Postmarketing Studies for Human Drugs and Licensed Biological Products; Status Reports

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 601

[Docket No. 99N-1852]

RIN 0910-AB83

Postmarketing Studies for Human Drugs and Licensed Biological

Products; Status Reports

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to revise

the status reports section of the postmarketing annual reporting

requirements for drug and biological products, and to require

applicants to submit annual status reports for certain postmarketing

studies of licensed biological products. This proposed rule would

describe the types of postmarketing studies covered by these status

reports, the information to be included in the reports, and the type of

information that FDA would consider appropriate for public disclosure.

The agency is taking this action to implement section 130 of the Food

and Drug Administration Modernization Act of 1997 (FDAMA).

DATES: Submit written comments on the proposed rule by February 14,

2000. Submit written comments on the information collection provisions

by January 3, 2000.

ADDRESSES: Submit written comments to the Dockets Management Branch

[[Page 67208]]

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,

Rockville, MD 20852. Submit written comments on the information

collection provisions to the Office of Information and Regulatory

Affairs, Office of Management and Budget (OMB), New Executive Office

Bldg., 725 17th St. NW., Washington, DC 20503, Attn: Wendy Taylor, Desk

Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Paula S. McKeever, Center for Biologics Evaluation and Research

(HFM-17), Food and Drug Administration, 1401 Rockville Pike, suite

200N, Rockville, MD 20852-1448, 301-827-6344; or

Audrey A. Thomas, Center for Drug Evaluation and Research (HFD-7),

Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,

301-594-5625.

SUPPLEMENTARY INFORMATION:

I. Introduction

On November 21, 1997, the President signed the FDAMA into law

(Public Law 105-115). Section 130(a) of the FDAMA amended the Federal

Food, Drug, and Cosmetic Act (the act) by adding a new provision on

reports of postmarketing studies) (section 506B of the act (21 U.S.C.

356b)). Section 506B of the act provides FDA with additional authority

for monitoring the progress of postmarketing studies that companies

have made a commitment to conduct and also requires the agency to make

information that pertains to the status of these studies publicly

available.

Under section 506B(a) of the act, applicants that have committed to

conduct a postmarketing study for a drug or biological product that is

approved for marketing must submit to FDA a report on the progress of

the study or the reasons for the failure of the applicant to conduct

the study. This provision directs FDA to issue regulations that

prescribe the content of these reports.

Section 506B(a) of the act also states that these reports must be

submitted to FDA within 1 year after the approval of the product and

annually thereafter until the study is completed or terminated. This

provision applies to commitments for postmarketing studies that were

made on or after enactment of FDAMA, as well as those made prior to

enactment of FDAMA. For commitments made prior to enactment of FDAMA,

the act requires that an initial report be submitted to FDA within 6

months after the date of issuance of the final rule implementing

section 506B of the act. Section 506B(b) of the act specifies which

information in a status report may be considered public information.

Under section 506B(b) of the act, FDA may publicly disclose any

information pertaining to a status report under section 506B(a) to the

extent that the information is necessary to identify the applicant, or

to establish the status of a study and the reasons, if any, for failure

to conduct, complete, and report the study.

Section 506B(c) of the act directs FDA to develop and publish

annually in the Federal Register a report concerning this activity.

This report must provide information on the status of postmarketing

studies that applicants have committed to conduct under this provision

and for which reports have been submitted.

FDAMA also directs FDA, under section 130(b), to submit a specific

report to Congress by October 1, 2001. This report must contain a

summary of the status reports submitted under section 506B of the act,

an evaluation of the performance of applicants in fulfilling their

commitments to conduct postmarketing studies under this provision and

of FDA's timeliness in reviewing these postmarketing studies, and any

legislative recommendations regarding postmarketing studies.

Under the agency's existing postmarketing reporting regulations for

human drug products, at Sec. 314.81(b)(2) (21 CFR 314.81(b)(2)), each

applicant holding an approved new drug application (NDA) or abbreviated

new drug application (ANDA) must submit an annual report to FDA for the

drug product. This annual report is required to contain, among other

information, a section on status reports that includes a statement on

the current status of any postmarketing studies of the drug product

performed by, or on behalf of, the applicant (Sec. 314.81(b)(2)(vii)).

This section also permits applicants to include a list of any open

regulatory business with FDA concerning the drug product. In the

Federal Register of December 2, 1998 (63 FR 66632), FDA issued a final

rule amending these postmarketing reporting regulations to require that

annual reports contain, among other information, specific information

about the status of postmarketing clinical studies in pediatric

populations. In this proposed rule, FDA is proposing to amend these

regulations, including the new provisions issued in the final rule of

December 2, 1998, to implement the requirements of section 506B of the

act for human drug products. In a separate rulemaking, FDA plans to

propose additional amendments to the annual report requirements

pertaining to the nonclinical laboratory studies and clinical data

sections of the annual report. However, these amendments are beyond the

scope of this proposed rule.

Each applicant holding a biologics license application (BLA) must

submit an annual report to FDA describing any minor changes that may

relate to the safety or effectiveness of the product (Sec. 601.12(d)

(21 CFR 601.12(d)) and must also submit a separate annual report, in

accordance with the final rule of December 2, 1998 (63 FR 66632),

regarding postmarketing pediatric studies (Sec. 601.37 (21 CFR

601.37)). In this proposed rule, FDA is proposing to amend the

biologics regulations at part 601 (21 CFR part 601) by revising the

postmarketing annual reporting requirement at Sec. 601.37 and by adding

a new postmarketing annual reporting requirement, Sec. 601.70, to

implement the requirements of section 506B of the act for licensed

biological products. Proposed Sec. 601.70 would only apply to licensed

biological products that meet the definition of ``drug'' under the act;

it would not apply to biological products that also meet the definition

of ``medical device'' under the act, since section 506B does not cover

medical devices.

This proposed rule would only apply to human drug and biological

products; it would not apply to animal drug products. FDA intends to

amend its regulations to implement section 506B of the act for animal

drug products in a separate rulemaking.

