[Federal Register Volume 59, Number 156 (Monday, August 15, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-19915]


[[Page Unknown]]

[Federal Register: August 15, 1994]


-----------------------------------------------------------------------


DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing the 
following changes to its Orphan Products Development (OPD) grant 
program. Previously, the OPD program consisted of two separate requests 
for applications (RFA's) published simultaneously with one receipt date 
for all applications. These two RFA's are now combined into one notice 
with two receipt dates each year. Previously, announcements were 
published in the Federal Register annually. From now on, a notice will 
be published annually in the Federal Register referencing this 
announcement.The notice will remind eligible applicants of the receipt 
dates, the estimated amount of funds available, the estimated number of 
awards to be made in that fiscal year (FY), and any changes in 
programmatic requirements or criteria.

DATES: Application receipt dates are October 1, 1994, and January 15, 
1995. 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.

ADDRESSES: Application forms are available from, and completed 
applications should be submitted to: Robert L. Robins, Grants 
Management Officer, Grants and Agreements Management Branch (HFA-520), 
Food and Drug Administration, Park Bldg., rm. 3-40, 5600 Fishers Lane, 
Rockville, MD 20857, 301-443-6170.
    Note: Applications hand-carried or commercially delivered should 
be addressed to the Park Bldg., rm. 3-40, 12420 Parklawn Dr., 
Rockville, MD 20857. Do not send applications to the Division of 
Research Grants, National Institutes of Health (NIH).

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: Carol A. Wetmore 
or Patricia R. Robuck, Office of Orphan Products Development (HF-35), 
Food and Drug Administration, 5600 Fishers Lane, rm. 8-73, Rockville, 
MD 20857, 301-443-4903.

SUPPLEMENTARY INFORMATION: FDA is announcing the anticipated 
availability of funds for FY 1995 for awarding grants to support 
clinical trials on safety and effectiveness of products for rare 
diseases and conditions (i.e., those affecting fewer than 200,000 
people in the United States). Contingent on availability of FY 1995 
funds, it is anticipated that $12 million will be available, of which 
$6.2 million will be for noncompeting continuation awards. This will 
leave $5.8 million for funding the following: Approximately $2.9 
million for 20 grants (phase 1, 2, or 3 trials) up to $100,000 each in 
direct costs per annum plus applicable indirect costs for up to 3 
years, and approximately $2.9 million for 10 grants (phase 2 and 3 
trials only) up to $200,000 each in direct costs per annum plus 
applicable indirect costs for up to 2 years. Applications exceeding 
this direct cost limit will be considered nonresponsive and will be 
returned to the applicant. The current, active investigational new drug 
(IND) or investigational device exemption (IDE) number for the proposed 
study must appear on the face page of the application with the title of 
the project.
     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 promote the non-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) or ``Healthy People 2000'' (Summary Report, stock no. 017-001-
00473-1) through the Superintendent of Documents, Government Printing 
Office, Washington, DC 20402-9325, 202-783-3238.
    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 grants 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., a 
prevalence, not incidence, of fewer than 200,000 people in the United 
States). Diagnostic tests will qualify only if the U.S. population to 
be screened for the disorder is fewer than 200,000.
    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 promulgated 
thereunder. The grants are funded under the legislative authority of 
section 301 of the PHS Act.
    The goal of FDA's OPD grants program is to encourage clinical 
development of products for use in rare diseases or conditions where no 
current therapy exists, where current therapy would be improved, and/or 
where pivotal clinical trials would occur. In furtherance of this goal, 
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 
``Description'' section of the application of how their proposed study 
will either facilitate product approval or provide essential data 
needed for product development. The application will be considered 
nonresponsive without this explanation in the ``Description'' section. 
Information regarding meetings and/or discussions with FDA reviewing 
division staff about development of the product to be studied should 
also be provided in 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 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). In most cases, preliminary clinical 
research suggesting effectiveness and relative safety will already be 
available. Studies of already approved products evaluating new orphan 
indications are also acceptable and are required to have an IND or IDE 
for new labeling purposes.
    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 drug 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 the drug. Phase 3 trials gather 
additional information about effectiveness and safety that is necessary 
to evaluate the overall benefit-risk relationship of the drug 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.
    Applications should propose a clinical trial of one therapy for one 
indication. The applicant must provide supporting evidence that 
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 should carefully review the section on human subjects in 
the application kit. ``Section B. Specific Instructions--Forms, Item 4, 
Human Subjects,'' on pages 11 through 13 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 must 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 (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 Financial Status Report (SF-269) in a 
timely fashion will be 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.
    A final program progress report, Financial Status Report (SF-269), 
and Invention Statement must be submitted within 90 days after the 
expiration of the project period as noted on the Notice of Grant Award.
    Program monitoring of grantees will be conducted on an ongoing 
basis and written reports will be done 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 and/or a site visit with appropriate officials of the 
grantee organization. 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..

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 promulgated 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 promulgated 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.

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; and (2) the 
availability of Federal funds.

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, the status of the IND or 
the IDE will be verified. If the IND/IDE for the proposed study is not 
active or the proposed study has not been submitted to an ongoing IND/
IDE, 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 will first be reviewed by grants management and program 
staff for responsiveness to this request for applications. If 
applications are found to be nonresponsive, they will be returned to 
the applicant.
    Responsive applications will be reviewed and evaluated for 
scientific and technical merit by a 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. Responsiveness will be based on the following 
criteria:
    1. The application proposes a clinical trial to determine safety 
and/or efficacy of an orphan product. This should include an 
explanation in the ``Description'' 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 is fewer than 200,000 individuals in the United States. The 
applicant should include 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, a statement so 
stating 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. If applicants have questions, they may call program 
staff, listed above.
    3. The number assigned to the current, active IND/IDE for the 
proposed study must 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. Studies of already approved 
products evaluating new orphan indications are also required to have a 
current, active IND/IDE. 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.
    4. The requested budget must be within the limits (either $100,000 
in direct costs for up to 3 years or $200,000 in direct costs for up to 
2 years) as stated in this request for applications.
    Applications considered nonresponsive will be returned to the 
applicant.

C. Scientific/Technical Review Criteria

    For the first level of review, the scientific and technical merit 
criteria are:
    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;
    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 request 
for applications.
    The priority score will be based on the above Scientific/Technical 
review criteria. In addition, the reviewers may advise the program 
staff concerning the appropriateness of the proposal to the goals (I. 
Research Goals and Priorities, described above) of the OPD Grants 
Program.

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. 9/91) 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). Application receipt dates are October 1, 1994, 
and January 15, 1995. 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 material will be 
accepted after the receipt date. Evidence of final IRB approval will be 
accepted for the file after the receipt date, but it will not be sent 
out to the first level reviewers.
    The outside of the mailing package and item 2 of the application 
face page should be labeled, ``Response to RFA-FDA-OP-95-1.''
    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.

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 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.
    Note: Applicants should note that the U.S. Postal Service does 
not uniformly provide dated postmarks. Before relying on the method, 
applicants should check with their local post office.

B. Format for Application

    Submission of the application must be on Grant Application Form PHS 
398 (Rev. 9/91). 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 should be submitted on Form PHS 5161 
(Rev. 7/92).
    The face page of the application must reflect the request for 
applications number RFA-FDA-OP-95-1. The title of the proposed study 
must 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 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: August 10, 1994.
Ronald G. Chesemore,
Associate Commissioner for Regulatory Affairs.
[FR Doc. 94-19915 Filed 8-12-94; 8:45 am]
BILLING CODE 4160-01-F