[Federal Register Volume 63, Number 118 (Friday, June 19, 1998)]
[Notices]
[Pages 33680-33686]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-16293]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Studies of Adverse Effects of Marketed Drugs; Availability of
Grants (Cooperative Agreements); Request for Application
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 $1.4 million for cooperative
agreements to study adverse effects of drugs marketed in Canada, the
United States and its territories, subject to the availability of
Fiscal Year 1999 funds. This amount is consistent with the level
[[Page 33681]]
of funding in the President's budget. FDA expects to make up to four
awards for $300,000 per year for 3 years for general data bases and up
to two awards for $100,000 per year for 3 years for special population
data bases. The purpose of these agreements is to conduct drug safety
analysis to the benefit of the public's health; 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: Submit applications by August 3, 1998.
ADDRESSES: Application kits are available from, and completed
applications should be submitted to: Robert L. Robins, Division of
Contracts and Procurement Management (HFA-520), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-7185.
Note: Applications hand-carried or commercially delivered should be
addressed to 5630 Fishers Lane, rm. 2129, Rockville, MD 20852. Please
DO NOT send applications to the Center for Scientific Review (CSR),
National Institutes of Health (NIH). Applications mailed to CSR and not
received by FDA in time for orderly processing, will be returned to the
applicant without consideration.
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: Thomas M.
Conrad, Division of Pharmacovigilance and Epidemiology (HFD-730), Food
and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-
827-3180.
SUPPLEMENTARY INFORMATION: Because of the reduction of funding
throughout the U.S. Government and particularly in this program,
continuation of funding will be evaluated annually to a higher degree
than ever before. As stated later in this document, funding of the
second and third years will be contingent upon: (1) Investigator's
demonstrated success collaborating with FDA scientists, as well as with
other investigators funded by this cooperative agreement program. Such
demonstration may include suggestions for and design of a study,
analysis of data sets, and publication of results among FDA and
cooperative agreement investigators, and (2) the availability of
Federal fiscal year appropriations. A points system has been
established to quantitate the grantee's usefulness in the Government's
collaborative efforts with non-Federal organizations to improve the
health of the American public.
It is determined that these cooperative agreements are exempt from
Protection of Human Subjects requirements in accordance with 45 CFR
46.102(b).
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 are required to undergo extensive testing before
marketing. With the submission of adequate data on safety and
effectiveness, FDA approves a new drug application (NDA) and 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
safety problems originating from reports of adverse reaction reports
received by FDA.
II. Program Research Goals
FDA shall fund a variety of data bases representing, without
overlap to each other or agency contracts, different patient
populations and/or types of patient care settings.
The goal for these cooperative agreements is to collaborate with
researchers with pharmacoepidemiological data bases, to investigate
suspected associations between specific drug exposures and specific
adverse events, and to estimate 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 specific drug safety questions within a few weeks; and (3) provide a
complete analysis to those questions deemed feasible within a few
months.
Additional points will be awarded for the collaborative sharing of
data sets with the agency and with other cooperative agreement
recipients.
Databases
For the purpose of this RFA, all $300,000 awards will be to
longitudinal data bases. Awards for data bases of special populations
($100,000 awards) may be either longitudinal or case control.
A. Longitudinal Data Bases
These data bases must be able to: (1) Provide exposure data on new
molecular entities (those approved within the last 5 years in the
United States); (2) perform feasibility studies of multiple drugs and/
or multiple outcomes; (3) identify adverse drug events that occur
infrequently (i.e., at rates lower than can be detected in clinical
trials); and (4) provide data and preliminary analysis within a very
short timeframe (2 to 4 weeks depending on the problem).
Data base characteristics of interest might include the ability to:
(1) Estimate adverse event rates or relative risks for a 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) obtain data from laboratory results; (5) link to state vital
statistics; (6) link to cancer registry; (7) determine inpatient
exposure; and (8) follow patients long term after an exposure to a
suspect drug.
In addition, FDA is interested in data bases capable of
innovatively applying the objectives stated previously to general
populations.
