Federal Register / Vol. 62, No. 24 / Wednesday, February 5, 1997 / Notices 5429

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing

that Alcide Corp. has filed a petition

proposing that the food additive

regulations be amended to provide for

the safe use of acidified sodium chlorite

solutions for red meat disinfection in

processing plants.

DATES: Written comments on the

petitioner’s environmental assessment

by March 7, 1997.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:

Robert L. Martin, Center for Food Safety

and Applied Nutrition (HFS–217), Food

and Drug Administration, 200 C St. SW.,

Washington, DC 20204, 202–418–3074.

SUPPLEMENTARY INFORMATION: Under the

Federal Food, Drug, and Cosmetic Act

(sec. 409(b)(5) (21 U.S.C. 348(b)(5))),

notice is given that a food additive

petition (FAP 7A4532) has been filed by

Alcide Corp., 8561 154th Ave. NE.,

Redmond, WA 98052. The petition

proposes to amend part 173 (21 CFR

part 173) of the food additive

regulations to provide for the safe use of

acidified sodium chlorite solutions for

red meat disinfection in processing

plants.

The potential environmental impact

of this action is being reviewed. To

encourage public participation

consistent with regulations promulgated

under the National Environmental

Policy Act (40 CFR 1501.4(b)), the

agency is placing the environmental

assessment submitted with the petition

that is the subject of this notice on

public display at the Dockets

Management Branch (address above) for

public review and comment. Interested

persons may, on or before March 7, 1997

submit to the Dockets Management

Branch (address above) written

comments. Two copies of any comments

are to be submitted, except that

individuals may submit one copy.

Comments are to be identified with the

docket number found in brackets in the

heading of this document. Received

comments may be seen in the office

above between 9 a.m. and 4 p.m.,

Monday through Friday. FDA will also

place on public display any

amendments to, or comments on, the

petitioner’s environmental assessment

without further announcement in the

Federal Register. If, based on its review,

the agency finds that an environmental

impact statement is not required and

this petition results in a regulation, the

notice of availability of the agency’s

finding of no significant impact and the

evidence supporting that finding will be

published with the regulation in the

Federal Register in accordance with 21

CFR 25.40(c).

Dated: January 17, 1997.

Alan M. Rulis,

Director, Office of Premarket Approval,

Center for Food Safety and Applied Nutrition.

[FR Doc. 97–2820 Filed 2–4–97; 8:45 am]

BILLING CODE 4160–01–F

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.

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
5430 Federal Register / Vol. 62, No. 24 / Wednesday, February 5, 1997 / Notices

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:
Federal Register / Vol. 62, No. 24 / Wednesday, February 5, 1997 / Notices 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
5432 Federal Register / Vol. 62, No. 24 / Wednesday, February 5, 1997 / Notices

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

[Docket No. 96E–0362]

Determination of Regulatory Review

Period for Purposes of Patent

Extension; DIFFERIN Topical Gel

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) has determined

the regulatory review period for

DIFFERIN Topical Gel and is publishing

this notice of that determination as

required by law. FDA has made the

determination because of the

submission of an application to the

Commissioner of Patents and

Trademarks, Department of Commerce,

for the extension of a patent which

claims that human drug product.

ADDRESSES: Written comments and

petitions should be directed to the

Dockets Management Branch (HFA–

305), Food and Drug Administration,

12420 Parklawn Dr., rm. 1–23,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:

Brian J. Malkin, Office of Health Affairs

(HFY–20), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–443–1382.

SUPPLEMENTARY INFORMATION: The Drug

Price Competition and Patent Term

Restoration Act of 1984 (Pub. L. 98–417)

and the Generic Animal Drug and Patent

Term Restoration Act (Pub. L. 100–670)

generally provide that a patent may be

extended for a period of up to 5 years

so long as the patented item (human

drug product, animal drug product,

medical device, food additive, or color

additive) was subject to regulatory

review by FDA before the item was

marketed. Under these acts, a product’s

regulatory review period forms the basis

for determining the amount of extension

an applicant may receive.

A regulatory review period consists of

two periods of time: A testing phase and

an approval phase. For human drug

products, the testing phase begins when

the exemption to permit the clinical

investigations of the drug becomes

effective and runs until the approval

phase begins. The approval phase starts

with the initial submission of an

application to market the human drug

product and continues until FDA grants

permission to market the drug product.

Although only a portion of a regulatory

review period may count toward the

actual amount of extension that the

Commissioner of Patents and

Trademarks may award (for example,

half the testing phase must be

subtracted as well as any time that may

have occurred before the patent was

issued), FDA’s determination of the

length of a regulatory review period for

a human drug product will include all

of the testing phase and approval phase

as specified in 35 U.S.C. 156(g)(1)(B).

FDA recently approved for marketing

the human drug product DIFFERIN

Topical Gel (adapalene). DIFFERIN

Topical Gel is indicated for the topical

treatment of acne vulgaris. Subsequent

to this approval, the Patent and

Trademark Office received a patent term

restoration application for DIFFERIN

Topical Gel (U.S. Patent No. Re. 34,440)

from Centre International de Recherches

Dermatologiques (CIRD), and the Patent

and Trademark Office requested FDA’s

assistance in determining this patent’s

eligibility for patent term restoration. In

a letter dated October 24, 1996, FDA

advised the Patent and Trademark

Office that this human drug product had

undergone a regulatory review period

and that the approval of DIFFERIN

Topical Gel represented the first

permitted commercial marketing or use

of the product. Shortly thereafter, the

Patent and Trademark Office requested

that FDA determine the product’s

regulatory review period.

FDA has determined that the

applicable regulatory review period for

DIFFERIN Topical Gel is 2,447 days. Of

this time, 1,401 days occurred during

the testing phase of the regulatory

review period, while 1,046 days

occurred during the approval phase.

These periods of time were derived from

the following dates:

1. The date an exemption under

section 505(i) of the Federal Food, Drug,

and Cosmetic Act (21 U.S.C. 355(i))

became effective: September 20, 1989.

FDA has verified the applicant’s claim

that the date that the investigational

new drug application became effective

was on September 20, 1989.

2. The date the application was

initially submitted with respect to the

human drug product under section

505(b) of the Federal Food, Drug, and