0308 AERs for BLAs SSA 2018 Ext

U.S. Food and Drug Administration
Adverse Experience Reporting for
Licensed Biological Products and General Records
OMB Control No. 0910-0308
SUPPORTING STATEMENT Part A: Justification
1. Circumstances Making the Collection of Information Necessary
This information collection supports Food and Drug Administration (FDA) regulations. 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 ensure its safe use. Regulations implementing adverse experience reporting (AER)
requirements are codified in 21 CFR Part 600 and enable FDA to take actions necessary for the
protection of the public health in response to reports of adverse experiences related to biologics
licensed under any provision of section 351 of the PHS Act (42 U.S.C 262). Reporting and
recordkeeping provisions found in the regulations include the following:
Reporting:
21 CFR 600.80(c)(1)
and 600.80(d)

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
(postmarketing 15-day Alert reports). 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, requires a person
who submits an adverse action report to the licensed manufacturer, rather
than FDA, to maintain a record of this action. Also includes a 15-day
Alert report based on information in the scientific literature which must
be accompanied by a copy of the published article.

21 CFR 600.82

Requires licensed manufacturers to report each permanent discontinuance
of manufacturing or each interruption in manufacturing of a biological
product that is likely to lead to a meaningful disruption in supply of that
biological product.

21 CFR 600.80(c)(2)

Requires licensed manufacturers to report each adverse experience not
reported in a postmarketing 15-day Alert report (21 CFR 600.80(c)(1)(i))
at quarterly intervals, for 3 years from the date of issuance of the
biologics license, and then at annual intervals.

21 CFR 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.

21 CFR 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 license, including the quantity distributed to distributors.

21 CFR 600.90,
600.80(h)(2), and
600.81(b)(2)

Licensed manufacturers may submit a waiver request for any requirement
that applies to the licensed manufacturer under §§ 600.80 and 600.81. A
waiver request must include supporting documentation.

Recordkeeping:
21 CFR 600.12(a),
(b)(1), (c), (d) & (e)

Requires, among other things, that records must be made concurrently
with the performance of each step in the manufacture and distribution of
a product and be retained for no less that 5 years after the records of
manufacture have been completed or 6 months after the latest expiration
date for the individual products, whichever represents a later date. In
addition, 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.

21 CFR 600.12(b)(2)

Requires manufacturers to maintain complete records pertaining to the
recall from distribution of any product.

21 CFR 600.80(k)

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.

21 CFR 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.

To assist respondents with the reporting provisions of the information collection, FDA has created
both paper-based and electronic forms. Information may be submitted electronically through
MEDWATCH or the Vaccine Adverse Experience Reporting System (VAERS). AER reports are filed
using the MEDWATCH Form FDA-3500A (approved under OMB Control No.0910-0291) or the
VAERS-1. Both versions of the forms and instructions are available on the internet. The forms can
also be downloaded so that computers can be used to fill out and print the report, which can then be
mailed or faxed to the agency.
We therefore request extension of OMB approval for the information collection found in the
regulations at 21 CFR Part 600 as discussed in this supporting statement, and the associated
collection instruments.