The ideal data source would: (1) Capture all drug exposures linked
longitudinally to each patient regardless of health care delivery
setting. 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; (2) have the statistical power to identify rare (<1 event="" per="" 1000="" exposures)="" adverse="" events="" in="" the="" population="" of="" interest;="" (3)="" be="" automated="" with="" a="" computerized="" system="" available="" for="" linking="" each="" patient="" to="" all="" relevant="" medical="" care="" data="" including="" drug="" exposure="" data,="" coded="" medical="" outcomes,="" vital="" records,="" cancer="" registries="" and="" birth="" defect="" registries;="" (4)="" have="" a="" low="" patient="" turn-over,="" thereby="" permitting="" long-term="" longitudinal="" followup="" of="" most="" patients="" for="" delayed="" [[page="" 33682]]="" adverse="" effects;="" (5)="" address="" effects="" from="" chronically="" used="" drugs="" (e.g.,="" framingham="" study);="" and="" (6)="" address="" delayed="" effects="" resulting="" from="" drug="" use.="" additional="" points="" would="" be="" awarded="" for="" linkage="" of="" data="" bases="" to="" laboratory="" values="" and="" readily="" accessible="" medical="" records="" as="" evidenced="" by="" past="" performance="" in="" studies.="" the="" ability="" to="" retrieve="" medical="" records="" relevant="" to="" study="" questions="" posed="" by="" fda="" is="" extremely="" important.="" submitted="" applications="" must="" include="" an="" indepth="" description="" of="" the="" data="" base="" and="" provide="" descriptive="" and="" quantitative="" information="" on="" diagnoses="" or="" drug="" exposures="" in="" the="" population.="" the="" applicant="" shall="" also="" provide="" evidence="" that="" their="" data="" base="" has="" sufficient="" exposure="" to="" marketed="" drugs="" (as="" evidenced="" by="" listing="" their="" top="" 50="" drug="" substances="" of="" exposure;="" including="" the="" drug="" and="" number="" of="" exposures).="" the="" quality="" and="" validity="" of="" the="" data="" should="" be="" described="" in="" detail.="" b.="" case-control="" data="" bases="" these="" data="" bases="" must="" be="" able="" to:="" (1)="" provide="" exposure="" data="" in="" general="" and/or="" hospital="" populations;="" (2)="" perform="" feasibility="" studies;="" and="" (3)="" provide="" data="" and="" preliminary="" analysis="" within="" a="" very="" short="" timeframe="" (2="" to="" 4="" weeks="" depending="" on="" the="" problem).="" 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="" specific="" drug="" safety="" questions="" within="" a="" few="" weeks;="" and="" (3)="" provide="" a="" complete="" analysis="" to="" those="" questions="" deemed="" feasible="" within="" a="" few="" months.="" characteristics="" of="" interest="" might="" include:="" (1)="" the="" use="" of="" standardized="" ascertainment="" and="" outcome="" methodology;="" (2)="" the="" ability="" to="" perform="" prospective="" and="" retrospective="" studies;="" (3)="" demonstrated="" validation="" of="" data;="" (4)="" 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);="" (5)="" availability="" of="" large="" numbers="" of="" cases="" with="" validated="" outcomes="" of="" interest="" in="" drug="" safety="" and="" associated="" controls;="" (6)="" construct="" cases="" and="" controls="" for="" case-controlled="" and="" nested="" case-="" controlled="" studies="" (include="" sampling="" scheme);="" (7)="" determine="" odds="" ratios;="" and="" (8)="" determine="" attributable="" risks.="" in="" addition,="" fda="" is="" interested="" in="" data="" bases="" capable="" of="" innovatively="" applying="" the="" objectives="" stated="" previously="" to="" general="" and="" specifically="" defined="" populations.="" the="" ideal="" data="" source="" would:="" (1)="" capture="" all="" drug="" exposures="" for="" each="" patient="" regardless="" of="" health="" care="" delivery="" setting;="" (2)="" identify="" rare=""><1 event="" per="" 1000="" exposures)="" adverse="" events="" in="" the="" population="" of="" interest;="" and="" (3)="" be="" automated="" with="" a="" computerized="" system="" available="" for="" linking="" each="" patient="" to="" all="" relevant="" medical="" care="" data="" including="" drug="" exposure="" data,="" coded="" medical="" outcomes.