In May 1996, the Office of Inspector General of the Department of

Health and Human Services issued a report regarding FDA's oversight of

postmarketing study commitments for prescription drugs (Ref. 1). This

study found that the number of postmarketing study commitments was

increasing and that the agency did not have formal standards or

procedures for monitoring postmarketing studies or for establishing

whether a postmarketing study commitment had been met. At the same

time, FDA was developing formal procedures for tracking the progress of

postmarketing study commitments, an effort that began in February 1995

when the agency recognized the need for such procedures. These

procedures were implemented in October 1996. The proposed revisions to

the human drug and biologics regulations in this rule will facilitate

FDA's current system for tracking postmarketing study commitments.

In addition to the regulatory changes proposed in this rule, FDA

will issue guidance regarding section 506B of the act. This guidance

will describe in greater detail the type of information

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that applicants should submit to the agency in a status report for a

postmarketing study of an approved drug or licensed biological product,

the implementation schedule for submission of these status reports to

the agency, how FDA will track information obtained for postmarketing

studies, and the schedule for FDA review of status reports and final

study reports for postmarketing studies. In accordance with the

agency's Good Guidance Practices (62 FR 8961, February 27, 1997), FDA

will make the guidance available in draft form for public comment

before issuing a final guidance. FDA is also in the process of

reviewing and revising, as necessary, its internal operating procedures

related to tracking commitments made for the conduct of postmarketing

studies under this provision for approved drug and licensed biological

products.

II. Description of the Proposed Rule

A. Introduction

The proposed rule would amend the postmarketing annual reporting

requirements for human drug products under Sec. 314.81(b)(2) by

reorganizing the status reports section, at Sec. 314.81(b)(2)(vii), to

require that the information contained in this section be provided to

FDA in a different format. FDA is proposing that this information be

included in the annual report in three different sections. One section

would contain, as described below (see section II.B of this document),

status reports for those postmarketing studies of the drug product

(i.e., clinical safety, clinical efficacy, clinical pharmacology and

nonclinical toxicology) that are required by FDA (e.g., pediatric

studies) or that an applicant has committed, in writing, to conduct

either at the time of approval of an application or a supplement to an

application, or after approval of an application or a supplement

consistent with section 506B of the act (proposed

Sec. 314.81(b)(2)(vii)). This section would also include, for pediatric

studies, a statement that indicates whether postmarketing clinical

studies in pediatric populations were required by FDA under Sec. 201.23

(21 CFR 201.23). Another section would contain status reports for any

other postmarketing studies of the drug product (proposed

Sec. 314.81(b)(2)(viii)) (e.g., chemistry, manufacturing, and controls,

stability of the product), and the third section would contain, at the

applicant's discretion, a list of any open regulatory business with FDA

concerning the drug product (proposed Sec. 314.81(b)(2)(ix)). FDA would

use the information provided under proposed Sec. 314.81(b)(2)(vii) to

meet its reporting obligations under section 506B of the act (annual

report in the Federal Register) and section 130(b) of FDAMA (report to

congressional committees by October 1, 2001). FDA does not intend to

use information provided under proposed Sec. 314.81(b)(2)(viii) for

this purpose. This proposed change in the structure of the annual

report would facilitate FDA's preparation of its annual reports and its

report to Congress without imposing a new reporting burden on

applicants with approved NDA's and ANDA's because these applicants are

currently required to report such information to FDA.

The proposed rule would also create a new subpart G under part 601

entitled ``Postmarketing Studies'' and a new Sec. 601.70 under subpart

G. Proposed Sec. 601.70 would require, as described in section II.B of

this document, annual reports of the status of postmarketing studies

for licensed biological products (i.e., clinical safety, clinical

efficacy, clinical pharmacology, and nonclinical toxicology) that are

required by FDA (e.g., pediatric studies) or that an applicant has

committed, in writing, to conduct either at the time of approval of an

application or a supplement to an application, or after approval of an

application or a supplement. Proposed Sec. 601.37(c) would require that

the status of postmarketing pediatric studies that are covered under

proposed Sec. 601.70 be reported to FDA under proposed Sec. 601.70

rather than under Sec. 601.37. FDA notes that biological products

previously approved under the product license application and

establishment license application process are included wherever BLA,

the new form of application for biological products, is used in this

preamble.

B. Scope of Proposed Rule

Postmarketing studies for marketed human drug and licensed

biological products are conducted for a variety of purposes (e.g., new

indication, safety, medication errors, pharmacokinetics, pharmacology,

chemistry, marketing, stability, use in special populations such as

children). Some of these postmarketing studies are conducted by an

applicant on its own initiative. Other postmarketing studies are

required by FDA to be conducted by applicants such as assessing the

safety and effectiveness of new drugs and biologics in pediatric

patients (Sec. 314.55 (21 CFR 314.55) and Sec. 601.27. Others result

from an applicant's commitment, in writing, to the agency to conduct

the study at the time of approval of an application (e.g, an NDA, ANDA,

BLA, or supplement), after approval of an application (e.g., as a

result of suspected adverse drug reaction reports), as a condition of

accelerated approval of new drugs and biological products for serious

or life-threatening illnesses (subpart H of part 314 (21 CFR part 314),

and subpart E of part 601 respectively), or as a deferred submission of

pediatric studies (Secs. 314.55(b) and 601.27(b)). Studies that

applicants commit to conduct at the time of approval of an application

are usually intended to address concerns about the risks, benefits, or

optimal use of a drug or biological product that do not warrant

delaying approval of the application.

This proposed rule would define postmarketing studies for which

status reports must be submitted under section 506B of the act as those

that concern clinical safety, clinical efficacy, clinical pharmacology

or nonclinical toxicology studies and that are required by FDA (e.g.,

pediatric studies) or that are committed to, in writing, either at the

time of approval of an application or a supplement or after approval of

an application or supplement. FDA is proposing to include clinical

studies such as safety, efficacy, and pharmacology studies within the

scope of this rule because these types of studies provide the most

relevant and useful additional information about the risks, benefits,

and optimal use to patients and consumers of an approved drug or

licensed biological product. In addition, FDA is proposing to include

nonclinical toxicology studies within the scope of this rule, although

such studies typically cannot be performed on human subjects, because

they are very useful to further evaluate the safety of a marketed drug

or biological product.

For the purpose of this rule, clinical safety and clinical efficacy

studies would include human epidemiological studies. Examples of

clinical pharmacology studies are pharmacokinetic and pharmacodynamic

studies. For all of the postmarketing studies described previously,

Secs. 314.81(b)(2)(vii) and 601.70 would require applicants to provide

status reports to FDA regarding the progress of such studies.

