[Federal Register Volume 62, Number 131 (Wednesday, July 9, 1997)]
[Notices]
[Pages 36832-36836]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-17799]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration


Clinical Studies of Safety and Effectiveness of Orphan Products; 
Availability of Grants; Request for Applications

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
following changes to its Orphan Products Development (OPD) grant 
program for fiscal year (FY) 1998. The previous announcement of this 
program, which was published in the Federal Register of June 6, 1996, 
is superseded by this announcement. In the future, a new announcement 
will be published annually.

DATES: Application receipt dates are: October 15, 1997, and March 15, 
1998. If the receipt date falls on a weekend, it will be extended to 
Monday; if the date falls on a holiday, it will be extended to the 
following workday.

ADDRESSES: Application forms are available from, and completed 
applications should be submitted to: Robert L. Robins, Grants 
Management Officer, Division of Contracts and Procurement Management 
(HFA-520), Food and Drug Administration, 5600 Fishers Lane, Park Bldg., 
rm. 3-40, Rockville, MD 20857, 301-443-6170. (Applications hand-carried 
or commercially delivered should be addressed to the Park Bldg., 12420 
Parklawn Dr., rm. 3-40, Rockville, MD 20852.)

FOR FURTHER INFORMATION CONTACT:
    Regarding the administrative and financial management aspects of 
this notice: Robert L. Robins (address above).
    Regarding the programmatic aspects of this notice: Ronda A. Balham, 
Office of Orphan Products Development (HF-35), Food and Drug 
Administration, 5600 Fishers Lane, rm. 8-73, Rockville, MD 20857, 301-
827-3666.

SUPPLEMENTARY INFORMATION: FDA is announcing the anticipated 
availability of funds for FY 1998 for awarding grants to support 
clinical trials on the safety and effectiveness of products for a rare 
disease or condition (i.e., one with a prevalence, not incidence, of 
fewer than 200,000 people in the United States). Contingent on 
availability of FY 1998 funds, it is anticipated that $11.3 million 
will be available, of which 3.5 million will be for noncompeting 
continuation awards. This will leave $7.8 million for funding 
approximately 30 new applications. Any phase clinical trial is eligible 
for up to $100,000 in direct costs per annum plus applicable indirect 
costs for up to 3 years. Phase 2 and 3 clinical trials are eligible for 
up to $200,000 in direct costs per annum plus applicable indirect costs 
for up to 3 years.
     FDA will support the clinical studies covered by this notice under 
section 301 of the Public Health Service Act (the PHS act) (42 U.S.C. 
241). FDA's research program is described in the Catalog of Federal 
Domestic Assistance, No. 93.103.
     The Public Health Service (PHS) strongly encourages all grant 
recipients to provide a smoke-free work place and to discourage the use 
of all tobacco products. This is consistent with the PHS mission to 
protect and advance the physical and mental health of the American 
people.
     PHS urges applicants to submit work plans that address specific 
objectives of ``Healthy People 2000.'' Potential applicants may obtain 
a copy of ``Healthy People 2000'' (Full Report, stock No. 017-001-
00474-0) through the Superintendent of Documents, Government Printing 
Office, Washington, DC 20402-9325, 202-512-1800.
     PHS policy is that applicants for PHS clinical research grants are 
required to include minorities and women in study populations so that 
research findings can be of benefit to all persons at risk of the 
disease, disorder, or condition under study; special emphasis must be 
placed on the need for inclusion of minorities and women in studies of 
diseases, disorders, and conditions which disproportionately affect 
them. This policy is intended to apply to males and females of all 
ages. If women or minorities are excluded or inadequately represented 
in clinical research, particularly in proposed population-based 
studies, a clear compelling rationale must be provided.

I. Program Research Goals

     OPD was established to identify and facilitate the availability of 
orphan products. In the OPD grant program, orphan products are defined 
as drugs, biologics, medical devices, and foods for medical purposes 
which are indicated for a rare disease or condition (i.e., one with a 
prevalence, not incidence, of fewer than 200,000 people in the United 
States). Diagnostic tests and vaccines will qualify only if the U.S. 
population of intended use is lower than 200,000 per annum.
     One way to make orphan products available is to support clinical 
research to determine whether the products are safe and effective. All 
funded studies are subject to the requirements of the Federal Food, 
Drug, and Cosmetic Act (the act) and regulations issued thereunder. The 
grants are funded under the legislative authority of section 301 of the 
PHS Act (42 U.S.C 241).
     The goal of FDA's OPD grant program is the clinical development of 
products for use in rare diseases or conditions where no current 
therapy exists or where current therapy would be improved. FDA provides 
grants to conduct clinical studies intended to provide data acceptable 
to the agency which will either result in or substantially contribute 
to approval of these products. Applicants should keep this goal in mind 
and must include an explanation in the ``Background and Significance'' 
section of the application of how their proposed study will either 
facilitate product approval or provide essential data needed for 
product development. Information regarding meetings and/or discussions 
with FDA reviewing division staff about the product to be studied 
should also be provided as an appendix to the application. This 
information is extremely important for the review process.
     Except for medical foods that do not require premarket approval, 
FDA will only consider awarding grants to support clinical studies for 
determining whether the products are safe and

