[Federal Register Volume 64, Number 46 (Wednesday, March 10, 1999)]
[Notices]
[Pages 11920-11922]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-5904]


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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