[Federal Register Volume 64, Number 141 (Friday, July 23, 1999)]
[Notices]
[Pages 40012-40016]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-18771]


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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 changes 
to its Orphan Products Development (OPD) grant program for fiscal year 
(FY) 2000. The previous announcement of this program, which was 
published in the Federal Register of August 5, 1998 (63 FR 41855), is 
superseded by this announcement. In the future, a new announcement will 
be published annually.

DATES: The application receipt dates are November 15, 1999, and April 
3, 2000.

ADDRESSES: Application forms are available from, and completed 
applications should be submitted to: Maura C. Stephanos, Grants 
Management Specialist, Division of Contracts and Procurement Management 
(HFA-522), Food and Drug Administration, 5600 Fishers Lane, rm. 2129, 
Rockville, MD 20857, 301-827-7183. (Applications hand-carried or 
commercially delivered should be addressed to 5630 Fishers Lane, rm. 
2129, Rockville, MD 20852.)

FOR FURTHER INFORMATION CONTACT:
     Regarding the administrative and financial management aspects of 
this notice: Maura C. Stephanos (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 2000 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 2000 funds, it is anticipated that $11.5 million 
will be available, of which $8.5 million will be for noncompeting 
continuation awards. This will leave $3 million for funding 
approximately 10 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 phase 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 
that 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.

[[Page 40013]]

    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 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 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. If a 
study is submitted as a phase 1/2 trial, the maximum budget support for 
all years requested may not exceed $100,000 per year. 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. Protection of Human Research Subjects

    Some activities carried out by a recipient under this announcement 
may be governed by the Department of Health and Human Services (DHHS) 
regulations for the protection of human research subjects (45 CFR part 
46). These regulations require recipients to establish procedures for 
the protection of subjects involved in any research activities. Prior 
to funding and upon request of the Office for Protection from Research 
Risks (OPRR), prospective recipients must have on file with OPRR an 
assurance to comply with 45 CFR part 46. This assurance to comply is 
called an Assurance document. It includes the designated Institutional 
Review Board (IRB) for review and approval of procedures for carrying 
out any research activities occurring in conjunction with this award. 
If an applicable Assurance document for the applicant is not already on 
file with OPRR, a formal request for the required Assurance will be 
issued by OPRR at an appropriate point in the review process, prior to 
award, and examples of required materials will be supplied at that 
time. No applicant or performance site, without an approved and 
applicable Assurance on file with OPRR, may spend funds on human 
subject activities or accrue subjects. No performance site, even with 
an OPRR-approved and applicable Assurance, may proceed without approval 
by OPRR of an applicable Assurance for the recipients. Applicants may 
wish to contact OPRR by fax (301-402-0527) to obtain preliminary 
guidance on human subjects issues. When contacting OPRR, applicants 
should provide their institutional affiliation, geographic location, 
and all available Request For Applications (RFA) citation information.
     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 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. Those approved 
applicants who do not have a current Multiple Project Assurance with 
OPRR will be required to obtain a Single Project Assurance from OPRR 
prior to award.

 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

[[Page 40014]]

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.
    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, a Final Financial Status Report 
(SF-269), and an 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, 512, 
and 515 of the act (21 U.S.C. 355, 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

[[Page 40015]]

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 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 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 FOR FURTHER 
INFORMATION CONTACT section 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 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 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. 
Multi-phase studies that include phase I are only eligible for $100,000 
per annum for the entire 3-year period. Any application received that 
requests support in excess of the maximum amount allowable for that 
particular study will be considered nonresponsive and returned to the 
applicant unreviewed.
    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.
    7. Evidence that a sufficient quantity of the product is available 
to the applicant in the form needed for the investigation must be 
included in the application. A current letter from the supplier as an 
appendix will be acceptable.

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 adequacy of the justification for the request for financial 
support;
    7. The adequacy of plans for complying with regulations for 
protection of human subjects; and
    8. 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 
(Program Research Goals) of this document.

 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 Maura C. 
Stephanos (address above). State and local governments may choose to 
use the PHS 398 application form in lieu of the PHS 5161. The 
application receipt dates are November 15, 1999 and April 3, 2000. 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.

[[Page 40016]]

    The outside of the mailing package and item 2 of the application 
face page should be labeled, ``Response to RFA FDA OPD-2000.''
    If an application for the same study was submitted in response to a 
previous RFA, but has not yet been acted upon, a submission in response 
to this RFA will be considered a request to withdraw the previous 
application. Resubmissions are treated as new applications; therefore, 
the applicant may wish to address the issues presented in the summary 
statements from the previous review.

 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 Center for Scientific Research 
(CSR), National Institutes of Health (NIH). Any application that is 
sent to the NIH, that is then forwarded to 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/funding/phs398/phs398.html''; the forms can be found 
at ``http://www.nih.gov/grants/funding/phs398/forms_toc.html''). 
However, as noted previously, 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 previously. 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 CSR, 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-OPD-000. 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. The format for all subsequent 
pages of the application should be single-spaced and single-side.
    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 DHHS 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: July 15, 1999
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-18771 Filed 7-22-99; 8:45 am]
BILLING CODE 4160-01-F