[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Draft Guidance for Industry on Special Protocol Assessment; 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availability of a draft guidance for industry entitled ``Special 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 This draft guidance is intended to provide 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DATES:  Submit written comments on the draft guidance and the 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ADDRESSES:  Copies of this draft guidance for industry are available on 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copies of the draft guidance to the Drug Information Branch (HFD-210), 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 Burden<SUP>1</SUP>
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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