="" additional="" points="" would="" be="" awarded="" for="" linkage="" of="" data="" bases="" to="" laboratory="" values="" and="" readily="" accessible="" medical="" records="" as="" evidenced="" by="" past="" performance="" in="" studies.="" the="" ability="" to="" retrieve="" medical="" records="" relevant="" to="" study="" questions="" posed="" by="" fda="" is="" extremely="" important.="" submitted="" applications="" shall="" include="" an="" indepth="" description="" of="" the="" data="" base="" and="" provide="" descriptive="" and="" quantitative="" information="" on="" diagnoses="" and="" drug="" exposures="" in="" the="" population.="" the="" quality="" and="" validity="" of="" the="" data="" should="" be="" described="" in="" detail.="" the="" applicant="" shall="" also="" provide="" evidence="" that="" their="" data="" base="" has="" sufficient="" exposure="" to="" marketed="" drugs="" (as="" evidenced="" by="" listing="" their="" top="" 50="" drug="" substances="" of="" exposure;="" including="" the="" drug="" and="" number="" of="" exposures)="" and="" demonstrate="" the="" prevalence="" of="" exposure="" in="" their="" control="" groups.="" iii.="" reporting="" requirements="" program="" progress="" reports="" will="" be="" required="" annually.="" these="" reports="" must="" be="" submitted="" 60="" days="" prior="" to="" the="" last="" day="" of="" the="" budget="" period="" of="" the="" cooperative="" agreement.="" the="" progress="" report="" summary="" required="" for="" non-competing="" continuation="" application="" is="" sufficient,="" if="" amended="" with="" the="" following="" information:="" (1)="" publications,="" abstracts,="" presentations="" to="" professional="" organizations;="" (2)="" top="" 50="" drug="" substance="" exposures="" for="" the="" previous="" year;="" and="" (3)="" summary="" of="" any="" changes="" in="" the="" demographics="" or="" capabilities="" of="" the="" data="" base="" over="" the="" last="" year.="" 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.="" send="" the="" original="" and="" one="" copy="" each,="" of="" the="" annual="" progress="" and="" financial="" reports="" to="" the="" grants="" office="" at="" the="" address="" listed="" above.="" failure="" to="" file="" the="" annual="" progress="" report="" or="" 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.="" 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.="" send="" the="" original="" and="" one="" copy="" to="" the="" grants="" management="" officer="" at="" the="" address="" listed="" above.="" 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,="" presentation="" on="" study="" design="" and="" findings="" and="" discussions="" with="" 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="" first="" year="" will="" be="" competitive="" and="" future="" support="" for="" the="" second="" and="" third="" years="" will="" be="" noncompetitive.="" future="" support="" will="" be="" contingent="" upon:="" (1)="" investigator's="" demonstrated="" success="" collaborating="" with="" fda="" scientists,="" as="" well="" as="" other="" investigators="" funded="" by="" this="" cooperative="" agreement="" program.="" such="" demonstration="" may="" include="" suggestions="" for="" and="" design="" of="" a="" study,="" analysis="" of="" data="" sets,="" and="" publication="" of="" [[page="" 33683]]="" results="" from="" investigations="" performed="" by="" fda="" and="" cooperative="" agreement="" investigators,="" and="" (2)="" the="" availability="" of="" federal="" fiscal="" year="" appropriations.="" d.="" funding="" plan="" up="" to="" four="" cooperative="" agreements="" may="" be="" funded="" with="" the="" intent="" that="" they="" will="" have="" large,="" general="" data="" bases="" with="" the="" ability="" to="" address="" a="" variety="" of="" questions="" in="" the="" field="" of="" pharmacoepidemiology.="" (if="" an="" application="" using="" case-control="" methods="" research="" is="" received,="" it="" will="" be="" placed="" in="" the="" special="" population="" data="" bases="" as="" described="" in="" the="" next="" paragraph.)="" these="" cooperative="" agreements="" have="" $1.2="" million="" dollars="" budgeted="" per="" year.