[Federal Register Volume 62, Number 24 (Wednesday, February 5, 1997)]
[Notices]
[Pages 5429-5432]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-2870]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Studies of Adverse Effects of Marketed Drugs, Biologics, and 
Devices; Availability of Grants (Cooperative Agreements); Request for 
Applications

Agency: Food and Drug Administration, HHS.
Action: Notice.

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SUMMARY: The Food and Drug Administration (FDA), Center for Drug 
Evaluation and Research, is announcing the availability of $1.4 million 
in Fiscal Year 1997 funds for cooperative agreements to study adverse 
effects of marketed drugs, biologics, and devices. This amount is 
consistent with the level of funding in the President's budget. FDA 
expects to make four to six awards in the range of $250,000 to $350,000 
for direct and indirect costs. The Government's obligation is 
contingent upon the availability of appropriated funds from which the 
cooperative agreements will be funded. The purpose of these agreements 
is to conduct drug, biologic, and device safety analysis for public 
health benefit; respond expeditiously to urgent public safety concerns; 
provide a mechanism for collaborative pharmacoepidemiological research 
designed to test hypotheses, particularly those arising from suspected 
adverse reactions reported to FDA; and enable rapid access to multiple 
data sources to ensure public safety when necessary.

DATES: Application receipt date is March 21, 1997.

ADDRESSES: Application kits 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, 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. Please 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: Charles M. 
Maynard, Division of Pharmacovigilance and Epidemiology (HFD-733), Food 
and Drug Administration, 5600 Fishers Lane, rm. 15B-18, Rockville, MD 
20857, 301-827-3187.

SUPPLEMENTARY INFORMATION: FDA's authority to fund research projects is 
set out in 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. Applications submitted under 
this program are not subject to the requirements of Executive Order 
12372.

I. Background

    New drugs, biologics, and devices are required to undergo extensive 
testing before marketing. With the submission of adequate data on 
safety and effectiveness, FDA approves a new drug, biologic, and device 
application (NDA/PLA/PMA) that permits a manufacturer to market its 
product in the United States. Although the information provided before 
marketing is sufficient for approval, it is not adequate to anticipate 
all effects of a product once it comes into general use.
    This request for applications (RFA) is intended to encourage 
collaboration between FDA and researchers with pharmacoepidemiological 
data bases to address postmarketing issues confronting the agency. FDA 
is also interested in the ability to measure and/or estimate incidence 
rates and test hypotheses based on signals of possible drug, biologic, 
and device safety problems originating from reports of adverse 
reactions received by FDA.

II. Program Research Goals

    FDA would prefer to fund a variety of data bases representing, 
without overlap, different patient populations and/or types of patient 
care settings. The data bases maintained through these agreements must 
be able to: (1) Provide data on exposure to new chemical entities; (2) 
perform feasibility studies of multiple drugs and/or multiple outcomes; 
(3) identify adverse drug, biologic, and device events that occur 
infrequently; and (4) provide a substantive response within a very 
short timeframe.
    The goal for these cooperative agreements is to investigate 
suspected associations between specific drug and

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possible biologic and device exposures and specific adverse events and 
to quantitate such risk. The specific objectives are to: (1) Provide 
immediate access to existing data sources with the capability of 
providing assessments of study feasibility; (2) respond to particular 
drug, biologic, and device safety questions within a few weeks; and (3) 
provide a substantive response to those questions deemed feasible 
within a few months.
Data base characteristics should include the ability to:
    (1) Estimate adverse event rates or relative risks for specific 
event.
    (2) Estimate the contribution of various risk factors associated 
with the occurrence of adverse events (e.g., age, sex, dose, coexisting 
disease, disease severity, concomitant medication).
    (3) Determine adverse event rates for generic entities as well as 
for classes of drugs.
    (4) Determine rate and depth of usage of new drugs into the 
formulary.
    (5) Obtain data from laboratory results.
    (6) Link to state vital statistics, if possible.
    (7) Link to cancer registry.
    (8) Determine inpatient exposure.
    (9) Long term followup of exposure and outcomes.
    (10) Determine adverse events related to vaccines.
    (11) Ability to follow cohort (retrospectively or prospectively) 
based on device exposure or clinical diagnosis for case-control or 
cohort studies.
    (12) Ability to study all medical devices, especially newer 
technologies approved by FDA since 1990.
In addition, FDA is interested in data bases capable of innovatively 
applying the objectives stated above to specifically defined 
populations including but not limited to children, pregnant women, and 
the elderly.
    The ideal data source would capture all drug exposures linked 
longitudinally to each patient regardless of health care delivery 
setting. Because the outcomes of interest could be either acute or 
chronic effects, all health provider encounters, i.e., medical records, 
would be captured whether in the ambulatory, emergency, chronic care, 
or acute care setting. The ideal data source would have the statistical 
power to identify rare adverse events in the population of interest. 
The ideal data base would also be automated with a computerized system 
available for linking each patient to all relevant medical care data 
including drugs, biologics, and device exposure data, coded medical 
outcomes, vital records, cancer registries, and birth defect 
registries. Additional points would be awarded for linkage of data 
bases to laboratory values and easy accessibility of records. The 
location and accessibility of the medical records are very important 
concerns to FDA. For rare events, the capability of performing case-
control studies is valuable.
    Submitted applications must include an indepth description of the 
data base and provide descriptive and quantitative information on 
diagnoses of drug, biologic, and device exposures in the population. 
The quality and validity of the data should be described in detail.