Postmarketing studies designed to evaluate other types of issues

such as manufacturing and control issues (e.g., stability of the

product, development of new tests or specifications) and medication

errors (e.g., attributable to the labels, labeling and/or packaging of

the product) would be reported for drug products, as described below,

under proposed Sec. 314.81(b)(2)(viii) rather than under proposed

Sec. 314.81(b)(2)(vii), and

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would not be required to be reported under Sec. 601.70 for licensed

biological products.

This proposed rule would require, as stated previously, status

reports, under proposed Secs. 314.81(b)(2)(vii) and 601.70, for

postmarketing studies that either are required by FDA (e.g., pediatric

studies) or that applicants commit, in writing, to conduct either at

the time of approval of an application or a supplement to an

application, or after approval of an application or a supplement.

Under proposed Sec. 314.81(b)(2)(viii), applicants with approved

NDA's and ANDA's would be required to provide status reports for any

postmarketing study not reported under proposed Sec. 314.81(b)(2)(vii)

(e.g., chemistry, manufacturing, and controls, stability of the

product, medication errors). These would include postmarketing studies

performed by, or on behalf of, the applicant, whether or not the

studies are required or subject to commitments. Proposed

Sec. 314.81(b)(2)(viii) does not represent a new reporting burden for

applicants with approved NDA's or ANDA's because these applicants are

currently required to provide status reports for these studies in their

postmarketing annual reports. FDA is not proposing a similar reporting

requirement for postmarketing studies of licensed biological products

in this proposed rule. Applicants with licensed biological products may

voluntarily submit status reports to FDA for postmarketing studies that

are not required to be reported under proposed Sec. 601.70.

The agency is committed to harmonizing its reporting requirements

for drugs and biologics as much as possible. Section 123(f) of FDAMA

requires FDA to take measures to minimize differences in the review and

approval of products required to have approved BLA's under section 351

of the Public Health Service Act (42 U.S.C. 262) and products required

to have approved NDA's under section 505(b)(1) of the act (21 U.S.C.

355(b)(1)). At the present time, FDA is considering whether to amend

its biologics regulations in a separate rulemaking to require the

submission of information in postmarketing annual reports currently

submitted to the agency by applicants with approved NDA's and ANDA's

under Sec. 314.81(b)(2)(i) through (b)(2)(vi). FDA requests comment on

whether the postmarketing annual report for licensed biological

products under Sec. 601.12(d), (changes to an approved application),

Sec. 601.37 (annual reports of postmarketing pediatric studies), and

proposed Sec. 601.70 should be combined into a single annual report and

whether such a report should include additional information as required

in Sec. 314.81(b)(2)(i) through (b)(2)(vi). However, FDA has determined

that requiring such additional information is beyond the scope of this

proposed rulemaking and that it is appropriate, at this time, to

harmonize only the drugs and biologics postmarketing annual reporting

requirements as they relate to section 506B of the act.

C. Content of Status Reports

Current regulations (Sec. 314.81(b)(2)(vii)) do not prescribe the

content of status reports of postmarketing studies. In this proposed

rule, FDA is proposing to set forth the format and content of these

reports, as described in section 506B of the act, which requires

sufficient information to identify the applicant of the postmarketing

study, the specific study being conducted, the status of the study, and

the reasons, if any, for the applicant's failure to complete the study.

Under proposed Sec. 314.81(b)(2)(vii) and (b)(2)(viii) and

Sec. 601.70(b), a status report for a postmarketing study would be

required to contain the following information:

1. Applicant's name.

2. Product name. This would include the approved product's

established/proper name and proprietary name, if applicable.

3. NDA number, ANDA number, BLA/reference number, or supplement

number of the approved product.

4. Date of product's U.S. approval.

5. Date of postmarketing study commitment. This date would be the

same as the date of the product's U.S. approval for commitments made,

in writing, at the time of U.S. approval of an application; would be

the date of U.S. approval of the supplement for commitments made, in

writing, at the time of U.S. approval of a supplement; and would be the

date of written commitment for commitments made after U.S. approval of

an application or supplement.

6. Description of postmarketing study commitment. For clinical

studies, this section would include the purpose of the postmarketing

study, the patient population addressed by the study, the number of

patients and/or subjects to be included in the study, and the

indication and dosage(s) that are to be studied. For nonclinical

studies, this section would include the type and purpose of the study

(e.g., carcinogenicity study to determine effects of chronic dosing).

7. Schedule for conduct, completion, and reporting of the

postmarketing study commitment. This section would include projected

dates for initiation of the different phases of the study, for

completion of the study, and for submission of the final study report

to FDA. This schedule should reflect a reasonable, but aggressive

timetable for completing the postmarketing study commitment. Although

some delays in a study may be unanticipated, it is expected that

studies would progress as originally scheduled. If the original

schedule is revised under section 9 of this status report, the revised

schedule would also be reported in this section (i.e., section 7) in

the next report with a note indicating that the schedule has been

revised as reported in the previous status report.

8. Current status of the postmarketing study commitment. Applicants

would categorize the status of each postmarketing study using one of

the following terms that describe the study's status on the U.S.

anniversary date of approval of the application or other agreed upon

date:

a. Pending. The study has not been initiated (i.e., first patient

has not been enrolled).

b. Ongoing. The study is proceeding according to or ahead of the

original schedule described in section 7 of the status report. If a

study has been completed but the final study report has not been

submitted to FDA, the date the study was completed would be provided.

c. Delayed. The study is proceeding but is behind the original

schedule described in section 7 of the status report. The original

schedule would serve as the basis for defining a study as ``delayed,''

even if a revised schedule is provided.

d. Terminated. The study was ended before completion.

e. Submitted. The study has been completed (i.e., last patient

finished the protocol) or terminated and a final study report has been

submitted to FDA. This category would include the date the final study

report was submitted to FDA.

9. Explanation of the study's status. This section would include a

brief description of the status of the study, including the number of

patients and/or subjects enrolled to date and an explanation of the

study's status identified under section 8 of the status report (e.g.,

delayed due to difficulty in patient accrual, terminated because study

would no longer provide useful information, terminated because study is

no longer feasible, terminated because of adverse events or other

safety issues associated with the use of the product). This section

would also include a

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revised schedule, as well as the reason(s) for the revision, if the

schedule under section 7 of the status report has changed since the

last annual report. This revised schedule would be included, as noted

previously, under section 7 of the next report.