="" up="" to="" two="" cooperative="" agreements="" may="" be="" funded="" for="" special="" populations,="" such="" as="" acquired="" immune="" deficiency="" syndrome="" (aids),="" pregnant="" women,="" pediatrics,="" maternal-child="" linked="" data="" bases.="" the="" data="" base="" type="" for="" these="" awards="" may="" be="" either="" longitudinal="" or="" case="" control.="" these="" two="" cooperative="" agreements="" have="" $200,000="" dollars="" budgeted="" per="" year.="" these="" amounts="" are="" to="" include="" all="" direct="" and="" indirect="" costs.="" federal="" funds="" for="" this="" program="" are="" limited;="" therefore,="" if="" two="" or="" more="" approved="" cooperative="" agreements="" are="" perceived="" as="" duplicative="" or="" very="" similar="" data="" sources="" with="" one="" another,="" fda="" will="" support="" only="" the="" source="" with="" the="" best="" score.="" if="" any="" data="" source="" is="" perceived="" as="" duplicative="" or="" very="" similar="" to="" an="" existing="" fda="" research="" contract,="" the="" contract="" will="" take="" precedence="" over="" the="" application.\1\="" ---------------------------------------------------------------------------="" \1\="" fda="" contracts="" include="" ims="" america's="" national="" prescription="" audit,="" national="" disease="" and="" therapeutic="" index,="" provider="" prospective,="" retail="" prospective="" (contract="" no.="" 223-98-5520)="" and="" mediplus="" (purchase="" order="" no.="" f-07396).="" ---------------------------------------------------------------------------="" applicants="" may="" compete="" for="" either="" type="" of="" cooperative="" agreement,="" but="" not="" both.="" an="" applicant="" can="" only="" be="" awarded="" one="" cooperative="" agreement="" under="" this="" rfa.="" applicants="" must="" clearly="" label="" block="" no.="" 2="" of="" the="" face="" page="" of="" their="" application="" either="" ``large''="" or="" ``special''.="" if="" the="" application="" appears="" to="" be="" eligible="" for="" both="" areas="" of="" consideration="" and="" is="" not="" labeled,="" reasonable="" efforts="" will="" be="" made="" to="" contact="" the="" applicant="" to="" determine="" their="" preference.="" if="" reasonable="" efforts="" to="" contact="" the="" applicant="" fail,="" program="" staff="" shall="" determine="" in="" which="" area="" the="" applicant="" will="" compete.="" 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="" 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:="" 1.="" fda="" staff="" will="" participate="" in="" the="" selection="" and="" approval="" of="" the="" drug="" and="" medical="" events="" to="" be="" studied="" as="" predicated="" by="" the="" needs="" of="" fda.="" the="" drug="" and="" medical="" events="" to="" be="" studied="" will="" be="" jointly="" agreed="" upon="" by="" the="" principal="" 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,="" design="" of="" protocols="" and="" where="" appropriate,="" coauthorship="" of="" publications.="" 3.="" because="" of="" the="" ad="" hoc="" and="" frequently="" urgent="" nature="" of="" the="" agency's="" request,="" we="" have="" decided="" to="" quantify="" the="" amount="" of="" requests="" we="" would="" ask="" of="" an="" awardee="" in="" one="" year's="" time.="" we="" expect="" that="" the="" grantee="" would="" perform="" at="" least="" one="" medium="" or="" large="" study="" in="" the="" course="" of="" each="" year.="" we="" also="" would="" expect="" that="" at="" least="" one="" large="" or="" one="" medium="" study,="" per="" year,="" result="" from="" requested="" feasibility="" studies.="" the="" following="" table="" illustrates="" our="" method="" to="" quantify="" work.="" table="" 1.--quantification="" of="" work="" large="">1 30-60 points
Medium Study2 15-40 points
Other3 1-3 points
(e.g., Data Base Search or
Feasibility Study)
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\1\ Large Study--a large study is one that would involve extensive use
of the data base (e.g., large studies with laboratory linkages) and,
possibly, the retrieval of medical records.
\2\ Medium Study--a medium study is one that might be a large data base
search only or a smaller data base search with medical records
retrieval required.
\3\ Other--include feasibility studies and requests for information that
may include a few tables describing demographics of the patients, drug
exposures and denominator data.
