a drug or biologic product
regulated by the agency under the act or section 351 of the PHS Act who
requests special protocol assessment.
2. Burden Estimate
Table 1 of this document provides an estimate of the annual
reporting burden for requests for special protocol assessment. The
procedures for requesting special protocol assessment that are set
forth in the draft guidance have not been previously described by the
agency, although the PDUFA goals and the requirements of section
505(b)(4)(B) of the act have been in effect since October and November
1998, respectively, as follows:
a. Notification for a carcinogenicity protocol. Based on data
collected from the review divisions and offices within CDER and CBER,
including the number of carcinogenicity protocols submitted for review
in the first half of fiscal year (FY) 1999 and the number of IND's for
new molecular entities that were received by the agency per year over
the last 5 years, CDER and CBER anticipate that approximately 30
respondents will notify the agency of an intent to request special
protocol assessment of a carcinogenicity protocol. The agency further
estimates that the total annual responses, i.e., the total number of
notifications that will be sent to CDER and CBER, will be 60, based on
data collected from the offices within CDER and CBER. Therefore, the
agency estimates that there will be approximately two responses per
respondent. The hours per response, which is the estimated number of
hours that a respondent would spend preparing the notification and
background information to be submitted in accordance with the draft
guidance, is estimated to be approximately 8 hours. While FDA has not
finalized the separate guidance describing background information that
should be submitted with notification of a carcinogenicity protocol for
assessment, the agency anticipates that it will take respondents
approximately 8 hours to gather and copy articles and study reports
that are relevant to the carcinogenicity protocol. Therefore, the
agency estimates that respondents will spend 480 hours per year
notifying the agency of an intent to request special protocol
assessment of a carcinogenicity protocol.
b. Requests for special protocol assessment. Based on data
collected from the review divisions and offices within CDER and CBER,
including the number of requests for special protocol assessment in the
first half of FY 1999, the number of IND's for new molecular entities
that were received by the agency per year over the past 5 years, the
number of sponsors who have submitted protocols for agency review in
the past and in the first half of FY 1999, and the number of end-of-
phase 2/pre-phase 3 meetings that occur between respondents and the
agency per year, FDA anticipates that 70 respondents will request
special protocol assessment per year. The total annual responses are
the total number of requests for special protocol assessment that are
submitted to CDER and CBER in 1 year. Based on data collected from the
review divisions and offices within CDER and CBER, FDA estimates that
it will receive approximately 180 requests for special protocol
assessment per year. Therefore, the agency estimates that there will be
approximately 2.57 responses per respondent. The hours per response is
the estimated number of hours that a respondent would spend preparing
the information to be submitted with a request for special protocol
assessment, including the time it takes to gather and copy questions to
be posed to the agency regarding the protocol and data, assumptions,
and information needed to permit an adequate evaluation of the
protocol. Based on estimates provided by the regulated industry and on
the agency's experience in requesting similar information, FDA
estimates approximately 15 hours on average would be needed per
response. Therefore, FDA estimates that 2,700 hours will be spent per
year by respondents requesting special protocol assessment. Overall,
FDA anticipates that respondents will spend 3,180 hours per year to
participate in the programs described in the draft guidance.
FDA estimates the burden of this collection of information as
follows:

[[Page 6380]]

Table1.--Estimated Annual Reporting Burden¹
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Number of
Notification and Requests Number of Responses per Total Annual Hours per Total Hours
Respondents Respondent Responses Response
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Notification for Carcinogenicity 30 2.0 60 8 480
Protocols
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Requests for Special Protocol 70 2.57 180 15 2,700
Assessment
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Total 3,180
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

Dated: February 1, 2000.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-2982 Filed 2-8-00; 8:45 am]
BILLING CODE 4160-01-F