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Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Adverse Experience Reporting for Licensed Biological Products; and General Records

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Food and Drug Administration, HHS.




The Food and Drug Administration (FDA) is announcing that a proposed collection of information has been submitted to the Office of Management and Budget (OMB) for review and clearance under the Paperwork Reduction Act of 1995.


Fax written comments on the collection of information by November 28, 2014.


To ensure that comments on the information collection are received, OMB recommends that written comments be faxed to the Office of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX: 202-395-7285, or emailed to All comments should be identified with the OMB control number 0910-0308. Also include the FDA docket number found in brackets in the heading of this document.

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FDA PRA Staff, Office of Operations, Food and Drug Administration, 8455 Colesville Rd., COLE-14526, Silver Spring, MD 20993-0002,

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In compliance with 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; and General Records—21 CFR Part 600—(OMB Control Number 0910-0308)—Extension

Under the Public Health Service (PHS) Act (42 U.S.C. 262), FDA may only approve a biologics license application for a biological product that is safe, pure, and potent. When a biological product is approved and enters the market, the product is introduced to a larger patient population in settings different from clinical trials. New information generated during the postmarketing period offers further insight into the benefits and risks of the product, and evaluation of this information is important to insure its safe use. FDA issued the Adverse Experience Reporting (AER) requirements in part 600 (21 CFR part 600) 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.[1]

The primary purpose of FDA's AER system is to identify potentially serious safety problems with licensed biological products. Although the premarket approval process is meant to disclose a general safety profile of a biological product'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. In addition, production and/or distribution problems have contaminated biological products in the past. AER reports are obtained from a variety of sources, including manufacturers, patients, physicians, foreign regulatory agencies, and clinical investigators. Identification of new and unexpected safety issues through the analysis of the data in AERS contributes directly to increased public health protection. For example, evaluation of these safety issues enables FDA to take focused regulatory action. Such action may include, but is not limited to, important changes to the product's labeling (such as adding a new warning), coordination with manufacturers to ensure adequate corrective action is taken, and removal of a biological product from the market when necessary.

Section 600.80(c)(1) requires licensed manufacturers or any person whose name appears on the label of a licensed biological product to report each adverse experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of the information by the licensed manufacturer. These reports are known as postmarketing 15-day Alert reports. This section also requires licensed manufacturers to submit any follow-up reports within 15 calendar days of receipt of new information or as requested by FDA, and if additional information is not obtainable, to maintain records of the unsuccessful steps taken to seek additional information. In addition, this section requires a person who submits an adverse action report to the licensed manufacturer, rather than FDA, to maintain a record of this action.

Section 600.80(e) requires licensed manufacturers to submit a 15-day Alert report for an adverse experience obtained from a postmarketing clinical study only if the licensed manufacturer concludes that there is a reasonable possibility that the product caused the adverse experience. Section 600.80(c)(2) requires licensed manufacturers to report each adverse experience not reported in a postmarketing 15-day Alert report at quarterly intervals, for 3 years from the date of issuance of the biologics license, and then at annual intervals. The majority of these periodic reports are submitted annually since a large percentage of currently licensed biological products have been licensed longer than 3 years. Section 600.80(i) requires 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 requires licensed manufacturers to submit, at an interval of every 6 months, information about the quantity of the product distributed under the biologics Start Printed Page 64393license, including the quantity distributed to distributors.

These distribution reports provide FDA with important information about products distributed under biologics licenses, including the quantity, certain lot numbers, labeled date of expiration, the fill lot numbers for the total number of dosage units of each strength or potency distributed (e.g., 50,000 per 10-milliliter vials), and date of release. FDA may require the licensed manufacturer to submit distribution reports under this section at times other than every 6 months. Under § 600.90, a licensed manufacturer may submit a waiver request for any requirements that apply to the licensed manufacturer under §§ 600.80 and 600.81. A waiver request submitted under § 600.90 must include supporting documentation.