The determination of the points per project will normally be
determined by the grantee and the program before work begins; however,
if circumstances dictate a change is needed after work has begun, it
will be permissible, if agreed by both the grantee and the agency.
All grantees will receive requests for all feasibility studies made
by the agency. This method will afford all grantees the opportunity to
respond to requests.
An additional 10 points will be awarded to medium and large studies
(after the above points have been negotiated) for sharing data sets
with the agency and other cooperative agreements.
These points will be used in determining continued support of the
cooperative agreement for the second and third years of the project
period.
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. Again,
this RFA is limited to data bases where data have been collected from
drugs marketed in Canada, the United States and its Territories.
Responsive applications will undergo dual peer review. A review
panel of experts, comprised primarily of non-Federal scientists, 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 or his
designee.
B. Review Criteria
Applications will be reviewed according to the following criteria,
with each criteria being of equal weight within each major category,
unless
[[Page 33684]]
otherwise specified. All applications will be scored with a maximum of
100 points allowable.
Specific review data base size and characteristics apply to each
type of data base (General Longitudinal or Special Populations, Case-
Control or Special Populations, Longitudinal). Each applicant will be
reviewed by the type of data base the applicant claims to be applying
for. Separate scores will not be given for the same data base.
1. Size and Characteristics of the Data Base (General Longitudinal;
Special Populations, Longitudinal; or Special Populations, Case-
Control) (45 points--Total)
General, Longitudinal Data Base
The size and characteristics of the general, longitudinal data base
should include the following:
a. Structure (10 points)
Common data structure and elements. With this, we would desire to
have a data base that has unified and linked data that has common
structure and data elements for critical variables (including, at a
minimum, demographics, drug use and clinical outcomes.)
b. Size (10 points)
1. Patient population >3 million individuals enrolled annually (10
points).
2. Patient population >2 million individuals enrolled annually (7
points).
3. Patient population >1 million individuals enrolled annually (4
points).
c. Duration (10 points)
A long calendar time-period for which patient longitudinal data are
available and linked.
No points to data bases with less than 2 years of drug
exposure and outcome data.
2 points for 2 years of drug exposure and outcome data.
2 points for each year greater than 2 years of drug
exposure and outcome data.
10 points (maximum) for 6 years or more of drug exposure
and outcome data.
d. General Data Base Features (15 points)
1. Ability to assemble and follow (retrospectively and
prospectively) well-defined cohorts based on exposure or clinical
diagnosis for the purpose of performing case-control or cohort studies.
2. Ability to access and to link to the patient, all health
provider encounters and drug exposure information regardless of patient
care setting.
3. Ability to detect rare (<1:1,000) adverse="" drug="" events="" in="" one="" or="" more="" specific="" target="" populations="" of="" interest="" (i.e.,="" children,="" pregnant="" women,="" and="" the="" elderly).="" 4.="" ability="" to="" detect="" and="" study,="" with="" sufficient="" power,="" birth="" defect="" and="" cancer="" outcomes="" related="" to="" drug="" exposure.="" 5.="" ability="" to="" study="" all="" drug="" products,="" especially="" new="" molecular="" entities="" (nme's)="" approved="" by="" fda="" since="" 1993.="" 6.="" ability="" to="" ascertain="" patient="" enrollment="" and="" turnover="" rates="" as="" demonstrated="" by="" descriptions="" of="" the="" entry="" and="" dropout="" rates="" and="" the="" average="" length="" of="" enrollment.="" 7.="" a="" standard="" set="" of="" drug="" and="" disease="" classification="" systems.="" 8.="" 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.="" 9.="" ability="" to="" link="" to="" cancer="" registry="" and="" to="" state="" vital="" statistics.="" 10.="" ability="" to="" identify="" risk="" factors="" for="" drug-associated="" outcomes="" and="" assess="" potential="" confounders.="" 11.="" ability="" to="" assess="" drug="" interactions.="" 12.="" a="" short="" lag="" time=""><6 months)="" between="" patient="" events="" (hospitalization,="" etc.)