[[Page 36833]]

effective for premarket approval under the act (21 U.S.C. 301 et seq.) 
or under section 351 of the PHS Act (42 U.S.C. 262). All studies of new 
drug and biological products must be conducted under the FDA's 
investigational new drug (IND) procedures and studies of medical 
devices must be conducted under the investigational device exemption 
(IDE) procedures. Studies of approved products to evaluate new orphan 
indications are also acceptable; however, these are also required to be 
conducted under an IND or IDE to support a change in official labeling. 
(See section V.B of this document ``Program Review Criteria'' for 
critical requirements concerning IND/IDE status of products to be 
studied under these grants.)
     Studies submitted for the larger grants ($200,000) must be 
continuing in phase 2 or phase 3 of investigation. Phase 2 trials 
include controlled clinical studies conducted to evaluate the 
effectiveness of the product for a particular indication in patients 
with the disease or condition and to determine the common or short-term 
side effects and risks associated with it. Phase 3 trials gather 
additional information about effectiveness and safety that is necessary 
to evaluate the overall risk-benefit relationship of the product and to 
provide an adequate basis for physician labeling. Studies submitted for 
the smaller grants ($100,000) may be phase 1, 2, or 3 trials. Budgets 
for all years of requested support may not exceed the $200,000 or 
$100,000 limitation, whichever is applicable.
     Applications must propose a clinical trial of one therapy for one 
indication. The applicant must provide supporting evidence that a 
sufficient quantity of the product to be investigated is available to 
the applicant in the form needed for the clinical trial. The applicant 
must also provide supporting evidence that the patient population has 
been surveyed and that there is reasonable assurance that the necessary 
number of eligible patients is available for the study.
     Funds may be requested in the budget for travel to FDA to meet 
with reviewing division staff about product development progress.

II. Human Subject Protection and Informed Consent

A. Research Involving Human Subjects

     Applicants are advised that the section on human subjects in the 
application kit entitled ``Section C. Specific Instructions--Forms, 
Item 4, Human Subjects,'' on pages 7 and 8 of the application kit, 
should be carefully reviewed for the certification of Institutional 
Review Board (IRB) approval requirements. Documentation of IRB approval 
for every participating center is required to be on file with the 
Grants Management Officer, FDA. The goal should be to include enough 
information on the protection of human subjects in a sufficiently clear 
fashion so reviewers will have adequate material to make a complete 
review.

B. Informed Consent

     Consent and/or assent forms, and any additional information to be 
given to a subject, should accompany the grant application. Information 
that is given to the subject or the subject's representative must be in 
language that the subject or his or her representative can understand. 
No informed consent, whether oral or written, may include any language 
through which the subject or the subject's representative is made to 
waive any of the subject's legal rights, or by which the subject or 
representative releases or appears to release the investigator, the 
sponsor, or the institution or its agent from liability.
     If a study involves both adults and children, separate consent 
forms should be provided for the adults and the parents or guardians of 
the children.

