Postmarketing Expedited Adverse Experience Reporting for Human Drug and Licensed Biological Products; Increased Frequency Reports

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 314, and 600

[Docket No. 96N-0108]

Postmarketing Expedited Adverse Experience Reporting for Human

Drug and Licensed Biological Products; Increased Frequency Reports

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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

SUMMARY: The Food and Drug Administration (FDA) is amending its

regulations on expedited reporting of postmarketing adverse experiences

to revoke the requirement for increased frequency reports as expedited

reports for human drug and licensed biological products. This action,

which is part of the President's regulatory reinvention initiative, is

based on FDA's determination that expedited increased frequency reports

have not contributed to the timely identification of safety problems

requiring regulatory action and are no longer necessary for FDA

surveillance of postmarketing adverse experiences. This action is

intended to streamline postmarketing expedited reporting of adverse

experiences for human drug and licensed biological products. This

action will not affect the requirement for expedited reporting of all

serious, unexpected adverse experiences.

EFFECTIVE DATE: July 25, 1997.

FOR FURTHER INFORMATION CONTACT:

For information concerning human drug products: Audrey A. Thomas,

Center for Drug Evaluation and Research (HFD-7), Food and Drug

Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-5625.

For information concerning human licensed biological products:

Marcel E. Salive, Center for Biologics Evaluation and Research (HFM-

220), Food and Drug Administration, 1401 Rockville Pike, suite 200S,

Rockville, MD 20852-1448, 301-827-3974.

SUPPLEMENTARY INFORMATION:

I. Background

Under current Secs. 310.305(c)(4), 314.80(c)(1)(ii) and

(c)(1)(iii), and 600.80(c)(1)(ii) and (c)(1)(iii) (21 CFR

310.305(c)(4), 314.80(c)(1)(ii) and (c)(1)(iii), and 600.80(c)(1)(ii)

and (c)(1)(iii)), applicants, manufacturers, packers, and distributors,

including licensed manufacturers and other manufacturers of biological

products, are required to review periodically the frequency of reports

of adverse experiences that are both serious and expected and reports

of therapeutic failure (lack of effect), regardless of source, and

report any significant increase in frequency as soon as possible but in

any case within 15 working days of determining that a significant

increase in frequency exists. An increased frequency exists if the

adjusted reporting for the reporting interval is at least two times

greater than the adjusted reporting for the comparison interval

(previous reporting interval). These regulations were issued by FDA to

ensure that applicants, manufacturers, packers, and distributors,

including licensed manufacturers and other manufacturers of biological

products, identify increases in the incidence of serious, labeled

adverse experiences that are not anticipated from premarketing clinical

trials and that occur with changes in medical practice, such as using a

drug or biological product in higher risk populations, at higher

dosages, or concomitantly with other drugs or biological products

causing interactions.

In the Federal Register of October 28, 1996 (61 FR 55602), FDA

proposed to amend its postmarketing expedited adverse experience

reporting regulations to revoke the requirement for expedited increased

frequency reports in Secs. 310.305(c)(4), 314.80(c)(1)(ii) and

(c)(1)(iii), and 600.80(c)(1)(ii) and (c)(1)(iii), and to revoke the

definition of ``increased frequency'' in Secs. 310.305(b)(5),

314.80(a), and 600.80(a). As explained in the proposal, FDA determined

that increased frequency reports rarely prompted regulatory action

during the time that the agency received such reports, and the reports

proved to be of little value in identifying increased incidences of

serious, labeled experiences. This action does not affect the

requirement for expedited reporting of all serious, unexpected adverse

experiences. Applicants, manufacturers, packers, and distributors,

including licensed manufacturers and other manufacturers of biological

products, must continue to submit 15-day Alert reports and followup

reports for serious, unexpected events, as required under

Secs. 310.305(c), 314.80(c), 314.98, and 600.80(c).

II. Rationale

Several factors have contributed to FDA's decision to revoke the

requirement for expedited increased frequency reports. Key factors

include: (1) Safety problems that have been the subject of these

reports could have been detected in other safety reports, (2) the

reliability of increased frequency reports is limited, and (3) this

action is consistent with recent international efforts to harmonize

reporting requirements. These factors are discussed in more detail in

the following paragraphs.

Only a small number of drug/biological product safety problems

where expedited increased frequency reports played a role in risk

assessment have resulted in regulatory action. In each case, the safety

problems could have been detected in other safety reports required by

FDA such as periodic adverse experience reports, field alert reports,

or annual reports. FDA has found that expedited postmarketing adverse

experience reporting systems are best used to identify rare, unexpected

adverse drug reactions such as aplastic anemia, hepatic necrosis, renal

failure, or anaphylaxis that were not detected in preclinical studies

or clinical trials during drug development.

