Agency Information Collection Activities; Submission for OMB Review; Comment Request; Adverse Experience Reporting for Licensed Biological Products, and General Records

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 98N-0482]

Agency Information Collection Activities; Submission for OMB

Review; Comment Request; Adverse Experience Reporting for Licensed

Biological Products, and General Records

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that the

proposed collection of information listed below has been submitted to

the Office of Management and Budget (OMB) for review and clearance

under the Paperwork Reduction Act of 1995 (the PRA).

DATES: Submit written comments on the collection of information by

April 9, 1999.

ADDRESSES: Submit written comments on the collection of information 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.

FOR FURTHER INFORMATION CONTACT: JonnaLynn P. Capezzuto, Office of

Information Resources Management (HFA-250), Food and Drug

Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-4659.

SUPPLEMENTARY INFORMATION: In compliance with section 3507 of the PRA

(44 U.S.C. 3507), FDA has submitted the following proposed collection

of information to OMB for review and clearance.

Adverse Experience Reporting for Licensed Biological Products--21 CFR

600.80, 600.81, and 600.90; and General Records--21 CFR 600.12 (OMB

Control Number 0910-0308)--Extension

Under the Federal Food, Drug, and Cosmetic Act (the act) (21

U.S.C. 201 et seq.) and the Public Health Service Act (42 U.S.C. 262

and 264), FDA is required to ensure the marketing of only those

biological products that are shown to be safe and effective. Under the

authority of section 301(e) of the act (21 U.S.C. 331(e)), FDA issued

regulations for adverse experience reports related to the use of

licensed biological products. FDA issued the adverse experience

reporting requirements to enable FDA to take actions necessary for the

protection of the public health in response to reports of adverse

experiences related to licensed biological products. The adverse

experience reporting system flags potentially serious safety problems

with licensed biological products, focusing especially on newly

licensed products. Although premarket testing discloses a general

safety profile of a new drug's comparatively common adverse effects,

the larger and more diverse patient populations exposed to the licensed

biological product provides the opportunity to collect information on

rare, latent, and long-term effects. Reports are obtained from a

variety of sources, including patients, physicians, foreign regulatory

agencies, and clinical investigators. Information derived from the

adverse experience reporting system contributes directly to increased

public health protection because such information enables FDA to

recommend important changes to the product's labeling (such as adding a

new warning), to initiate removal of a biological product from the

market when necessary, and to assure the manufacturer has taken

adequate corrective action, if necessary.

Manufacturers of biological products for human use must also keep

records of each step in the manufacture and distribution of products

including any recalls of the product. The recordkeeping requirements

serve preventative and remedial purposes. These requirements establish

accountability and traceability in the manufacture and distribution of

products, and enable FDA to perform meaningful inspections.

Section 600.12 (21 CFR 600.12) requires that all records of each

step in the manufacture and distribution of a product be made and

retained for no less than 5 years after the records of manufacture have

been completed or 6 months after the latest expiration date for the

individual product, whichever represents a later date. In addition,

records of sterilization of equipment and supplies, animal necropsy

records, and records in cases of divided manufacturing of a product are

required to be maintained. Section 600.12(b)(2) requires complete

records to be maintained pertaining to the recall from distribution of

any product.

Section 600.80(c)(1) (21 CFR 600.80(c)(1)) requires the licensed

manufacturer to report each adverse experience that is both serious and

unexpected, regardless of source, as soon as possible but in any case

within 15 working days of initial receipt of the information. Section

600.80(e) requires licensed manufacturers to submit a 15-day alert

report obtained from a postmarketing clinical study only if there is a

reasonable possibility that the

[[Page 11921]]

product caused the adverse experience. Section 600.80(c)(2) requires

the licensed manufacturer to report each adverse experience not

reported under paragraph (c)(1) at quarterly intervals, for 3 years

from the date of issuance of the product license, and then at annual

intervals. The majority of the periodic reports will be submitted

annually since a large percentage of the current licensed biological

products have been licensed longer than 3 years. Section 600.80(i)

requires the licensed manufacturers to maintain for a period of 10

years records of all adverse experiences known to the licensed

manufacturer, including raw data and any correspondence relating to the

adverse experiences. Section 600.81 (21 CFR 600.81) requires the

licensed manufacturer to submit information about the quantity of the

product distributed under the product license, including the quantity

distributed to distributors at an interval of every 6 months. The

semiannual distribution report informs FDA of the quantity, the lot

number, and the dosage of different products. Section 600.90 (21 CFR

600.90) requires a licensed manufacturer to submit a waiver request

with supporting documentation when asking for waiving the requirement

that applies to them under Secs. 600.80 and 600.81.

In the Federal Register of July 10, 1998 (63 FR 37394), a 60-day

notice for public comment on the information collection provisions was

published. Two comments were received in response to the 60-day notice.

Both comments agreed there is practical value in this proposed

collection of information. However they questioned the estimate of the

annual responses and provided estimates of burden hours for

Sec. 600.80(c)(2). Based on these comments and further internal

research, the estimated annual reporting burden has been revised as

follows. A periodic report submitted under Sec. 600.80(c)(2) may

include one or more, even hundreds, of individual MedWatch and Vaccine

Adverse Event Reporting System (VAERS)-1 Forms. These forms are

attached to the report. The original estimate of periodic reports

(5,903) included the number of individual attached forms, whereas the

current estimate (1,129) reflects only the number of periodic reports

received regardless of the number of attachments. More than half of

these reports are monthly reports on plasma derivatives that should

take on the average 2 hours each to complete. The balance of the

reports are quarterly and annual reports that may each require an

average of 28 hours to prepare. The burden hours required to complete

the MedWatch Form for Sec. 600.80(c)(1), (e), and (f) are reported

under OMB Control No. 0910-0291. The VAERS-1 Form is exempt from

compliance with paperwork reduction requirements under the National

Childhood Vaccine Injury Act (42 U.S.C. 300aa-1) (section 321 of Pub.