="" and="" availability="" of="" clean="" data.="" 13.="" a="" listing="" of="" the="" data="" base's="" top="" 50="" drug="" substances="" of="" exposure="" to="" include="" the="" drug="" and="" number="" of="" exposures="" at="" the="" time="" of="" the="" panel="" review.="" special="" populations="" data="" base,="" longitudinal="" the="" size="" and="" characteristics="" of="" the="" data="" base="" should="" include="" the="" following:="" a.="" size="" (15="" points)="" special="" population="" data="" bases="" shall="" demonstrate="" that="" their="" data="" base="" is="" representative="" of="" their="" special="" population="" as="" a="" whole.="" these="" special="" data="" bases="" can="" be="" awarded="" full="" points="" if="" sufficient="" evidence="" is="" submitted="" that="" demonstrates="" that="" their="" special="" population="" is="" adequately="" represented.="" b.="" general="" data="" base="" features="" (30="" points)="" 1.="" ability="" to="" assemble="" and="" follow="" (retrospectively="" and="" prospectively)="" well="" defined="" cohorts="" based="" on="" drug="" exposure="" or="" clinical="" diagnosis="" for="" the="" purpose="" of="" performing="" case-control="" or="" cohort="" studies.="" 2.="" ability="" to="" access="" and="" to="" link="" to="" the="" patient,="" all="" health="" provider="" encounters="" and="" drug="" exposure="" information="" regardless="" of="" patient="" care="" setting.="" 3.="" ability="" to="" study="" all="" drug="" products,="" especially="" nme's="" approved="" by="" fda="" since="" 1993.="" 4.="" ability="" to="" detect="" and="" study,="" with="" sufficient="" power,="" birth="" defect="" and="" cancer="" outcomes="" related="" to="" drug="" exposure="" (if="" applicable).="" 5.="" ability="" to="" ascertain="" patient="" enrollment="" and="" turnover="" rates="" as="" demonstrated="" by="" descriptions="" of="" the="" entry="" and="" dropout="" rates="" and="" the="" average="" length="" of="" enrollment.="" 6.="" a="" standard="" set="" of="" drug="" and="" disease="" classification="" systems.="" 7.="" 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.="" 8.="" ability="" to="" link="" to="" state="" vital="" statistics.="" 9.="" ability="" to="" identify="" risk="" factors="" for="" drug-associated="" outcomes="" and="" assess="" potential="" confounders.="" 10.="" ability="" to="" assess="" drug="" interactions.="" 11.="" 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.="" 12.="" a="" short="" lag="" time=""><6 months)="" between="" patient="" events="" (hospitalization,="" etc.)="" and="" availability="" of="" clean="" data.="" 13.="" a="" listing="" of="" the="" data="" base's="" top="" 50="" drug="" substances="" of="" exposure="" to="" include="" the="" drug="" and="" number="" of="" exposures="" at="" the="" time="" of="" the="" panel="" review.="" special="" populations="" data="" base,="" case-control="" the="" size="" and="" characteristics="" of="" the="" case="" controlled="" data="" base="" should="" include="" the="" following:="" a.="" size="" (15="" points)="" investigators="" 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.="" controls="" (15="" points)="" evidence="" of="" past="" experience="" performing="" case-control="" studies,="" estimating="" sample="" size,="" exposure="" rates="" and="" proper="" use="" of="" controls="" as="" evidenced="" in="" literature="" and="" abstracts.="" c.="" general="" data="" base="" features="" (15="" points)="" 1.="" ability="" to="" provide="" information="" on="" a="" variety="" of="" diseases="" or="" disorders="" and="" drug="" exposures.="" 2.="" ability="" to="" assemble="" and="" follow="" cases="" and="" controls="" based="" on="" drug="" exposure="" and="" clinical="" diagnosis.="" 3.="" ability="" to="" access="" and="" to="" link="" to="" the="" cases,="" all="" health="" provider="" encounters="" and="" drug="" exposure="" information="" regardless="" of="" patient="" care="" setting.="" 4.="" ability="" to="" study="" drug-induced="" risks="" in="" one="" or="" more="" specific="" target="" populations="" of="" interest="" (i.e.,="" children,="" pregnant="" women,="" and="" the="" elderly).="" [[page="" 33685]]="" 5.="" ability="" to="" study="" all="" drug="" products,="" especially="" nme's="" approved="" by="" fda="" since="" 1993.="" 6.="" ability="" to="" attain="" complete="" and="" unbiased="" ascertainment="" of="" cases="" and="" controls.="" 7.="" a="" standard="" set="" of="" drug="" and="" disease="" classification="" systems.="" 8.="" 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.="" 9.