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2. Purpose and Use of the Information Collection
The primary purpose of FDA’s AER system is to identify 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, for
the first time, the opportunity to collect information on rare, latent, and long-term effects. 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 the AERS system 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 not be limited to important changes in 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 where necessary.
The recordkeeping provisions under 21 CFR 600.12 require manufacturers of licensed biological
products for human use to maintain records of each step in the manufacture and distribution of
products. These requirements provide FDA with the necessary information to help ensure the safety,
purity, and potency of biological products. 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 No. 0910-0139.
The semiannual 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. This allows FDA to estimate
more accurately the incidence of a product’s adverse effects in relation to the volume of the product
distributed.
The 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. Without this information, FDA could not
monitor industry procedures and discharge its statutory responsibility for protecting the nation’s
health.
3. Use of Improved Information Technology and Burden Reduction
The regulations prescribe no particular use of information technology, however we believe nearly all
respondents will use electronic means to satisfy the reporting elements of the information collection.
In addition, section 321 of the National Childhood Vaccine Injury Act (NCVIA, Public Law 99-660)
specifically provides for the waiver of paperwork reduction in the implementation of this statute.
Under § 600.80(f)(3), a manufacturer may also use an alternative report form provided the format is
equivalent to all elements of information specified in the designated forms and the format is preapproved by MEDWATCH or FDA.
4. Efforts to Identify Duplication and Use of Similar Information
We are unaware of duplicative information collection. While FDA has received OMB approval for
other collections that support product experience reporting (e.g., OMB Control Nos., 0910-0284,
0910-0290, 0910-0291), adverse experience reports under this information collection are exclusively
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relicensed biological products refers to biologics licensed under any provision of section 351 of the
PHS Act (42 U.S.C 262).
5. Impact on Small Businesses or Other Small Entities
Because of the public health protection provisions, there are no exceptions to the information
collection requirements. At the same time, FDA aids small businesses in complying with its
requirements through the agency’s Regional Small Business Representatives and through the
scientific and administrative staffs within the agency. FDA has provided a Small Business Guide on
the agency’s website at
http://www.fda.gov/ForIndustry/SmallBusinessAssistance/default.htm.
6. Consequences of Collecting the Information Less Frequently
Information collection is consistent with statutory requirements under the PHS and the FFDCA, and
with existing agency regulations.
7. Special Circumstances Relating to the Guidelines of 5 CFR 1320.5
The licensed manufacturers are required to submit to FDA a 15-day Alert report for each serious and
unexpected adverse experience as well as any follow-up reports within 15 calendar days of receipt of
new information or as requested by FDA. This requirement enables FDA to promptly investigate
and, when necessary, initiate corrective action to protect the public from potential adverse product
interactions.
8. Comments in Response to the Federal Register Notice and Efforts to Consult Outside the
Agency
In accordance with 5 CFR 1320.8(d), FDA published a 60-day notice for public comment in the
Federal Register of July 18, 2017 (82 FR 32836). FDA received one comment from the public. The
comment was not responsive to the comment request on the four specified aspects of the collection of
information and did not provide any data or explanation that would support a change regarding the
information collection requirements.
9. Explanation of Any Payment or Gift to Respondents
No payment or gift was provided to respondents.
10. Assurance of Confidentiality Provided to Respondents
The confidentiality of information received by FDA is consistent with the Freedom of Information
Act (FOIA) and FDA’s published regulations under 21 CFR Part 20, 21 CFR 312.130, 314.430,
601.50, and 601.51.
11. Justification for Sensitive Questions
Questions of a sensitive nature are not applicable to this collection of information.

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12. Estimates of Annualized Burden Hours and Costs
We estimate the burden of the information collection as follows:
12a. Annualized Hour Burden Estimate
Table 1 – Estimated Annual Reporting Burden1
21 CFR Section;
Activity
600.80(c)(1) 600.80(d) and
600.80(e); Postmarketing 15day alert reports
600.82; Notification of
discontinuance or interruption
in Manufacturing
600.80(c)(2)
Periodic adverse experience
reports
600.81; Distribution reports

93

Number of
Responses per
Respondent
1,348.07

18

1.61

29

2

58

93

1,941.72

180,580

28

5,056,240

93

7.28

677

1

677

600.80(h)(2), 600.81(b)(2),
and 600.90; Waiver requests
Total

40

2.02

81

1

1

Number of
Respondents

Total
Annual
Responses
125,371

Average
Burden per
Response
1

Total
Hours
125,371

81
5,182,427

There are no capital or operating and maintenance costs associated with the information collection.

Respondents to this collection of information are manufacturers of biological products and
any person whose name appears on the label of a licensed biological product. 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 CBER and CDER, FDA, in fiscal year (FY) 2016.
Based on information obtained from the FDA’s database system, there were 93 manufacturers of
licensed biologics. 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(m).
The total annual responses are based on the number of submissions received annually by FDA
in FY 2016. There were an estimated 125,371 15-day Alert reports, 180,580 periodic reports, and
677 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 81
requests from 40 manufacturers for waivers under § 600.90 (including §§ 600.80(h)(2) and
600.81(b)(2)), of which 79 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 No. 0910-0291.

