[Federal Register Volume 67, Number 166 (Tuesday, August 27, 2002)]
[Notices]
[Pages 55020-55024]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-21736]


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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 (Catalog of Federal 
Domestic Assistance No. 93.103)

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing changes 
to its Office of Orphan Products Development (OPD) grant program for 
fiscal year (FY) 2003. This announcement supercedes the previous 
announcement of this program, which was published in the Federal 
Register on August 27, 2001.

DATES: The application receipt dates are October 16, 2002, and April 2, 
2003.

ADDRESSES: Application requests and completed applications should be 
submitted to Maura Stephanos, Grants Management Specialist, Grants 
Management Staff, Division of Contracts and Procurement Management 
(HFA-520), Food and Drug Administration, 5600 Fishers Lane, Rockville, 
MD 20857, 301-827-7183, FAX 301-827-7101, e-mail: [email protected]. 
Applications that are hand-carried or commercially delivered should be 
addressed to 5630 Fishers Lane, rm. 2129, Rockville, MD 20857. 
Applications may also be obtained from the OPD on the Internet at 
http://www.fda.gov/orphan or at http://grants.nih.gov/grants/funding/phs398/phs398.html. Note: Do not send applications to the Center for 
Scientific Research (CSR), National Institutes of Health (NIH).

FOR FURTHER INFORMATION CONTACT:
    Regarding the administrative and financial management issues of 
this notice: Maura Stephanos (see ADDRESSES).
    Regarding the programmatic issues of this notice: Debra Y. Lewis, 
Office of Orphan Products Development (HF-35), Food and Drug 
Administration, 5600 Fishers Lane, rm. 15A-08, Rockville, MD 20857, 
301-827-3666, FAX 301-827-0017, e-mail: [email protected].

SUPPLEMENTARY INFORMATION: 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 acceptable; 
however, these must also be conducted under an IND or IDE to support a 
change in labeling. The study protocol proposed in the grant 
application must be under an active IND or IDE (not on clinical hold) 
to qualify the application for scientific and technical review. (See 
Program Review Criteria for important information about the IND/IDE 
status of products to be studied under these grants.)
    Except for medical foods that do not need premarket approval, FDA 
will only consider awarding grants to support premarket clinical 
studies to find out whether the products are safe and effective for 
approval under section 301 of the Federal Food, Drug, and Cosmetic Act 
(the act) (21 U.S.C. 331 et seq.) or under section 351 of the Public 
Health Service Act (the PHS Act) (42 U.S.C. 262).
    FDA will support the clinical studies covered by this notice under 
the authority of section 301 of the PHS Act. 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 workplace 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.

[[Page 55021]]

    PHS's policy is that applicants for PHS clinical research grants 
should include minorities and women in study populations so research 
findings can be of benefit to all people at risk of the disease, 
disorder, or condition under study. Special emphasis should be placed 
on the need for inclusion of minorities and women in studies of 
diseases, disorders, and conditions that disproportionately affect 
them. This policy applies to research subjects of all ages. If women or 
minorities are excluded or poorly represented in clinical research, the 
applicant should provide a clear and compelling rationale that shows 
inclusion is inappropriate.
    FDA is committed to achieving the health promotion and disease 
prevention objectives of ``Healthy People 2010,'' a national effort 
designed to reduce morbidity and mortality and to improve quality of 
life. Applicants may obtain a paper copy of the ``Healthy People 2010'' 
objectives, vols. I and II, for $70 ($87.50 foreign) S/N 017-000-00550-
9, by writing to the Superintendent of Documents, P.O. Box 371954, 
Pittsburgh, PA 15250-7954. Telephone orders can be placed to 202-512-
2250. The document is also available in CD-ROM format, S/N 017-001-
00549-5 for $19 ($23.50 foreign) as well as on the Internet at http://health.gov/healthypeople/. Internet viewers should proceed to 
``Publications.''

I. Program Research Goals

    OPD was created to identify and promote the development of orphan 
products. Orphan products are drugs, biologics, medical devices, and 
foods for medical purposes that are indicated for a rare disease or 
condition (that is, 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 fewer than 
200,000 people a year.
    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 the product will improve the existing therapy. 
FDA provides grants for clinical studies that will either result in or 
substantially contribute to market approval of these products. 
Applicants should keep this goal in mind and must include an 
explanation in the application's ``Background and Significance'' 
section of how their proposed study will either help gain product 
approval or provide essential data needed for product development. All 
funded studies are subject to the requirements of the act and 
regulations issued under it.

