[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
[[Page 5430]]
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="" [[page="" 5432]]="" 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="">