C. Elements of Informed Consent

     The elements of informed consent are stated in the regulations at 
45 CFR 46.116 and 21 CFR 50.25 as follows:
1. Basic Elements of Informed Consent
     In seeking informed consent, the following information shall be 
provided to each subject:
     (a) A statement that the study involves research, an explanation 
of the purposes of the research and the expected duration of the 
subject's participation, a description of the procedures to be 
followed, and identification of any procedures which are experimental.
     (b) A description of any reasonably foreseeable risks or 
discomforts to the subject.
     (c) A description of any benefits to the subject or to others 
which may reasonably be expected from the research.
     (d) A disclosure of appropriate alternative procedures or courses 
of treatment, if any, that might be advantageous to the subject.
     (e) A statement that describes the extent, if any, to which 
confidentiality of records identifying the subject will be maintained, 
and that notes the possibility that FDA may inspect the records.
     (f) For research involving more than minimal risk, an explanation 
as to whether any compensation and any medical treatments are available 
if injury occurs and, if so, what they consist of or where further 
information may be obtained.
     (g) An explanation of whom to contact for answers to pertinent 
questions about the research and research subject's rights, and whom to 
contact in the event of research-related injury to the subject.
     (h) A statement that participation is voluntary, that refusal to 
participate will involve no penalty or loss of benefits to which the 
subject is otherwise entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which 
the subject is otherwise entitled.
2. Additional Elements of Informed Consent
     When appropriate, one or more of the following elements of 
information shall also be provided to each subject:
     (a) A statement that the particular treatment or procedure may 
involve risks to the subject (or the embryo or fetus, if the subject is 
or may become pregnant) which are currently unforeseeable.
     (b) Anticipated circumstances under which the subject's 
participation may be terminated by the investigator without regard to 
the subject's consent.
     (c) Any costs to the subject that may result from participation in 
the research.
     (d) The consequences of a subject's decision to withdraw from the 
research and procedures for orderly termination of participation by the 
subject.
     (e) A statement that significant new findings developed during the 
course of the research which may relate to the subject's willingness to 
continue participation will be provided to the subject.
     (f) The approximate number of subjects involved in the study.
     The informed consent requirements are not intended to preempt any 
applicable Federal, State, or local laws which require additional 
information to be disclosed for informed consent to be legally 
effective.
     Nothing in the notice is intended to limit the authority of a 
physician to provide emergency medical care to the extent that a 
physician is permitted to do so under applicable Federal, State, or 
local law.

III. Reporting Requirements

     An annual Financial Status Report (FSR) (SF-269) is required. The 
original and two copies of this report must be submitted to FDA's 
Grants Management Officer within 90 days of the budget expiration date 
of the grant. Failure to file the FSR in a timely fashion will be

[[Page 36834]]

grounds for suspension or termination of the grant.
     For continuing grants, an annual program progress report is also 
required. The noncompeting continuation application (PHS 2590) will be 
considered the annual program progress report.
     Additionally, all new and continuing grants must comply with all 
regulatory requirements necessary to maintain active status of their 
IND/IDE. This includes, but is not limited to, submission of an annual 
report to the appropriate regulatory review division within the FDA. 
Failure to meet regulatory requirements will be grounds for suspension 
or termination of the grant.
     Program monitoring of grantees will be conducted on an ongoing 
basis and written reports will be prepared by the project officer. The 
monitoring may be in the form of telephone conversations between the 
project officer/grants management specialist and the principal 
investigator. Periodic site visits with appropriate officials of the 
grantee organization may also be conducted. The results of these 
reports will be recorded in the official grant file and may be 
available to the grantee upon request consistent with FDA disclosure 
regulations. Additionally, the grantee organization will be required to 
comply with all special terms and conditions which state that future 
funding of the study will be contingent on recommendations from the OPD 
Project Officer verifying that: (1) There has been adequate progress 
toward enrollment, based on specific circumstances of the study; (2) 
there is an adequate supply of the product/device; and (3) there is 
continued compliance with all FDA regulatory requirements for the trial 
(e.g., annual report to IND/IDE file, communication of all protocol 
changes to the appropriate FDA Center, etc.).
     A final program progress report, FSR, and Invention Statement must 
be submitted within 90 days after the expiration of the project period 
as noted on the Notice of Grant Award.

IV. Mechanism of Support

A. Award Instrument

     Support will be in the form of a grant. All awards will be subject 
to all policies and requirements that govern the research grant 
programs of PHS, including the provisions of 42 CFR part 52 and 45 CFR 
parts 74 and 92. The regulations issued under Executive Order 12372 do 
not apply to this program.
     All grant awards are subject to applicable requirements for 
clinical investigations imposed by sections 505, 507, 512, and 515 of 
the act (21 U.S.C. 355, 357, 360b, and 360e), section 351 of the PHS 
act (42 U.S.C. 262), and regulations issued under any of these 
sections.

B. Eligibility

    These grants are available to any public or private nonprofit 
entity (including State and local units of government) and any for-
profit entity. For-profit entities must commit to excluding fees or 
profit in their request for support to receive grant awards. 
Organizations described in section 501(c)(4) of the Internal Revenue 
Code of 1968 that engage in lobbying are not eligible to receive grant 
awards.

C. Length of Support

     The length of the study will depend upon the nature of the study. 
For those studies with an expected duration of more than 1 year, a 
second or third year of noncompetitive continuation of support will 
depend on: (1) Performance during the preceding year; (2) the 
availability of Federal funds; and, (3) compliance with regulatory 
requirements of the IND/IDE.