II. Award Amounts

    FDA is announcing the expected availability of FY 2003 funds for 
awarding grants to support clinical studies on the safety and 
effectiveness of products (drugs, biologics, and devices) for rare 
diseases or conditions (that is, with a prevalence, not incidence, of 
fewer than 200,000 people in the United States).
    Of the estimated FY 2003 funding ($13.3 million), approximately 
$9.3 million will fund noncompeting continuation awards, and 
approximately $4 million will fund 12 to 15 new awards. In the first 
part of the funding cycle, approximately $1 million will be awarded to 
successful applications received by the October 16, 2002, due date 
(with the award starting after March 1, 2003). All applications 
recommended for approval that are not funded in the first part of the 
cycle will remain in competition for the second part of the funding 
cycle with applications received by the April 2, 2003, due date. The 
expected start date for these awards will be September 30, 2003. 
Applications submitted for the first due date may be withdrawn and 
resubmitted for the second due date.
    Any phase (1, 2, or 3) clinical trial is eligible for up to 
$150,000 in direct costs a year, plus applicable indirect costs, for up 
to 3 years. Phase 2 and 3 clinical trials are also eligible for up to 
$300,000 in direct costs a year, plus applicable indirect costs, for up 
to 3 years. Study proposals for the smaller grants ($150,000) may be 
for phase 1, 2, or 3 clinical trials. Study proposals for the larger 
grants ($300,000) 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 more information about effectiveness and safety 
that is necessary to evaluate the overall risk-benefit ratio of the 
product and to provide an acceptable basis for product labeling. 
Budgets for all years of requested support may not exceed the $150,000 
or $300,000 direct cost limit, whichever is applicable.

III. Human Subject Protection and Informed Consent

A. Protection of Human Research Subjects

    All institutions engaged in human subject research supported by the 
Department of Health and Human Services (DHHS) must file an 
``assurance'' of protection for human subjects with the Office for 
Human Research Protection (OHRP) (45 CFR part 46). Applicants are 
advised to visit the OHRP Internet site at http://ohrp.osophs.dhhs.gov/ 
for guidance on human subjects issues. The requirement to file an 
assurance includes both ``awardee'' and collaborating ``performance 
site'' institutions. Awardee institutions are automatically considered 
to be engaged in human subject research whenever they receive a direct 
DHHS award to support such research, even where all activities 
involving human subjects are carried out by a subcontractor or 
collaborator. In such cases, the awardee institution bears the ultimate 
responsibility for protecting human subjects under the award. The 
awardee institution is also responsible for ensuring that all 
collaborating performance site institutions engaged in the research 
hold an approved assurance prior to their initiation of the research. 
No awardee or performance site institution may spend funds on human 
subject research or enroll subjects without the approved and applicable 
assurance(s) on file with OHRP.
    Applicants must also provide certification of Institutional Review 
Board (IRB) review and approval for every site taking part in the 
study. This documentation need not be on file with the FDA Grants 
Management Office prior to the award, but must be on file before 
research can begin at a site.
    Applicants should review the section on human subjects in the 
application instructions entitled ``I. Preparing Your Application, 
Section C. Specific Instructions, Item 4, Human Subjects'' for further 
information.

B. Key Personnel Human Subject Protection Education

    The awardee institution should ensure that all key personnel 
receive appropriate training in their human subject protection 
responsibilities. Key personnel include all principal investigators, 
co-investigators, and performance site investigators responsible for 
the design and conduct of the study. Within 30 days of award, the 
principal investigator should provide a letter which includes the names 
of the key personnel, the title of

[[Page 55022]]

the human subjects protection education program completed by each named 
personnel, and a one-sentence description of the program. This letter 
should be signed by the principal investigator and co-signed by an 
institution official and sent to the Grants Management Office. Neither 
DHHS, FDA, or OPD prescribe or endorse any specific education programs. 
Many institutions have already developed educational programs on the 
protection of research subjects and have made participation in such 
programs a requirement for their investigators. Other sources of 
appropriate instruction might include the online tutorials offered by 
the Office of Human Subjects Research, NIH at http://ohsr.od.nih.gov/ 
and by OHRP at http://ohrp.osophs.dhhs.gov/educmat.htm. Also, the 
University of Rochester has made available its training program for 
individual investigators. Their manual can be obtained through 
Centerwatch, Inc., at http://www.centerwatch.com.

C. Informed Consent

    Consent forms, assent forms, and any other information given to a 
subject, should be sent with the grant application (even if such a form 
is in a draft version). Information given to the subject or his or her 
representative must be in language the subject or representative can 
understand. No informed consent, whether verbal or written, may include 
any language through which the subject or representative waives 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. The applicant is 
referred to DHHS regulations at 45 CFR 46.116 and 21 CFR 50.25 for 
details regarding the (required) elements of informed consent.