="" ability="" to="" identify="" risk="" factors="" for="" drug-associated="" outcomes="" and="" assess="" potential="" confounders.="" 10.="" ability="" to="" assess="" drug="" interactions.="" 11.="" a="" listing="" of="" the="" data="" base's="" top="" 50="" drug="" substances="" of="" exposure="" to="" include="" the="" drug="" and="" number="" of="" exposures="" at="" the="" time="" of="" the="" panel="" review.="" the="" remaining="" criteria="" apply="" to="" general,="" longitudinal;="" special="" populations,="" longitudinal;="" and="" special="" populations,="" case-controlled="" data="" bases:="" 2.="" identification="" of="" nme's="" (15="" points)="" nme's="" in="" a="" data="" base="" (as="" identified="" in="" the="" following="" list)="" with:=""> at least 6,000 exposures will be awarded 3 points for each
NME;
at least 4,000 exposures will be awarded 2 points for each
NME;
at least 2,000 exposures will be awarded 1 point for each
NME.
Applicant's may choose five NME's from the following list for
evaluation and scoring by the panel.
NME's eligible for scoring with the previously described criteria
are shown below in Table 2:
Table 2.--New Molecular Entities
------------------------------------------------------------------------
Brand names Approval year
------------------------------------------------------------------------
Cedax 1995
Claritin 1994
Cognex 1993
Cozaar 1995
Effexor 1993
Felbatol 1993
Fosamax 1995
Glucophage 1994
Lamictal 1994
Lovenox 1993
Neurotin 1993
Propulsid 1993
Risperdal 1993
Serevent 1994
Ultram 1995
------------------------------------------------------------------------
3. Information Systems and Software Capabilities (10 points)
Information systems and software capabilities should include the
following (2 points each):
a. A well-defined and acceptable description of computer resources
and the extent of automation and software capabilities.
b. Availability of computerized data elements (inpatient drugs,
diagnostic procedures and diagnosis; outpatient drugs, diagnostic
procedures and diagnosis; medical records) or progress toward
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 statistical, ASCII or other
appropriate data sets to facilitate data transfer and research
collaboration.
4. Personnel (20 points)
Personnel should have the following qualifications:
a. Scientific (10 points)--Extensive research experience, training
and competence of all personnel. Special consideration will be given to
teams with knowledge and previous experience in drug epidemiology.
Applicants with strong acute and chronic disease epidemiology
backgrounds and a demonstrated ability to draw on consultative
expertise (particularly in the areas of postmarketing surveillance and
epidemiology) are encouraged to apply. (If consultants are used,
letters of intent or other contractual agreements, with beginning and
end dates, shall be included in the application to fulfill this
requirement.) Demonstrated ability to initiate, conduct, complete and
publish epidemiology studies in a timely manner.
b. Support (10 points)--Project management and information systems
expertise with previous experience in the organization and manipulation
of large data sets and specific experience in data bases under
agreement.
5. Data Sharing (5 points)
To provide study data sets (free of patient identifiers and in a
format usable to the agency) with members of FDA for analysis and with
other cooperative agreement holders in studies that would require data
pooling.
6. Budget (5 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 records linkage) if otherwise scientifically
acceptable.
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) or Form PHS 398 for applications from State and local
governments, with sufficient copies of the appendix for each
application should be delivered to Robert L. Robins (address above). No
supplemental material will be accepted after the closing date. The
outside of the mailing package should be labeled ``Response to RFA-FDA-
CDER-99-1''.
[[Page 33686]]
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 August 3, 1998.
Applications will be considered received on time if sent or mailed
on or before the receipt dates as evidenced by the 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 of 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 addresses. Do not send applications
to the Center for Scientific Review, NIH. This information collection
is approved under OMB control number 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-99-1. 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 the 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: June 9, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-16293 Filed 6-18-98; 8:45 am]
BILLING CODE 4160-01-F