D. Funding Plan

     The number of studies funded will depend on the quality of the 
applications received and the availability of Federal funds to support 
the projects. Before an award will be made, OPD will verify the active 
status of the IND/IDE for the proposed study. If the IND/IDE for the 
proposed study is not active or if an annual report has not been 
submitted to the IND file in the last 12 months, no award will be made. 
Further, documentation of IRB approvals for all performance sites must 
be on file with the Grants Management Officer, FDA (address above), 
before an award can be made.

V. Review Procedure and Criteria

A. Review Method

     All applications submitted in response to this request for 
applications (RFA) will first be reviewed by grants management and 
program staff for responsiveness to this RFA. If applications are found 
to be nonresponsive, they will be returned to the applicant without 
further consideration.
     Responsive applications will be reviewed and evaluated for 
scientific and technical merit by an ad hoc panel of experts in the 
subject field of the specific application. Responsive applications will 
also be subject to a second level of review by a National Advisory 
Council for concurrence with the recommendations made by the first-
level reviewers, and funding decisions will be made by the Commissioner 
of Food and Drugs.

B. Program Review Criteria

     Applications will be evaluated by program and grants management 
staff for responsiveness. Applications considered nonresponsive will be 
returned to the applicant, without being reviewed. Applicants are 
strongly encouraged to contact the FDA to resolve any questions 
regarding criteria prior to the submission of their application. All 
questions of a technical or scientific nature must be directed to the 
OPD program staff and all questions of an administrative or financial 
nature must be directed to the grants management staff. (See the ``For 
Further Information Contact'' section at the beginning of this 
document.) Responsiveness will be based on the following criteria:
     (1) The application must propose a clinical trial intended to 
provide safety and/or efficacy data of one therapy for one orphan 
indication. Additionally, there must be an explanation in the 
``Background and Significance'' section of how the proposed study will 
either facilitate product approval or provide essential data needed for 
product development.
     (2) The prevalence, not incidence, of population to be served by 
the product must be fewer than 200,000 individuals in the United 
States. The applicant should include, in the ``Background and 
Significance'' section, a detailed explanation supplemented by 
authoritative references in support of the prevalence figure. If the 
product has been designated by FDA as an orphan product for the 
proposed indication, a statement of that fact will suffice. Diagnostic 
tests and vaccines will qualify only if the population of intended use 
is fewer than 200,000 individuals in the United States per annum.
     (3) The number assigned to the IND/IDE for the proposed study 
should appear on the face page of the application with the title of the 
project. Only medical foods that do not require premarket approval are 
exempt from this requirement. The IND/IDE must be in active status and 
in compliance with all regulatory requirements of the FDA at the time 
of submission of the application. In order to meet this requirement, 
the original IND/IDE application, pertinent amendments, and the 
protocol for the proposed study must have been received by the 
appropriate FDA reviewing division a minimum of 30 days prior to the 
due

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date of the grant application. Studies of already approved products, 
evaluating new orphan indications, must also have an active IND. Exempt 
IND's must have their status changed to active to be eligible for this 
program. If the sponsor of the IND/IDE is other than the principal 
investigator listed on the application, a letter from the sponsor 
verifying access to the IND/IDE is required, and both the application's 
principal investigator and the study protocol must have been submitted 
to the IND/IDE.
     (4) The requested budget should be within the limits (either 
$100,000 in direct costs for each year for up to 3 years for any phase 
study, or $200,000 in direct costs for each year for up to 3 years for 
phase 2 or 3 studies) as stated in this request for applications.
     (5) Consent and/or assent forms, and any additional information to 
be given to a subject, should be included in the grant application.
     (6) All applicants should follow guidelines specified in the PHS 
398 Grant Application kit.

C. Scientific/Technical Review Criteria

     The ad hoc expert panel will provide the first level of review. 
The application will be judged on the following scientific and 
technical merit criteria:
     (1) The soundness of the rationale for the proposed study;
     (2) The quality and appropriateness of the study design to include 
the rationale for the statistical procedures;
     (3) The statistical justification for the number of patients 
chosen for the trial, based on the proposed outcome measures and the 
appropriateness of the statistical procedures to be used in analysis of 
the results;
     (4) The adequacy of the evidence that the proposed number of 
eligible subjects can be recruited in the requested timeframe;
     (5) The qualifications of the investigator and support staff, and 
the resources available to them;
     (6) The evidence that a sufficient quantity of the product is 
available to the applicant in the form needed for the investigation. A 
current letter from the supplier as an appendix will be acceptable;
     (7) The adequacy of the justification for the request for 
financial support;
     (8) The adequacy of plans for complying with regulations for 
protection of human subjects; and
     (9) The ability of the applicant to complete the proposed study 
within its budget and within time limitations stated in this RFA.
     The priority score will be based on the scientific/technical 
review criteria in section V.C of this document. In addition, the 
reviewers may advise the program staff concerning the appropriateness 
of the proposal to the goals of the OPD Grant Program described in 
section I of this document ``Program Research Goals.''