FDA believes that the information proposed to be required in status

reports would provide the agency with sufficient data for review of the

progress of ongoing postmarketing studies under this section. These

reports would also provide FDA with sufficient information to meet the

agency's reporting obligations under section 130 of FDAMA (i.e., annual

report in the Federal Register on the status of postmarketing studies,

report to congressional committees by October 1, 2001).

D. Log of Outstanding Regulatory Business

Current regulations (Sec. 314.81(b)(2)(vii)), as noted previously

(see section I of this document), permit applicants with approved NDA's

and ANDA's to include in the status reports section of annual reports a

list of any open regulatory business with FDA concerning the drug

product that is the subject of the annual report. FDA would continue to

permit applicants to submit such information in annual reports under

proposed Sec. 314.81(b)(2)(ix). For clarification, FDA is proposing to

provide examples of the types of open regulatory business that would be

reported under proposed Sec. 314.81(b)(2)(ix). These would include a

list of the applicant's unanswered correspondence with the agency and a

list of the agency's unanswered correspondence with the applicant.

Proposed Sec. 601.70 does not contain a similar provision for

outstanding regulatory business. However, as noted previously (see

section II.B of this document), FDA is considering a separate

rulemaking that would require the same postmarketing annual reporting

requirements for drugs and biologics.

E. Report Submission Requirements

Current regulations at Sec. 314.81(b), require applicants with

approved drug products to submit two copies of an annual report to FDA.

Under Sec. 314.81(b)(2), these annual reports are required to be

submitted within 60 days of the anniversary date of U.S. approval of

the application to the FDA division responsible for reviewing the

application and these reports. Each annual report is required to be

accompanied by a completed transmittal Form FDA-2252 (Transmittal of

Periodic Reports for Drugs for Human Use) that includes all the

information required under Sec. 314.81(b)(2) that the applicant

received or otherwise obtained during the annual reporting interval,

which ends on the U.S. anniversary date. FDA is proposing to amend

these regulations by replacing the phrase ``Periodic Reports'' with the

phrase ``Annual Reports'' to correct an error and by making other minor

changes to provide clarity.

Currently, applicants with licensed biological products must submit

reports, under Sec. 601.12(d), describing certain minor changes to an

approved BLA, and under Sec. 601.37, providing information on

postmarketing pediatric studies, each year within 60 days of the

anniversary date of approval of the application. Proposed

Sec. 601.70(c) and (d) would require applicants with licensed

biological products to submit a separate annual report to FDA

describing the status of certain postmarketing studies using submission

requirements similar to those required for drugs under

Sec. 314.81(b)(2) and for licensed biologics under Secs. 601.12(d) and

601.37. Applicants with licensed biological products would submit two

copies of an annual progress report to FDA within 60 days of the

anniversary date of the U.S. approval of the application for the

product. Each annual progress report would be accompanied by a

completed transmittal Form FDA-2252 that includes all the information

required under proposed Sec. 601.70 that the applicant received or

otherwise obtained during the annual reporting interval, which ends on

the U.S. anniversary date. These annual progress reports would be

submitted for all postmarketing studies of a licensed biological

product covered under the scope of this proposed rule including those

that are required by FDA (e.g., pediatric studies) and those that an

applicant committed, in writing, to conduct on or after the effective

date of any final rule that may issue based on this proposed rule and

prior to the effective date.

For drugs and biologics with approved NDA's, ANDA's, and BLA's, FDA

intends, as noted previously (see section II.A of this document), to

fulfill its annual reporting requirement mandated by section 506B(c) of

the act by publishing in the Federal Register, the status of

postmarketing study commitments reported under proposed

Secs. 314.81(b)(2)(vii) and 601.70. Furthermore, FDA will post

additional information on the agency's web page (see section G.2 of

this document). This additional information will include an applicant's

failure to submit a status report under proposed

Secs. 314.81(b)(2)(vii) and 601.70 for any postmarketing study

commitment that the agency has formally tracked (i.e., commitments

included in agency databases which were made, in writing, at the time

of approval or after approval of an application or a supplement to an

application, and commitments made as a condition of accelerated

approval, or required studies for assessing the safety and

effectiveness of drugs and biologics in pediatric patients).

A status report under proposed Secs. 314.81(b)(2)(vii) and 601.70

would be submitted to FDA until the agency notifies the applicant, in

writing, that the study commitment has been fulfilled or acknowledges

that the study is either no longer feasible or would no longer provide

useful information. Applicants may indicate in their status report that

a study has been terminated because it is either no longer feasible or

would no longer provide useful information. However, these applicants

would be required to submit a final study report to FDA and continue to

submit status reports for the study until the agency evaluates the

final study report and concurs, in writing, with the applicant's

determination. To expedite the process, FDA encourages applicants to

submit a final study report to the agency as soon as they have

determined that a postmarketing study commitment is to be terminated.

F. Public Disclosure of Information

Section 506B(b) of the act requires FDA to publicly disclose any

information pertaining to a status report described in section 506B(a)

of the act to the extent that such information is necessary to: (1)

Identify the sponsor or (2) establish the status of the postmarketing

study and the reasons, if any, for any failure to carry out the study.

Therefore, FDA is proposing to state in the rule its authority to

disclose any information contained within or relating to postmarketing

studies under proposed Sec. 314.81(b)(2)(vii) or proposed Sec. 601.70,

if the information is necessary to establish the identity of the

applicant or the status of the study, including the reasons, if any,

for the applicant's failure to conduct, complete, and report the study.

However, FDA would not disclose trade secrets as defined in 21 CFR

20.61(a) or information described in 21 CFR 20.63, the disclosure of

which would constitute an unwarranted invasion of personal privacy.

Information necessary to establish the status of a postmarketing study

would include the study protocol, patient accrual rates, reports of

unexpected (i.e., unlabeled) suspected adverse drug

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reactions, and study results. Some of these types of information such

as study protocols for certain postmarketing studies and adverse event

reports for certain postmarketing studies are currently publicly

available. Section 130(b) of FDAMA provides FDA with statutory

authority to disclose data and information, including certain

information that may be considered to constitute confidential

commercial information. Section 130(b) of FDAMA constitutes

authorization by law for the purposes of 18 U.S.C. 1905 to disclose

certain information that could otherwise be considered nondisclosable

confidential commercial information.