Manufacturers of biological products for human use must keep records of each step in the manufacture and distribution of a product including any recalls. These recordkeeping requirements serve preventative and remedial purposes by establishing accountability and traceability in the manufacture and distribution of products. These requirements also enable FDA to perform meaningful inspections. Section 600.12 requires, among other things, that records must be made concurrently with the performance of each step in the manufacture and distribution of products. These records must be 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, under § 600.12, manufacturers must maintain records relating to the sterilization of equipment and supplies, animal necropsy records, and records in cases of divided manufacturing responsibility with respect to a product. Under § 600.12(b)(2), manufacturers are also required to maintain complete records pertaining to the recall from distribution of any product. Furthermore, § 610.18(b) requires, in part, that the results of all periodic tests for verification of cultures and determination of freedom from extraneous organisms be recorded and maintained. The recordkeeping requirements for §§ 610.12(g), 610.13(a)(2), 610.18(d), 680.2(f) and 680.3(f) are approved under OMB control number 0910-0139.

Respondents to this collection of information include manufacturers of biological products and any person whose name appears on the label of a licensed biological product. In table 1, the number of respondents is based on the estimated number of manufacturers that are subject to those regulations or that submitted the required information to the Center for Biologics Evaluation and Research and Center for Drugs Evaluation and Research, FDA, in fiscal year (FY) 2013. Based on information obtained from FDA's database system, there were 131 licensed biologics manufacturers. This number excludes those manufacturers who produce Whole Blood or components of Whole Blood and in vitro diagnostic licensed products, because of the exemption under § 600.80(k). The total annual responses are based on the number of submissions received by FDA in FY 2013. There were an estimated 92,470 15-day Alert reports, 132,667 periodic reports, and 334 lot distribution reports submitted to FDA. The number of 15-day Alert reports for postmarketing studies under § 600.80(e) is included in the total number of 15-day Alert reports. FDA received 64 requests from 35 manufacturers for waivers under § 600.90, of which 63 were granted. The hours per response are based on FDA experience. The burden hours required to complete the MedWatch Form for § 600.80(c)(1), (e), and (f) are reported under OMB control number 0910-0291.

In the Federal Register of April 7, 2014 (79 FR 19097), FDA published a 60-day notice requesting public comment on the proposed collection of information. FDA received one comment; however, this comment did not address the information collection.

FDA estimates the burden of this collection of information as follows:

Table 1—Estimated Annual Reporting Burden 1

21 CFR sectionNumber of respondentsNumber of responses per respondentTotal annual responsesAverage burden per responseTotal hours
600.80(c)(1) and 600.80(e)131705.8892,470192,470
1 There are no capital costs or operating and maintenance costs associated with this collection of information.

In table 2, the number of respondents is based on the number of manufacturers subject to those regulations. Based on information obtained from FDA's database system, there were 334 licensed manufacturers of biological products in FY 2013. However, the number of recordkeepers listed for § 600.12(a) through (e) excluding (b)(2) is estimated to be 164. This number excludes manufacturers of blood and blood components because their burden hours for recordkeeping have been reported under § 606.160 in OMB control number 0910-0116. The total annual records is based on the annual average of lots released in FY 2013 (6,887), number of recalls made (1,679), and total number of adverse experience reports received (225,137) in FY 2013. The hours per record are based on FDA experience.

FDA estimates the burden of this recordkeeping as follows:

Table 2—Estimated Annual Recordkeeping Burden 1

21 CFR sectionNumber of recordkeepersNumber of records per recordkeeperTotal annual recordsAverage burden per recordkeepingTotal hours
600.12 216441.996,88732220,384
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600.80(c)(1) and 600.80(i)1311,718.60225,1371225,137
1 There are no capital costs or operating and maintenance costs associated with this collection of information.
2 The recordkeeping requirements in § 610.18(b) are included in the estimate for § 600.12.
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Dated: October 23, 2014.

Leslie Kux,

Assistant Commissioner for Policy.

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1.  Please note that throughout the regulations referenced in relation to these information collections, licensed biological products refers to biologics licensed under any provision of section 351 of the PHS Act.

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[FR Doc. 2014-25637 Filed 10-28-14; 8:45 am]