L. 99-660).

Both comments questioned the statement that there are no capital,

operating, or maintenance costs associated with maintaining records of

adverse experience reports for 10 years. FDA believes there are no

maintenance costs associated with the storage/retention of records

because respondents already have the facilities and the infrastructure

for ongoing record retention, and that existing and emerging data

storage technology minimizes space and costs of long-term record

retention.

Both comments recommended ways to enhance the quality, utility,

and clarity of the information to be collected, and to minimize the

burden of the collection of information on the respondents. FDA is in

the process of revising its safety reporting and recordkeeping

regulations and will consider these comments in developing its

rulemaking. FDA has provided notice and requested comments on several

proposed rules. In the Federal Register of October 27, 1994 (59 FR

54046), FDA published a proposed rule to amend its postmarketing

expedited and periodic safety reporting requirements, as well as

others, to implement international standards and to facilitate the

reporting of adverse drug experiences. In the Federal Register of

October 27, 1997 (62 FR 52237), FDA published a final rule amending its

expedited safety reporting regulations to implement certain

recommendations in the International Conference on Harmonization of

Technical Requirements for Registration of Pharmaceuticals for Human

Use (ICH) E2A guidance on definitions and standards for expedited

reporting (58 FR 37408, July 9, 1993). At this time, the agency is

further considering recommendations in the ICH E2A guidance for

additional amendments to its postmarketing expedited safety reporting

regulations. With respect to the proposed amendments to the periodic

adverse drug experience reporting requirements in the proposal of

October 27, 1994, FDA has decided to repropose these amendments based

on recommendations in the ICH E2C guidance on periodic safety update

reports (62 FR 27470, May 19, 1997). In developing the reproposal, FDA

will also consider comments submitted in response to the proposed rule

of October 27, 1994, regarding periodic adverse experience reports. FDA

is also considering rulemaking concerning the electronic submission of

postmarketing expedited and periodic safety reports using standardized

medical terminology, data elements, and electronic transmission

standards recommended by ICH. The respondents to the collection of

information discussed here will, therefore, have further opportunity to

provide comment on these rulemaking initiatives.

Description of Respondents: Respondents to this collection of

information are manufacturers of biological products.

Reporting Burden: The total number of respondents in the chart, is

based upon information submitted to FDA in fiscal year (FY) 1996, which

shows that 69 licensed manufacturers (excluding 3 manufacturers who

received waivers from Adverse Event Reporting (AER) requirements,

produced 242 licensed biological products. The 69 licensed

manufacturers excludes those manufacturers who only produce blood and

blood components or in vitro diagnostic licensed products and are

exempt from the AER regulations. In FY 1996, licensed manufacturers

submitted approximately 1,616 15-day alert reports under

Sec. 600.80(c)(1) and (e); 1,129 periodic reports under

Sec. 600.80(c)(2); and 464 distribution reports under Sec. 600.81. The

MedWatch Form that is used to submit the information provided under

Sec. 600.80(c)(1), (e), and (f) has received approval under OMB Control

No. 0910-0291.

Table 1.--Estimated Annual Reporting Burden1

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Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Respondents Response Responses Response

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600.80(c)(1) and (e) 69 23.4 1,616 1 1,616

600.80(c)(2) 69 16.4 1,129 28 31,612

[[Page 11922]]

600.81 69 6.7 464 1 464

600.90 3 1 3 1 3

Total 33,695

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

Recordkeeping Burden: There are approximately 391 licensed

manufacturers of biological products. The number of recordkeepers under

Sec. 600.12(a), (c), (d), and (e) is estimated to be 102. That number

excludes the 189 manufacturers of blood and blood components whose

recordkeeping is conducted under 21 CFR 606.160, which is approved

under OMB Control No. 0910-0116. FDA expects that the total number of

AER records kept by the respondent will parallel the total number of

reports submitted to FDA. The total number of annual records,

therefore, is based on reporting information provided to FDA by

manufacturers. Based on FY 1996 data, the total annual records are

estimated as follows: Under Sec. 600.12(a), (c), (d), and (e), the

number of lots released was 9,027; under Sec. 600.12(b)(2), the number

of recalls was 710; and under Sec. 600.80(i), the total number of AER

reports received was 2,745. Based on FDA's experience, the agency

estimates that the total number of hours per recordkeeper under

Sec. 600.12(a), (c), (d), and (e) would be 32 hours per lot multiplied

by 88.5 lot records on the average per recordkeeper, totaling 2,832

hours; the total number of hours per recordkeeper under

Sec. 600.12(b)(2) would be 24 hours per recall multiplied by 1.8

recalls on the average per recordkeeper, totaling 43 hours; and the

total number of hours per recordkeeper under Sec. 600.80(i) would be 1

hour per report multiplied by 39.8 AER records on the average per

recordkeeper, totaling 40 hours.

Table 2.--Estimated Annual Recordkeeping Burden1

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Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Recordkeepers Recordkeeping Records Recordkeeper

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600.12(a), (c), (d) and (e) 102 88.5 9,027 2,832 288,864

600.12(b)(2) 391 1.8 710 43 16,813

600.80(i) 69 39.8 2,745 40 2,760

Total 308,437

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

Dated: March 4, 1999.

William K. Hubbard,

Acting Deputy Commissioner for Policy.

[FR Doc. 99-5904 Filed 3-9-99; 8:45 am]

BILLING CODE 4160-01-F