G. Proposed Implementation Scheme

1. Effective Dates

FDA proposes that any final rule that may issue based on this

proposed rule become effective 90 days after its date of publication in

the Federal Register. Applicants with approved applications for human

drug and licensed biological products (that are not medical devices)

would be subject to the annual reporting requirements in this proposed

rule. In addition, applicants that have entered into a commitment prior

to November 21, 1997, to conduct a postmarketing study described under

proposed Sec. 314.81(b)(2)(vii) or proposed Sec. 601.70 would be

required, as mandated by FDAMA, to submit an initial report to FDA

within 6 months after the effective date of any final rule that may

issue based on this proposed rule. Thus, in some cases, an applicant

would be required to submit two reports to FDA in the first year after

the effective date of the final rule (i.e., an initial report

containing only information required under proposed

Sec. 314.80(b)(2)(vii) or proposed Sec. 601.70 due within 6 months

after the effective date and a complete annual report based on the

product's anniversary date of U.S. approval due in the 7th to 12th

month after the effective date). After the first year, applicants would

only be required to submit one annual report to FDA each year.

This proposed rule does not affect the existing reporting

requirements issued in the final rule of December 2, 1998 (63 FR

66632). Any changes to the provisions in the final rule of December 2,

1998, that are proposed in this rule would be in effect on the

effective date of any final rule that may issue based on this proposed

rule.

2. Annual Federal Register Report

Consistent with section 506B(c) of the act, FDA will publish

annually a report in the Federal Register. This report will provide a

brief summary of the status of postmarketing study commitments for

approved drugs and licensed biological products that applicants have

submitted to FDA under proposed Secs. 314.81(b)(2)(vii) and 601.70. The

report will include the number of pending, ongoing, delayed, and

terminated postmarketing study commitments, as well as the number of

final study reports that have been submitted to FDA, the number of

study commitments that FDA has deemed fulfilled, and the number of

applicants that failed to submit a status report to the agency for

unfulfilled postmarketing study commitments. Detailed information

regarding the status of these postmarketing studies will be posted on

FDA's web page at ``http://www.fda.gov''. The web site will contain, at

a minimum, the following information for each postmarketing study

commitment: Name of the applicant, application number, product name,

dosage form, product use category, type of study, commitment

description, commitment date, projected study completion date, current

status of commitment, applicant summary of status, annual report due

date, and date annual report received.

III. Request for Comments

Interested persons may, on or before February 14, 2000, submit to

the Dockets Management Branch (address above) written comments

regarding this proposal. 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.

IV. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

V. Analysis of Impacts

FDA has examined the impact of this proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). Under the Regulatory

Flexibility Act, if a rule would have a significant economic impact on

a substantial number of small entities, the agency must analyze

regulatory options that would minimize any significant impact of the

rule on small entities. Title II of the Unfunded Mandates Reform Act (2

U.S.C. 1501 et seq.) requires that agencies prepare a written statement

and economic analysis before proposing any rule that may result in an

expenditure by State, local, and tribal governments, in the aggregate,

or by the private sector of $100 million (adjusted annually for

inflation) in any 1 year.

The agency believes that this rule is consistent with the

principles set out in the Executive Order and in these two statutes.

OMB has determined that the proposed rule is a significant regulatory

action as defined by the Executive Order and so is subject to review.

The rule would require applicants that have committed, in writing, to

conduct a postmarketing study for an approved drug or biologic product

to submit annual reports on the progress of the study or on the reasons

for the failure of the applicant to conduct, complete, and report the

study. The rule would permit FDA to publicly disclose information

concerning these postmarketing studies, thereby providing patients,

consumers, and the medical community with access to important and

useful information.

A. Nature of Impact

Currently, applicants holding approved NDA's or ANDA's are required

to submit annual reports to the agency that include information on the

current status of any postmarketing studies of the drug product

performed by, or on the behalf of the applicant. Although the proposed

rule prescribes the format for the required information, this

requirement would add no new economic burden for the majority of NDA

and ANDA applicants. About half of the applicants holding approved

NDA's or ANDA's with outstanding postmarketing study commitments made

prior to the enactment of FDAMA may incur a small cost the first year,

if their annual report is due within the last 6 months after the

effective date of issuance of the final rule and they must submit one

initial report within the first 6 months after the effective date. FDA

estimates that there will be approximately 116 such reports submitted,

which will require about 16 hours per report to complete. Assuming an

average wage rate of $35 per hour,

[[Page 67213]]

the estimated, one-time cost of this provision is $64,960.

Applicants with licensed biological products are currently required

to submit information on postmarketing studies in pediatric populations

in annual reports to the agency. These applicants will incur additional

costs to comply with the proposed requirements in this proposed rule.

The agency estimates that about 33 applicants will submit approximately

43 postmarketing status reports annually for approved licensed

biological products. As the reporting requirements are not extensive

and the information is readily accessible to the applicant, FDA

estimates that establishments will require about 16 hours to complete

the required information. Assuming an average wage rate of $35 per

hour, the estimated incremental cost of the annual reporting

requirement will be $560 per report, for an industry total of $24,080

per year. As with applicants holding NDA's or ANDA's, a few applicants

with licensed biological products with outstanding postmarketing study

commitments may also incur an additional, one-time cost because they

must submit their initial report within the first 6 months after the

effective date of the final rule and an annual report within the last 6

months of the year. FDA estimates there will be approximately seven

such reports, for a total one-time cost of about $4,000.

B. Small Business Impacts

The requirements in this proposed rule will not have a significant

economic impact on a substantial number of small entities. Although it

is possible that some firms may feel added pressure to honor the agreed

upon commitments, the agency does not expect the proposed rule to

result in an increased number of completed postmarketing studies. Nor

does it believe that applicants will incur significantly increased

costs from completing studies earlier than intended, as a result of the

reporting, tracking, and disclosure activities implemented by the

agency. Because affected applicants holding NDA's and ANDA's must

currently submit annual reports to the agency, they already have

procedures in place to monitor their postmarketing studies. The

additional reporting requirement for applicants holding approved BLA's

and the reformatting of the annual reports for applicants holding NDA's

and ANDA's would be minimal. To simplify the reporting requirement

further, however, the agency will publish a guidance for industry to

aid applicants in preparing reports in the proper format.