IV. Reporting Requirements

    The original and two copies of the annual Financial Status Report 
(FSR) (SF-269) must be sent to FDA's grants management officer within 
90 days of the budget period end date of the grant. Failure to file the 
FSR 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. Also, all new 
and continuing grants must comply with all regulatory requirements 
necessary to keep active status of their IND/IDE. Failure to meet 
regulatory requirements will be grounds for suspension or termination 
of the grant.
    The program project officer will monitor grantees quarterly and 
will prepare written reports. The monitoring may be in the form of 
telephone conversations or e-mail between the project officer/grants 
management specialist and the principal investigator. Periodic site 
visits with officials of the grantee organization may also occur. The 
results of these reports will be recorded in the official grant file 
and may be available to the grantee on request consistent with FDA 
disclosure regulations. Also, the grantee organization must comply with 
all special terms and conditions, which state that future funding of 
the study will depend on recommendations from the OPD project officer. 
The scope of the recommendations will confirm that: (1) There has been 
acceptable 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.
    The grantee must file a final program progress report, FSR and 
invention statement within 90 days after the end date of the project 
period as noted on the notice of grant award.

V. 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 the 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. The NIH modular grant program does not 
apply to this FDA grant 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

    The grants are available to any foreign or domestic, public or 
private nonprofit entity (including state and local units of 
government) and any foreign or domestic, 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 lobby are not 
eligible to receive grant awards.

C. Length of Support

    The length of support will depend on 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) Federal funds 
availability, 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. Resources for this program are limited. Therefore, if two 
applications propose duplicative or similar studies, FDA may support 
only the study with the better score. Funds may be requested in the 
budget to travel to FDA for meetings with OPD or reviewing division 
staff about the progress of product development.
    Before an award will be made, the OPD will confirm the active 
status of the protocol under the IND/IDE. If the protocol is under FDA 
clinical hold for any reason, no award will be made. Also, if the IND/
IDE for the proposed study is not active and in regulatory compliance, 
no award will be made. Documentation of IRB approvals for all 
performance sites must be on file with the FDA Grants Management Office 
before research can begin at that site. This grant program does not 
require the applicant to match or share in the project costs if an 
award is made.

VI. Review Procedures and Criteria

A. Review Procedures

    FDA's grants management and program staff will review all 
applications sent in response to this notice. To be responsive, an 
application must: (1) Be received by the specified due date; (2) be 
submitted in accordance with sections V.B ``Eligibility,'' VII 
``Submission Requirements,'' and VIII.A ``Submission Instructions'' of 
this notice; (3) not exceed the recommended funding amount stated in 
section II ``Award Amounts'' of this document; (4) be in compliance 
with the following section VI.B `` Program Review Criteria;'' and (5) 
bear the original signatures of both the principal investigator and the 
Institution's/Organization's Authorized Official. Applications found to 
be nonresponsive

[[Page 55023]]

will be returned to the applicant without further consideration 
(unreviewed). Applicants are strongly encouraged to contact FDA to 
resolve any questions about criteria before submitting their 
application. Please direct all questions of a technical or scientific 
nature to the OPD program staff and all questions of an administrative 
or financial nature to the grants management staff (see ADDRESSES).
    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. Consultation with the proper 
FDA review division may also occur during this phase of the review to 
determine whether the proposed study will provide acceptable data that 
could contribute to product approval. Responsive applications will be 
subject to a second 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

    Program review criteria include the following:
    1. The application must propose a clinical trial intended to 
provide safety and/or efficacy data of one therapy for one orphan 
indication.
    2. There must be an explanation in the ``Background and 
Significance'' section of how the proposed study will either contribute 
to product approval or provide essential data needed for product 
development.
    3. The prevalence, not incidence, of the 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. 
Diagnostic tests and vaccines will qualify only if the population of 
intended use is fewer than 200,000 individuals in the United States per 
year.
    4. The study protocol proposed in the grant application must be 
under an active IND or IDE (not on clinical hold) to qualify the 
application for scientific and technical review. Additional IND/IDE 
information is described below:
     The proposed clinical protocol should be submitted to the 
FDA IND/IDE reviewing division a minimum of 30 days before the grant 
application deadline.
     The number assigned to the IND/IDE that includes the 
proposed study should appear on the face page of the application with 
the title of the project. The date the subject protocol was submitted 
to FDA for the IND/IDE review should also be provided.
     Protocols that would otherwise be eligible for an 
exemption from the IND regulations must be conducted under an active 
IND to be eligible for funding under this FDA grant program.
     If the sponsor of the IND/IDE is other than the principal 
investigator listed on the application, a letter from the sponsor 
permitting access to the IND/IDE must be submitted. Both the name of 
the principal investigator identified in the application and the study 
protocol must have been submitted to the IND/IDE.
     Studies of already approved products, evaluating new 
orphan indications, are also subject to these IND/IDE requirements.
     Only medical foods that do not need premarket approval are 
exempt from these IND/IDE requirements.
    5. The requested budget must be within the limits (either $150,000 
in direct costs for each year for up to 3 years for any phase study, or 
$300,000 in direct costs for each year for up to 3 years for phase 2 or 
3 studies) as stated in this notice. Any application received that 
requests support over the maximum amount allowable for that particular 
study will be considered nonresponsive.
    6. Proposed consent forms, assent forms, and any other information 
given to a subject, should be included in the grant application (even 
if they are in a draft version).
    7. Evidence that the product to be studied is available to the 
applicant in the form and quantity needed for the clinical trial must 
be included in the application. A current letter from the supplier as 
an appendix will be acceptable.
    8. Applicants must follow guidelines named in the PHS 398 (Rev. 5/
01) grant application instructions.