The reliability of increased frequency reports is limited because

of the difficulty in accurately estimating incidence rates. Increased

frequency information is derived from incidence rates, which are

estimated by dividing

[[Page 34167]]

the number of adverse experiences by the number of persons exposed to a

drug or biological product. Reporters compare incidence rates estimated

for the reporting interval with rates estimated for the previous

reporting interval. However, a number of uncertainties contribute to

the unreliability of incidence rates. For example, health care

providers do not report all adverse experiences or may report them to

the sponsor many months after they became aware of them. The number of

persons exposed to a drug or biological product during a reporting

period is not precisely known; it is only estimated based on sales or

production data. The lag time between production or sales by the

manufacturer and consumption by patients can vary, adding further

distortion to comparisons between reporting periods. Finally, because

of incomplete data and the uncertainty caused by the underlying

illness, indication, or other drug exposures, adverse experience

reports may be attributed to a drug or biological product even though

it may not necessarily have caused the adverse experience.

FDA's decision to revoke the requirement for expedited increased

frequency reports is also consistent with recent international

harmonization initiatives. In the Federal Register of October 27, 1994

(59 FR 54046), FDA proposed amending, among other things, its

regulations for periodic postmarketing reporting of adverse experiences

for human drug and licensed biological products based on

recommendations developed by the World Health Organization's Council

for International Organizations of Medical Sciences (CIOMS) Working

Group II. The revised regulations would include a section for overall

safety evaluation that would contain a critical analysis and full

discussion of the safety information provided in the periodic report as

it pertains to a number of matters, including increased frequencies of

known toxicity. Recently, the International Conference on Harmonisation

of Technical Requirements for Registration of Pharmaceuticals for Human

Use (ICH) developed, based on the CIOMS II proposals, a final guideline

for periodic reporting entitled ``Clinical Safety Data Management:

Periodic Safety Update Reports for Marketed Drugs.'' The guideline,

published in the Federal Register of May 19, 1997 (62 FR 27470),

recommends that the overall safety evaluation section of periodic

safety update reports highlight any new information on increased

frequencies of known adverse drug reactions, including comments on

whether it is believed that these data reflect a meaningful change in

adverse drug reaction occurrences. Under this guideline, regulatory

authorities will be able to obtain reports of increased frequencies

from periodic reports. FDA plans to finalize its proposed amendments to

the periodic postmarketing safety reporting regulations in a future

issue of the Federal Register. These amendments will be based on the

CIOMS and ICH recommendations.

III. Comments on the Proposed Rule

The agency received five comments from industry and the public. All

of the comments supported FDA's decision to revoke the requirement for

expedited increased frequency reports, stating that these reports have

not contributed to timely identification of safety problems requiring

regulatory action, nor to information for physicians or patient care.

All of the comments expressed the belief that because serious and

unexpected reports of adverse experiences are investigated and reported

under the 15-day Alert report requirement and because overall safety

and adverse experience data are summarized in periodic reports, FDA's

action to revoke the requirement of increased frequency reports will

result in the elimination of resource intensive procedures and provide

industry with more time to focus on evaluation of serious and

unexpected adverse drug experiences and other important medical product

events.

IV. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(8) 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. Paperwork Reduction Act of 1995

This final rule does not require information collections and, thus,

is not subject to review by the Office of Management and Budget (OMB)

under the Paperwork Reduction Act of 1995 (Pub. L. 104-13).

VI. Analysis of Impacts

FDA has examined the impacts of the final 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). The agency believes that

this final rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. In addition, the final

rule is not a significant regulatory action as defined by the Executive

Order and so is not subject to review under the Executive Order.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities. Because this final rule will simplify and streamline

current requirements, the Commissioner of Food and Drugs certifies that

the final rule will not have a significant economic impact on a

substantial number of small entities. Therefore, under the Regulatory

Flexibility Act, no further analysis is required.

List of Subjects

21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping requirements.

21 CFR Part 314

Administrative practice and procedure, Confidential business

information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

Biologics, Reporting and recordkeeping requirements.

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, 21 CFR parts 310, 314, and 600 are

amended as follows:

PART 310--NEW DRUGS

1. The authority citation for 21 CFR part 310 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-

516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,

360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301,

302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.

216, 241, 242(a), 262, 263b-263n).