C. Conclusion

The previous cost estimates demonstrate that this rule is not

economically significant under Executive Order 12866. The Unfunded

Mandates Reform Act does not require a cost-benefit analysis of this

rule, because the rule will not result in an expenditure by State,

local, or tribal governments, in the aggregate, or by the private

sector of $100 million in any 1 year. Finally, the agency certifies

that the proposed rule will not have a significant economic impact on a

substantial number of small entities.

VI. The Paperwork Reduction Act of 1995

This proposed rule contains information collection provisions that

are subject to review by OMB under the Paperwork Reduction Act of 1995

(44 U.S.C. 3501-3520). A description of these provisions is shown below

with an estimate of the annual reporting burden. Included in the

estimate is the time for reviewing the instructions, searching existing

data sources, gathering and maintaining the data needed, and completing

and reviewing each collection of information.

FDA invites comments on: (1) Whether the proposed collection of

information is necessary for the proper performance of FDA's functions,

including whether the information will have practical utility; (2) the

accuracy of FDA's estimate of the burden of the proposed collection of

information, including the validity of the methodology and assumptions

used; (3) ways to enhance the quality, utility, and clarity of the

information to be collected; and (4) ways to minimize the burden of the

collection of information on respondents, including through the use of

automated collection techniques, when appropriate, and other forms of

information technology.

Title: Reporting the Status of Postmarketing Studies for Human

Drugs and Licensed Biological Products.

Description: Section 506B of the act provides FDA with additional

authority for monitoring the progress of postmarketing studies that

companies have made a commitment to conduct and also requires the

agency to make the status of these studies publicly available.

Under section 506B(a) of the act, applicants that have committed to

conduct a postmarketing study for an approved human drug or biological

product must submit to FDA a report of the progress of the study or the

reasons for the failure of the applicant to conduct the study. This

report must be submitted within 1 year after the U.S. approval of the

product and annually thereafter until the study is completed or

terminated. Under Secs. 314.81(b)(2)(vii) and (b)(2)(viii), and

601.70(b), information submitted in a status report would be limited to

that which is needed to sufficiently identify each applicant that has

committed to conduct a postmarketing study, the status of the study

that is being reported, and the reasons, if any, for the applicant's

failure to conduct, complete, and report the study.

Currently under Sec. 314.81(b)(2), applicants holding an NDA or an

ANDA must submit status reports on postmarketing studies for the

approved human drug product as part of an annual report to FDA. The

agency is proposing to amend Sec. 314.81(b)(2)(vii) to specify

information that must be included in status reports submitted under

section 506B of the act (studies of clinical safety, clinical efficacy,

clinical pharmacology, and nonclinical toxicology that are required by

FDA or that an applicant commits, in writing, to conduct either at the

time of approval of an application or a supplement to an application or

after approval of an application or supplement). Proposed

Sec. 314.81(b)(2) also adds paragraph (b)(2)(viii) which would require

status information on any postmarketing study commitments not reported

under paragraph (b)(2)(vii) that are being performed by, or on behalf

of, the applicant; and paragraph (b)(2)(ix) which would allow the

applicant to list any open regulatory business with FDA concerning the

drug product subject to the application. For licensed biological

products, FDA proposes to create Sec. 601.70 to require postmarketing

status reports for studies of clinical safety, clinical efficacy,

clinical pharmacology, and nonclinical toxicology that are required by

FDA or that an applicant of a BLA commits to conduct, in writing, at

the time of approval of an application or a supplement to an

application or after approval of an application or a supplement. FDA is

also proposing to revise Sec. 601.37(c) to require that the status of

postmarketing pediatric studies described in proposed Sec. 601.70 be

reported under proposed Sec. 601.70 rather than Sec. 601.37.

This proposed rule is intended to provide FDA with specific

procedures for monitoring the progress of postmarketing studies that

companies have made a commitment, in writing, to conduct and also to

permit the agency to make the status of these studies publicly

available.

Description of Respondents: Applicants holding approved

[[Page 67214]]

applications for human drugs and biological products that have

committed to conduct postmarketing studies.

Under current Sec. 314.81(b)(2), applicants with approved NDA's and

ANDA's for human drugs are required to submit to the agency two copies

of the annual reports that must include information on the current

status of any postmarketing study (OMB No. 0910-0001).

Proposed Sec. 314.81(b)(2)(vii), (b)(2)(viii), and (b)(2)(ix) would

expressly require status information to be provided in a specific

format as part of the status reports of postmarketing study commitments

(clinical safety, clinical efficacy, clinical pharmacology, and

nonclinical toxicology), a subpart of the annual report. Based on past

experience, the agency estimates that each applicant holding an

approved NDA or ANDA would expend an additional 8 hours, to reformat

the annual report. This is a one-time burden required under proposed

Sec. 314.81(b)(2)(vii). Based on the number of drug applicants in past

years who have committed to conduct postmarketing studies, the agency

estimates that this provision would apply to approximately 183

applicants and approximately 462 postmarketing studies.

Based upon information obtained from the Center for Biologics

Evaluation and Research's computerized application and license tracking

database, the agency estimates that approximately 33 applicants with 43

approved BLA's have committed to conduct approximately 86 postmarketing

studies (clinical safety, clinical efficacy, clinical pharmacology, and

nonclinical toxicology) and would be required to submit an annual

progress report on those postmarketing studies under proposed

Sec. 601.70. Proposed Sec. 601.70 requires postmarketing studies status

reports for the first time for biological products. Based on past

experience with reporting under Sec. 314.81(b)(2), the agency estimates

that approximately 8 hours annually is required for an applicant to

gather, complete, and submit the appropriate information for each

report (approximately two studies per report). Included in these 8

hours is the time necessary to initially format the status report.

Applicants holding NDA's, ANDA's, and BLA's whose anniversary date

of U.S. approval of the application falls within the latter half of the

year after the effective date of any final rule that may issue based on

this proposed rule are required under section 506B of the act to submit

an initial report to FDA for postmarketing studies committed to be

conducted prior to November 21, 1997, within 6 months after the

effective date of any final rule in addition to the reports required by

the final rule. This information collection is a statutory requirement

for which the proposed regulations add no additional burden other than

prescribing the format. The burden of setting up the format is

calculated under Secs. 314.81(b)(2)(vii) and 601.70(b).