C. Scientific/Technical Review Criteria

    The ad hoc expert panel will review the application based 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 including 
the rationale for the statistical procedures.
    3. The statistical justification for the number of patients chosen 
for the study, based on the proposed outcome measures and the 
appropriateness of the statistical procedures for 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.
    8. The ability of the applicant to complete the proposed study 
within its budget and within time limits stated in this RFA.
    A score will be assigned based on the above scientific/technical 
review criteria. The review panel may advise the program staff about 
the appropriateness of the proposal to the goals of the OPD grant 
program described in the section I ``Program Research Goals'' of this 
document.

VII. Submission Requirements

    The original and two copies of the completed Grant Application Form 
PHS 398 (Rev. 5/01) or the original and two copies of PHS 5161-1 (Rev. 
7/00) for State and local governments, with three copies of the 
appendices should be submitted to Maura Stephanos (see ADDRESSES). 
State and local governments may use the PHS 398 (Rev. 5/01) application 
form in lieu of the PHS 5161-1. The application receipt dates are 
October 16, 2002, and April 2, 2003. The only material will be accepted 
after the receipt date is evidence of final IRB approval. The mailing 
package and item 2 of the application face page should be labeled, 
``Response to RFA-FDA-OPD-2003.'' If an application for the same study 
was submitted in response to a previous RFA but has not yet been 
funded, an application in response to this notice 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 statement from the previous review, and 
include a copy of the summary statement itself as part of the 
application.

VIII. Method of Application

A. Submission Instructions

    Applications will be accepted during normal working hours, from 8 
a.m. to 4:30 p.m., Monday through Friday, by the established receipt 
dates. Applications will be considered received on time if sent or 
mailed by the receipt dates as shown by a legible U.S. Postal Service 
dated postmark or a legible date receipt from a commercial carrier. 
Private metered postmarks shall

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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 the U.S. Postal Service does not 
uniformly provide dated postmarks. Before relying on this method, 
applicants should check with their local post office.) Please do not 
send applications to the CSR at NIH. Any application sent to NIH that 
is then forwarded to FDA and received after the applicable due date 
will be judged nonresponsive and returned to the applicant. 
Applications must be submitted via mail or hand delivered as stated 
above. FDA is unable to receive applications electronically.

B. Format for Application

    Submission of the application must be on Grant Application Form PHS 
398 (Rev. 5/01). Applications from State and local governments may be 
sent on Form PHS 5161-1 (Rev. 7/00) or Form PHS 398 (Rev. 5/01). All 
``General Instructions'' and ``Specific Instructions'' in the 
application kit should be followed except for the receipt dates and the 
mailing label address. The face page of the application should reflect 
the request for applications number RFA-FDA-OPD-2003. The title of the 
proposed study should include the name of the product and the disease/
disorder to be studied and the IND/IDE number. The format for all 
following pages of the application should be single-spaced and single-
sided. FDA does not adhere to the page limits or the type size and line 
spacing requirements imposed by NIH on its applications.
    Applicants have the option of omitting from the application copies 
(not the original) specific salary rates or amounts for individuals 
specified in the application budget and Social Security numbers if 
otherwise required for individuals. The copies may include summary 
salary information.
    Data and information included in the application will generally not 
be publicly available prior to the funding of the application. Data and 
information included in the application, if identified by the applicant 
as trade secret or confidential commercial information, will be given 
confidential treatment to the extent permitted by the Freedom of 
Information Act (5 U.S.C. 552(b)(4)) and FDA's implementing regulations 
(including inter alia 21 CFR 20.61) even after funding has been 
granted. Information collection requirements requested on Form PHS 398 
(Rev. 5/01) have been sent by the PHS to the Office of Management and 
Budget (OMB) and have been approved and assigned OMB control number 
0925-0001. The requirements requested on Form PHS 5161-1 (Rev. 7/00) 
were approved and assigned OMB control number 0348-0043.
    Applicants should provide a summary of any meetings or discussions 
about the clinical study that have occurred with FDA reviewing division 
staff as an appendix to the application.

    Dated: August 21, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-21736 Filed 8-26-02; 8:45 am]
BILLING CODE 4160-01-S