D. Award Criteria

     Resources for this program are limited. Therefore, should two or 
more applications be received and approved by FDA which propose 
duplicative or very similar studies, FDA will support only the study 
with the best score.

VI. Submission Requirements

     The original and five copies of the completed Grant Application 
Form PHS 398 (Rev. 5/95) or the original and two copies of the PHS 5161 
(Rev. 7/92) for State and local governments, with copies of the 
appendices for each of the copies, should be delivered to Robert L. 
Robins (address above). State and local governments may choose to use 
the PHS 398 application form in lieu of the PHS 5161. Application 
receipt dates are October 15, 1997, and March 15, 1998. If the receipt 
date falls on a weekend, it will be extended to Monday; if the date 
falls on a holiday, it will be extended to the following work day. No 
supplemental or addendum material will be accepted after the receipt 
date. Evidence of final IRB approval will be accepted for the file 
after the receipt date.
     The outside of the mailing package and item 2 of the application 
face page should be labeled, ``Response to RFA FDA OP-98-1''.
     If an application for the same study was submitted in response to 
the previous RFA, a submission in response to this RFA will be 
considered a request to withdraw the previous application. Applications 
originally submitted for the October closing date will also be 
administratively withdrawn, if resubmitted the following March. 
Resubmissions are treated as new applications; therefore, the applicant 
may wish to address the issues presented in the previous summary 
statements.

VII. Method of Application

A. Submission Instructions

     Applications will be accepted during normal working hours, 8 a.m. 
to 4:30 p.m., Monday through Friday, on or before the established 
receipt dates.
     Applications will be considered received on time if sent or mailed 
on or before the receipt dates as evidenced by a legible U.S. Postal 
Service dated postmark or a legible date receipt from a commercial 
carrier, unless they arrive too late for orderly processing. Private 
metered postmarks shall not be acceptable as proof of timely mailing. 
Applications not received on time will not be considered for review and 
will be returned to the applicant. (Applicants should note that the 
U.S. Postal Service does not uniformly provide dated postmarks. Before 
relying on this method, applicants should check with their local post 
office.)
    Do not send applications to the Division of Research Grants, 
National Institutes of Health (NIH). Any application that is sent to 
the NIH, that is then forwarded to the FDA and received after the 
applicable due date, will be deemed unresponsive and returned to the 
applicant. Instructions for completing the application forms can be 
found on the NIH home page on the Internet (address http://www.nih.gov/
grants/phs398/phs398.html; the forms can be found at http://
www.nih.gov/grants/phs398/forms_toc.html). However, as noted above, 
applications are not to be mailed to the NIH. Applicants are advised 
that the FDA does not adhere to the page limitations or the type size 
and line spacing requirements imposed by the NIH on its applications). 
Applications must be submitted via mail delivery as stated above. FDA 
is unable to receive applications via the Internet.

B. Format for Application

     Submission of the application must be on Grant Application Form 
PHS 398 (Rev. 5/95). All ``General Instructions'' and ``Specific 
Instructions'' in the application kit should be followed with the 
exception of the receipt dates and the mailing label address. Do not 
send applications to the Division of Research Grants, NIH. Applications 
from State and Local Governments may be submitted on Form PHS 5161 
(Rev. 7/92) or Form PHS 398 (Rev. 5/95).
     The face page of the application should reflect the request for 
applications number RFA-FDA-OP-98-1. The title of the proposed study 
should include the name of the product and the disease/disorder to be 
studied along with the IND/IDE number.
     Data included in the application, if restricted with the legend 
specified below, may be entitled to confidential treatment as trade 
secret or confidential commercial information within the meaning of the 
Freedom of Information Act (5 U.S.C. 552(b)(4)) and FDA's implementing 
regulations (21 CFR 20.61).
     Information collection requirements requested on Form PHS 398 and 
the instructions have been submitted by the

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PHS to the Office of Management and Budget (OMB) and were approved and 
assigned OMB control number 0925-0001.

C. Legend

     Unless disclosure is required by the Freedom of Information Act as 
amended (5 U.S.C. 552) as determined by the freedom of information 
officials of the Department of Health and Human Services or by a court, 
data contained in the portions of this application which have been 
specifically identified by page number, paragraph, etc., by the 
applicant as containing restricted information shall not be used or 
disclosed except for evaluation purposes.

    Dated: June 30, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-17799 Filed 7-8-97; 8:45 am]
BILLING CODE 4160-01-P