Table 1.--Estimated Annual Reporting Burden\1\

----------------------------------------------------------------------------------------------------------------

No. of Annual Frequency Total Annual Hours per

21 CFR Section Respondents per Response Responses Response Total Hours

----------------------------------------------------------------------------------------------------------------

314.81(b)(2)(vii), 183 2.5 462 8 3,696

(b)(2)(viii),

(b)(2)(ix)\2\

601.70(b) and (d) 33 2.6 86 8 688

Total 4,384

----------------------------------------------------------------------------------------------------------------

\1\ There are no capital costs or operating and maintenance costs with this collection of information.

\2\ One-time burden for reformatting annual report.

In compliance with section 3507(d) of the Paperwork Reduction Act

of 1995 (44 U.S.C. 3507(d)), the agency has submitted the information

collection provisions of this proposed rule to OMB for review.

Interested persons are requested to send comments regarding this

information collection by January 3, 2000, to the Office of Information

and Regulatory Affairs, OMB, New Executive Office Bldg., 725 17th St.

NW., rm. 10235, Washington, DC 20503, Attn: Desk Officer for FDA.

VII. Reference

The following reference has been placed on display in the Dockets

Management Branch (address above) and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday through Friday.

1. ``Postmarketing Studies of Prescription Drugs,'' Department

of Health and Human Services, Office of the Inspector General Final

Report, May 1996.

List of Subjects

21 CFR Part 314

Administrative practice and procedure, Confidential business

information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 601

Administrative practice and procedure, Biologics, Confidential

business information.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the

Public Health Service Act, and under authority delegated to the

Commissioner of Food and Drugs, it is proposed that 21 CFR parts 314

and 601 be amended as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

1. The authority citation for 21 CFR part 314 is revised to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356b, 371,

374, 379e.

2. Section 314.81 is amended by revising the introductory text of

paragraph (b)(2), by revising paragraph (b)(2)(vii), and by adding

paragraphs (b)(2)(viii) and (b)(2)(ix) to read as follows:

Sec. 314.81 Other postmarketing reports.

* * * * *

(b) * * *

(2) Annual report. The applicant shall submit the following

information each year within 60 days of the anniversary date of U.S.

approval of the application. The applicant shall submit two copies of

the report to the FDA division responsible for reviewing the

application. Each annual report is required to be accompanied by a

completed transmittal Form FDA-2252 (Transmittal of Annual Reports for

Drugs for Human Use), which may be obtained from the PHS Forms and

Publications Distribution Center, 12100 Parklawn Dr., Rockville, MD

20857, and is required to include all the information required under

this section that the applicant received or otherwise obtained during

the annual reporting interval, which ends on the U.S. anniversary date.

The report is required to contain in the order listed:

* * * * *

(vii) Status reports of postmarketing study commitments. A status

report of each postmarketing study of the drug product concerning

clinical safety, clinical efficacy, clinical pharmacology,

[[Page 67215]]

and nonclinical toxicology that is required by FDA (e.g., pediatric

studies) or that the applicant has committed, in writing, to conduct

either at the time of approval of an application for the drug product

or a supplement to an application, or after approval of an application

or a supplement. For pediatric studies, the status report shall include

a statement indicating whether postmarketing clinical studies in

pediatric populations were required by FDA under Sec. 201.23 of this

chapter. The status of these postmarketing studies shall be reported

annually until FDA notifies the applicant, in writing, that the agency

concurs with the applicant's determination that the study commitment

has been fulfilled or that the study is either no longer feasible or

would no longer provide useful information.

(a) Content of status report. The following information shall be

provided for each postmarketing study reported under this paragraph:

(1) Applicant's name.

(2) Product name. Include the approved drug product's established

name and proprietary name, if applicable.

(3) NDA, ANDA (abbreviated new drug application), or supplement

number.

(4) Date of product's U.S. approval.

(5) Date of postmarketing study commitment.

(6) Description of postmarketing study commitment. For clinical

studies, include the purpose of the postmarketing study, the patient

population addressed by the study, the number of patients and/or

subjects to be included in the study, and the indication and dosage(s)

that are to be studied. For nonclinical studies, include the type and

purpose of the study.

(7) Schedule for conduct, completion, and reporting of the

postmarketing study commitment. Include projected dates for initiation

of the different phases of the study, for completion of the study, and

for submission of the final study report to FDA. Provide a revised

schedule, in addition to the original schedule, if the original

schedule was revised in the previous report.

(8) Current status of the postmarketing study commitment.

Categorize the status of each postmarketing study using one of the

following terms that describes the study's status on the anniversary

date of U.S. approval of the application or other agreed upon date:

(i) Pending. The study has not been initiated.

(ii) Ongoing. The study is proceeding according to or ahead of the

original schedule described under paragraph (b)(2)(vii)(a)(7) of this

section. Include the date the study was completed, if a study has been

completed but the final study report has not been submitted to FDA.

(iii) Delayed. The study is proceeding but is behind the original

schedule described under paragraph (b)(2)(vii)(a)(7) of this section.

(iv) Terminated. The study was ended before completion.

(v) Submitted. The study has been completed or terminated and a

final study report has been submitted to FDA. Include the date the

final study report was submitted to FDA.

(9) Explanation of the study's status. Provide a brief description

of the status of the study, including the number of patients and/or

subjects enrolled to date and an explanation of the study's status

identified under paragraph (b)(2)(vii)(a)(8) of this section. Provide a

revised schedule, as well as the reason(s) for the revision, if the

schedule under paragraph (b)(2)(vii)(a)(7) of this section has changed

since the last report.

(b) Public disclosure of information. Except for the information

described in this paragraph, FDA may publicly disclose any information

concerning a postmarketing study, within the meaning of paragraph

(b)(2)(vii) of this section, if the agency determines that the

information is necessary to identify the applicant or to establish the

status of the study including the reasons, if any, for failure to

conduct, complete, and report the study. Information necessary to

establish the status of a postmarketing study includes the study

protocol, patient accrual rates, reports of unexpected suspected

adverse drug reactions, and study results. Under this section, FDA will

not publicly disclose trade secrets, as defined in Sec. 20.61 of this

chapter, or information, described in Sec. 20.63 of this chapter, the

disclosure of which would constitute an unwarranted invasion of

personal privacy.