III. Reporting Requirements

    Program progress reports will be required quarterly. These reports 
must be submitted within 30 days after the last day of each quarter 
based on the budget period of the cooperative agreement. Financial 
Status Reports (SF-269) will be required annually. These reports must 
be submitted within 90 days after the last day of the budget period of 
the cooperative agreement. Failure to file the Financial Status Report 
(SF-269) in a timely fashion will be grounds for suspension or 
termination of the grant.
    Program monitoring of the 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 and/or 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.
    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.
    Up to two representatives from each cooperative agreement may be 
required, if requested by the Project Officer, to travel to FDA up to 
twice a year for no more than 2 days at a time. These meetings will 
include, but are not limited to, presentations on study design and 
findings and discussions with the FDA staff involved in the 
collaborative research. At least one FDA employee may visit the 
cooperative agreement site at least once a year for collaboration and 
information exchange.

IV. Mechanism of Support

A. Award Instrument

    Support of this program will be in the form of cooperative 
agreements. All awards will be subject to all policies and requirements 
that govern the research grant programs of the Public Health Service 
(PHS), including the provisions of 42 CFR part 52, 45 CFR parts 74 and 
92, and PHS Grants Policy Statement.

B. Eligibility

    These cooperative agreements are available to any public or private 
nonprofit organization (including State, local, and foreign units of 
government) and any for-profit organization. For profit organizations 
must exclude fees or profit from their requests for support. 
Organizations described in section 501(c)4 of the Internal Revenue Code 
of 1968 that engage in lobbying are not eligible to receive grant/
cooperative agreement awards.

C. Length of Support

    The length of support will depend upon the nature of the study and 
may extend beyond 1 year, but may not exceed 3 years. The first year 
will be competitive and the remaining 2 years will be noncompetitive. 
Future support will be contingent upon: (1) Performance during the 
preceding year, and (2) the availability of Federal fiscal year 
appropriations.

D. Funding Plan

    The number of cooperative agreements funded will depend on the 
quality of the applications received and the availability of Federal 
funds to support the projects. $1.4 million is budgeted for this 
program. It is anticipated that four to six awards will be made for 
approximately $250,000 to $350,000 total direct and indirect cost. 
Federal funds for this program are limited. Therefore, should FDA 
approve two or more applications that propose duplicative or very 
similar data resources, FDA will support only the source with the best 
score.

V. Delineation of Substantive Involvement

    Program support will be offered through cooperative agreements 
because FDA will have a substantive involvement in the programmatic 
activities of all the projects funded under this RFA. Involvement may 
be modified to fit the unique characteristics of each application. 
Substantive involvement includes, but is not limited to the following:

[[Page 5431]]

    1. FDA staff will participate in the selection and approval of the 
drug, biologic, and device exposures and medical events to be studied 
predicated upon public health needs. The drug exposure and medical 
events to be studied will be jointly agreed upon by the extramural 
investigator and the FDA staff.
    2. FDA scientists will collaborate with awardees in study design 
and data analysis. Collaboration may include sharing of the analysis 
data set, interpretation of findings, review of manuscripts, and where 
appropriate, coauthorship of publications.

VI. Review Procedure and Criteria

A. Review Procedure

    All applications submitted must be responsive to the RFA. Those 
applications found to be nonresponsive will not be considered for 
funding under this RFA and will be returned to the applicant.
    Responsive applications will undergo dual peer review. An external 
review panel of experts in the fields of epidemiology, statistics, and 
data base management will review and evaluate each application based on 
its scientific merit. Responsive applications will also be subject to a 
second level review by the National Advisory Environmental Health 
Science 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. Review Criteria