2. Section 310.305 is amended by revising paragraph (a), by

removing paragraph (b)(5), by removing paragraph (c)(4), by

redesignating paragraphs (c)(5) and (c)(6) as paragraphs (c)(4) and

(c)(5),

[[Page 34168]]

respectively, by revising the first sentence of newly redesignated

paragraph (c)(4), and by revising paragraph (f)(1) to read as follows:

Sec. 310.305 Records and reports concerning adverse drug experiences

on marketed prescription drugs for human use without approved new drug

applications.

(a) Scope. FDA is requiring manufacturers, packers, and

distributors of marketed prescription drug products that are not the

subject of an approved new drug or abbreviated new drug application to

establish and maintain records and make reports to FDA of all serious,

unexpected adverse drug experiences associated with the use of their

drug products.

* * * * *

(c) * * *

(4) To avoid unnecessary duplication in the submission of, and

followup to, reports required in this section, a packer's or

distributor's obligations may be met by submission of all reports of

serious adverse drug experiences to the manufacturer of the drug

product. * * *

* * * * *

(f) Recordkeeping. (1) Each manufacturer, packer, and distributor

shall maintain for a period of 10 years records of all adverse drug

experiences required under this section to be reported, including raw

data and any correspondence relating to the adverse drug experiences,

and the records required to be maintained under paragraph (c)(4) of

this section.

* * * * *

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

ANTIBIOTIC DRUG

3. The authority citation for 21 CFR part 314 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,

704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,

331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).

4. Section 314.80 is amended by removing the definition for

Increased frequency in paragraph (a), by removing paragraph (c)(1)(ii),

by redesignating paragraphs (c)(1)(iii) and (c)(1)(iv) as paragraphs

(c)(1)(ii) and (c)(1)(iii), respectively, by revising the first two

sentences in the introductory text of newly redesignated paragraph

(c)(1)(ii), by removing the last sentence in paragraph (d)(1), by

revising paragraph (f)(1), and by revising the last sentence in

paragraph (l) to read as follows:

Sec. 314.80 Postmarketing reporting of adverse drug experiences.

* * * * *

(c) * * *

(1) * * *

(ii) The requirements of paragraph (c)(1)(i) of this section,

concerning the submission of 15-day Alert reports, shall also apply to

any person (other than the applicant) whose name appears on the label

of an approved drug product as a manufacturer, packer, or distributor.

However, to avoid unnecessary duplication in the submission to FDA of,

and followup to, reports required by paragraph (c)(1)(i) of this

section, obligations of a nonapplicant may be met by submission of all

reports of serious adverse drug experiences to the applicant. * * *

* * * * *

(f) Reporting Form FDA-1639. (1) Except as provided in paragraph

(f)(3) of this section, the applicant shall complete a Form FDA-1639

(Adverse Reaction Report) for each report of an adverse drug

experience.

* * * * *

(l) * * * For purposes of this provision, the term ``applicant''

also includes any person reporting under paragraph (c)(1)(ii) of this

section.

* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

5. The authority citation for 21 CFR part 600 continues to read as

follows:

Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of

the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,

353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125

of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a,

264, 300aa-25).

6. Section 600.80 is amended by removing the definition for

Increased frequency in paragraph (a), by removing paragraph (c)(1)(ii),

by redesignating paragraphs (c)(1)(iii) and (c)(1)(iv) as paragraphs

(c)(1)(ii) and (c)(1)(iii), respectively, by revising the first

sentence in the introductory text of newly redesignated paragraph

(c)(1)(ii), by removing the last sentence in paragraph (d)(1), by

revising paragraph (f)(1), and by revising the last sentence in

paragraph (m) to read as follows:

Sec. 600.80 Postmarketing reporting of adverse experiences.

* * * * *

(c) * * *

(1) * * *

(ii) The requirements of paragraph (c)(1)(i) of this section,

concerning the submission of 15-day Alert reports, shall also apply to

any person other than the licensed manufacturer of the final product

whose name appears on the label of a licensed biological product as a

manufacturer, packer, distributor, shared manufacturer, joint

manufacturer, or any other participant involved in divided

manufacturing. * * *

* * * * *

(f) Reporting forms. (1) Except as provided in paragraph (f)(3) of

this section, the licensed manufacturer shall complete the reporting

form designated by FDA (FDA-3500A, or, for vaccines, a VAERS form) for

each report of an adverse experience.

* * * * *

(m) * * * For purposes of this provision, this paragraph also

includes any person reporting under paragraph (c)(1)(ii) of this

section.

Dated: June 19, 1997.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 97-16684 Filed 6-20-97; 3:54 pm]

BILLING CODE 4160-01-F