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Table 2 – Estimated Annual Recordkeeping Burden1
21 CFR Section;
Activity

600.122 ; Maintenance
of records
600.12(b)(2); Recall
records
600.80(k); Recordkeeping
requirements
TOTAL
1
2

No. of
Recordkeepers

114

No. of
Records per
Recordkeeper
63.14

Total
Annual
Records
7,198

Avg. Burden
per
Recordkeeping
32

Total
Hours

230,336

263

2.19

575

24

13,800

93

3,289.80

305,951

1

305,951
550,087

There are no capital or operating and maintenance costs associated with the information collection.
The recordkeeping requirements in § 610.18(b) are included in the estimate for § 600.12.

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 263 licensed
manufacturers of biological products in FY 2016. However, the number of recordkeepers listed for
§ 600.12(a) through (e), excluding (b)(2), is estimated to be 114. This number excludes
manufacturers of blood and blood components because their burden hours for recordkeeping have
been reported/approved under § 606.160 in OMB Control No. 0910-0116. The total annual records is
based on the annual average of lots released in 2016 (7,198), number of recalls made (575), and total
number of adverse experience reports received (305,951) in FY 2016. The hours per record are based
on FDA experience.
12b. Annualized Cost Burden Estimate
The estimated annualized cost to the respondents is $367,894,271.
Cost to Respondents
Activity
Reporting
Recordkeeping

Total Burden Hours

Hourly Wage Rate

5,182,427
550,087

$66
$47

TOTAL

Total Respondent Cost
$342,040,182
$25,854,089
$367,894,271

This cost is based on an average pay rate of $66.00 per hour for an upper level manager, and
mid-level professional that handle the various reporting requirements. This cost is also based on a
pay rate of $47 per hour for a mid-level professional that handles the various recordkeeping
requirements. This salary estimate includes benefits but no overhead costs.
13. Estimates of Other Total Annual Costs to Respondents and/or Recordkeepers/Capital Costs
There are no capital costs, operating and maintenance costs associated with this information
collection.

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14. Annualized Cost to the Federal Government
The estimated annual cost to FDA is $117,797,140.
Annual Cost to FDA
Activity

Number of Reports

Hours per Report

Cost per Hour

Total Cost

Report
Distribution
Report Review

5,182,427

0.1

$32

$16,583,766

5,182,427

0.33

$59

$100,901,854

TOTAL

$117,485,620

The cost is based on two Regulatory Information Specialists, (GS-9/11), who are responsible for
distributing the reports. The cost is also based on a GS-14 Reviewer who is responsible for
reviewing the reports. The salaries include benefits but no overhead costs.
Annual Cost to FDA
Activity
Inspection

Number of
Respondents
132

Hours per Inspection

Cost per Hour

Total Cost

40

$59

$311,520

There are 263 licensed manufacturers of biological products that will be inspected on a biennial basis.
Therefore, it is estimated that approximately one-half (132 establishments) will be inspected
annually. The cost estimate is based on a FDA inspector at an average grade of GS-13/5 who takes
an average of 40 hours for each establishment to perform the on-site inspection, review the records,
and write the report.
15. Explanation for Program Changes or Adjustments
The information collection reflects agency adjustments by +1,439,133 burden hours and +161,233
annual responses for an overall increase. We attribute this to an increase in the number of
submissions received by the agency, as well as a greater number of biological products entering the
marketplace for which the underlying regulatory requirements apply. We also note that burden for
provisions under 21 CFR Part 600 established by our final rule of June 10, 2014 (79 FR 33072),
entitled, “Postmarketing Safety Reports for Human Drug and Biological Products: Electronic
Submission Requirements” and previously included under OMB Control No. 0910-0770 (21 CFR
600.80(h)(2) and 600.81(b)(2)), have now been consolidated into this collection request.
Finally, we have we have revised the IC list appearing at www.reginfo.gov by consolidating the
previously itemized regulatory provisions. We believe this will assist the reader by more easily
identifying the summary of cumulative fluctuations for the collection. At the same time, readers may
still view estimated burden associated with individual provisions by referring to the agency’s 60-day
and 30-day notices and in the burden tables found in Q.12: Estimates of Annualized Burden Hours
and Costs of this supporting statement.

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16. Plans for Tabulation and Publication and Project Time Schedule
There are no tabulated results to publish for this information collection.
17. Reason(s) Display of OMB Expiration Date is Inappropriate
FDA is not seeking approval to exempt display of the expiration date for OMB approval.
18. Exceptions to Certification for Paperwork Reduction Act Submissions
There are no exceptions to the certification.

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