    Applications will be reviewed according to the following criteria 
with each criteria being of equal weight. All applications will be 
scored with a maximum of 100 points allowable.
    1. Size and Characteristics of the Data Base (67 points). The size 
and characteristics of the data base should include the following:
    a. A large population size of individuals for whom drug, device, 
and biologic exposure and medical outcome data are available. Our goal 
will be to award data bases with a population of at least 2,000,000 
current enrollees. No points will be awarded for data bases with a 
population size of less than 250,000. Data bases comprised of only one 
of the special populations for which data are desired (i.e., children, 
pregnant women, and the elderly) may be awarded full points for smaller 
population sizes. Investigators who mainly use a case-control design, 
should be able to provide information on at least 500 cases of a 
specific disease or disorder and exposure primarily to new molecular 
entities.
    b. Ability to assemble and follow (retrospectively or 
prospectively) well defined cohorts based on drug, device, and biologic 
exposure or clinical diagnosis for the purpose of performing case-
control or cohort studies.
    c. Ability to access and to link to the patient all health provider 
encounters and drug, biologic, and device exposure information 
regardless of patient care setting. Full points will be awarded to data 
bases that capture full drug, device, and biologic exposure and in-
patient outcome data from hospital, ambulatory care and long-term care 
settings.
    d. Ability to detect rare adverse drug, biologic, or device events 
in one or more specific target populations of interest (i.e., children, 
pregnant women, and the elderly).
    e. Ability to study all drug products especially new molecular 
entities (NME's) approved by FDA since 1991 and newly approved medical 
devices and biologics.
    f. Ability to ascertain patient enrollment and turnover rates as 
demonstrated by descriptions of the entry and dropout rates and the 
average length of enrollment. For investigators primarily employing the 
case control design, ability to attain complete and unbiased 
ascertainment of cases and controls.
    g. A standard set of drug and disease classification systems.
    h. Ability to successfully retrieve a high proportion of medical 
records (sufficient to address the issue presented ) in a timely 
fashion. Documentation of a large proportion of medical records 
retrieved in a specified time period should be included.
    i. Ability to link to cancer registry and to state vital 
statistics.
    j. Ability to identify risk factors for drug-associated outcomes 
and assess potential confounders.
    k. Ability to assess drug interactions.
    l. A long calendar time period for which data are available and 
longitudinally linkable. No points will be awarded to data bases with 
less than 2 years of history.
    m. A short lag time (< 6 months) between patient events 
(hospitalization, etc.) and availability of clean data.
    2. Information Systems and Software Capabilities (12 points). 
Information systems and software capabilities should include the 
following:
    a. A well defined and acceptable description of computer resources 
and the extent of automation and software capabilities.
    b. Availability of computerized data elements (in patient drugs and 
diagnoses, outpatient drugs and diagnostic procedures, medical records) 
or progress towards automation of those data elements not yet 
available.
    c. Existing software to calculate person time at risk and time of 
event occurrence.
    d. Ability to complete routine searches of the data base within a 
short time period of about 15 working days.
    e. Ability to generate customized SAS, ASCII, or other appropriate 
data sets to facilitate data transfer and research collaboration.
    3. Personnel (15 points). Personnel should have the following 
qualifications:
    a. Extensive research experience, training, and competence with a 
demonstrated ability to draw on consultative expertise in the areas of 
postmarketing surveillance and epidemiology.
    b. Information systems expertise with previous experience in the 
organization and manipulation of large data sets, and specific 
experience in data bases under agreement.
    c. Investigators should demonstrate a willingness to collaborate 
with FDA scientists as well as with other investigators funded by this 
cooperative agreement program. Such demonstration may include 
suggestions for design of the study, analysis of data sets, and 
publication of results among FDA and Cooperative Agreement 
investigators.
    4. Budget (3 points). Reasonableness of the proposed budget. 
Special consideration will be given to methodology which is cost 
effective (e.g., well-structured medical records and/or record linkage) 
if otherwise scientifically acceptable.
    5. Demonstrated ability to initiate, conduct, complete, and publish 
epidemiology studies in a timely manner (1 point).
    6. Plans for complying with regulations for protection of human 
subjects as applicable to the proposed study project (1 point).
    7. Research experience, training, and competence of the principal 
investigator and the support staff and the resources available to them. 
Special consideration will be given to investigators with knowledge and 
previous experience in postmarketing surveillance and drug 
epidemiology, but applicants with strong acute and chronic disease 
epidemiology background are encouraged to apply (1 point).

VII. 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 Form 5161 
(Rev. 7/92) for applications from State and local governments, with 
sufficient copies of

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the appendix for each application, should be delivered to Robert L. 
Robins (address above). No supplemental material will be accepted after 
the closing date. FDA's authority to fund research projects is under 
section 301 of the PHS Act. FDA's research program is described in the 
Catalog of Federal Domestic Assistance, No. 93.103. Applications 
submitted under this program must comply with 45 CFR part 46--
Protection of Human Subjects where applicable and requirements of the 
Office of Protection from Research Risks. The outside of the mailing 
package and item 2 of the application face page should be labeled 
``Response to RFA-FDA-CDER-97-1''.

VIII. 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 March 14, 1997, 
deadline.
    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.
    Note: (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.)

B. Format for Application

    Applications must be submitted 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. This information collection is 
approved under OMB No. 00925-0001. Applications from State and local 
governments may be submitted on Form PHS 5161 (Rev. 7/92) or PHS 398 
(Rev. 5/95). The face page of the application must reflect the request 
for applications number RFA-FDA-CDER-97-1. This information collection 
is approved under OMB control number 0937-0189.

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 an application that have been 
specifically identified by page number, paragraph, etc., by the 
applicant as containing confidential commercial information or other 
information that is exempt from public disclosure will not be used or 
disclosed except for evaluation purposes.

    Dated: January 30, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-2870 Filed 2-4-97; 8:45 am]
BILLING CODE 4160-01-F