(viii) Status of other postmarketing studies. A status report of

any postmarketing study not included under paragraph (b)(2)(vii) of

this section that is being performed by, or on behalf of, the

applicant. The applicant shall provide information as prescribed under

paragraphs (b)(2)(vii)(a)(1) through (b)(2)(vii)(a)(9) of this section

for each of the postmarketing studies required to be reported under

this paragraph.

(ix) Log of outstanding regulatory business. To facilitate

communications between FDA and the applicant, the report may, at the

applicant's discretion, also contain a list of any open regulatory

business with FDA concerning the drug product subject to the

application (e.g., a list of the applicant's unanswered correspondence

with the agency, a list of the agency's unanswered correspondence with

the applicant).

PART 601--LICENSING

3. The authority citation for 21 CFR part 601 is revised to read as

follows:

Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,

355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C.

216, 241, 262, 263, 264; sec. 122, Pub. L. 105-115, 111 Stat. 2322

(21 U.S.C. 355 note).

4. Section 601.37 is amended by revising the second sentence in

paragraph (c) to read as follows:

Sec. 601.37 Annual reports of postmarketing pediatric studies.

* * * * *

(c) * * * The statement shall include whether postmarketing

clinical studies in pediatric populations were required or agreed to,

and, if so, the status of these studies shall be reported to FDA in

annual progress reports of postmarketing studies under Sec. 601.70

rather than under this section.

5. Subpart G, consisting of Sec. 601.70, is added to part 601 to

read as follows:

Subpart G--Postmarketing Studies

Sec. 601.70 Annual progress reports of postmarketing studies

(a) General requirements. This section applies to all required

postmarketing studies (e.g., pediatric studies) and postmarketing

studies that an applicant has committed, in writing, to conduct either

at the time of approval of an application or a supplement to an

application, or after approval of an application or a supplement.

Postmarketing studies within the meaning of this section are those that

concern:

(1) Clinical safety;

(2) Clinical efficacy;

(3) Clinical pharmacology; and

(4) Nonclinical toxicology.

(b) What to report. Each applicant of a licensed biological product

shall submit a report to FDA on the status of postmarketing studies for

each approved product application. The report shall include the status

of each study which is required by FDA (e.g., pediatric studies) or

which the applicant has committed, in writing, to conduct, including

any reasons for the applicant's failure to conduct or to progress with

the study. The status of these postmarketing studies shall be

[[Page 67216]]

reported annually until FDA notifies the applicant, in writing, that

the agency concurs with the applicant's determination that the study

commitment has been fulfilled, or that the study is either no longer

feasible or would no longer provide useful information. Each annual

progress report shall be accompanied by a completed transmittal Form

FDA-2252, which may be obtained from the PHS Forms and Publications

Distribution Center, 12100 Parklawn Dr., Rockville, MD 20857, and shall

include all the information required under this section that the

applicant received or otherwise obtained during the annual reporting

interval, which ends on the U.S. anniversary date. The report shall

provide the following information for each postmarketing study:

(1) Applicant's name.

(2) Product name. Include the approved product's proper name and

the proprietary name, if applicable.

(3) Biologics license application (BLA)/reference or supplement

number. The biologics license application number, reference number, or

supplement number of the approved product.

(4) Date of product's U.S. approval.

(5) Date of postmarketing study commitment.

(6) Description of postmarketing study commitment. For clinical

studies, include the purpose of the postmarketing study, the patient

population addressed by the postmarketing study, the number of patients

and/or subjects to be included in the study, and the indication and

dosage(s) that are to be studied. For nonclinical studies, include the

type and purpose of the study.

(7) Schedule for conduct, completion, and reporting of the

postmarketing study commitment. Include projected dates for initiation

of the different phases of the study, for completion of the study, and

for submission of the final study report to FDA. Provide a revised

schedule, in addition to the original schedule, if the original

schedule was revised in the previous report.

(8) Current status of the postmarketing study commitment.

Categorize the status of each postmarketing study using one of the

following terms that describes the study's status on the anniversary

date of the U.S. approval of the application or other agreed date:

(i) Pending. The study has not been initiated.

(ii) Ongoing. The study is proceeding according to or ahead of the

original schedule described under paragraph (b)(7) of this section.

Include the date the study was completed, if a study has been completed

but the final study report has not been submitted to FDA.

(iii) Delayed. The study is proceeding but is behind the original

schedule described under paragraph (b)(7) of this section.

(iv) Terminated. The study was ended before completion.

(v) Submitted. The study has been completed or terminated, and a

final study report has been submitted to FDA. Include the date the

final study report was submitted to FDA.

(9) Explanation of the study's status. Provide a brief description

of the status of the study, including the number of patients and/or

subjects enrolled to date and an explanation of the study's status

identified under paragraph (b)(8) of this section. Provide a revised

schedule, as well as the reason(s) for the revision, if the schedule

under paragraph (b)(7) of this section has changed since the previous

report.

(c) When to report. Annual progress reports for postmarketing study

commitments entered into by applicants shall be reported to FDA within

60 days of the anniversary date of the U.S. approval of the application

for the product.

(d) Where to report. Submit two copies of the annual progress

report of postmarketing studies to the Food and Drug Administration,

Center for Biologics Evaluations and Research, Document Control Center

(HFM-99), suite 200N, 1401 Rockville Pike, Rockville, MD 20852-1448.

(e) Public disclosure of information. Except for the information

described in this paragraph, FDA may publicly disclose any information

concerning a postmarketing study, within the meaning of this section,

if the agency determines that the information is necessary to identify

an applicant or to establish the status of the study including the

reasons, if any, for failure to conduct, complete, and report the

study. Information necessary to establish the status of a postmarketing

study includes the study protocol, patient accrual rates, reports of

unexpected suspected adverse drug experiences, and study results. Under

this section, FDA will not publicly disclose trade secrets, as defined

in Sec. 20.61 of this chapter, or information described in Sec. 20.63

of this chapter, the disclosure of which would constitute an

unwarranted invasion of personal privacy.

Dated: August 9, 1999.

Margaret M. Dotzel,

Acting Associate Commissioner for Policy.

[FR Doc. 99-31123 Filed 11-30-99; 8:45 am]

BILLING CODE 4160-01-F