OMB INFORMATION COLLECTION

## SUPPORTING STATEMENT

0910-0308

Adverse Experience Reporting for Licensed Biological Products; and
General Records

**[JUSTIFICATION]{.underline}**

**1. [Circumstances Which Make This Information Collection
Necessary]{.underline}**

The Food and Drug Administration (FDA) is requesting an extension of
Office of Management and Budget (OMB) Control No. 0910-0308 and OMB
approval of the information collection requirements in 21 CFR 600.12,
600.80, 600.81, and 600.90 (Tab A) listed below:

+------------------+------------+--------------------------------------+
| 21 CFR           | Reporting  | Requires the licensed manufacturer   |
| 600.80(c)(1)     |            | 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.                     |
+------------------+------------+--------------------------------------+
| 21 CFR           | Reporting  | Requires the licensed manufacturer   |
| 600.80(c)(2)     |            | to report all adverse experiences in |
|                  |            | a narrative summary, not reported    |
|                  |            | under paragraph (c) (1) (i) at       |
|                  |            | quarterly intervals for 3 years from |
|                  |            | the date of issuance of the product  |
|                  |            | license, and then at annual          |
|                  |            | intervals.                           |
+------------------+------------+--------------------------------------+
| 21 CFR 600.80(e) | Reporting  | Requires the licensed manufacturers  |
|                  |            | to submit a 15-day Alert report      |
|                  |            | obtained from a postmarketing        |
|                  |            | clinical study only if there is a    |
|                  |            | reasonable possibility that the      |
|                  |            | product caused the adverse           |
|                  |            | experience.                          |
+------------------+------------+--------------------------------------+
| 21 CFR 600.81    | #          | Requires the licensed manufacturers  |
|                  |  Reporting | to report semiannually the quantity  |
|                  |            | of the product distributed under the |
|                  |            | product license, including the       |
|                  |            | quantity distributed to              |
|                  |            | distributors.                        |
+------------------+------------+--------------------------------------+
| 21 CFR 600.90    | Reporting  | Requires the licensed manufacturer   |
|                  |            | to submit a waiver request with      |
|                  |            | supporting documentation for waiving |
|                  |            | the requirements under 21 CFR 600.80 |
|                  |            | and 600.81.                          |
+------------------+------------+--------------------------------------+
| 21 CFR           | Rec        | Requires records of each step in the |
| 600.12(a), (c),  | ordkeeping | manufacture and distribution of a    |
| (d) & (e)        |            | product to be maintained for a       |
|                  |            | prescribed period of time.           |
+------------------+------------+--------------------------------------+
| 21 CFR           | Rec        | Requires records to be maintained    |
| 600.12(b)(2)     | ordkeeping | pertaining to the recall from        |
|                  |            | distribution of any product.         |
+------------------+------------+--------------------------------------+
| 21 CFR 600.80(i) | Rec        | Requires records of all adverse      |
|                  | ordkeeping | experiences to be maintained for ten |
|                  |            | years.                               |
+------------------+------------+--------------------------------------+

Under the Public Health Service Act (42 U.S.C. 262, Tab B), FDA is
required to ensure the marketing and production of only those biological
products which are safe, pure, and potent. FDA must, therefore, be
promptly informed of all adverse experiences occasioned by the use of
licensed biological products. FDA issued the adverse experience
reporting (AER) requirements in 21 CFR §§ 600.80 and 600.81 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 licensed manufacturers are required to report
to FDA on all serious and unexpected adverse reactions regardless of the
source from which the manufacturer obtained the reaction information.
These reports are filed using the MedWatch Form FDA-3500A (approved
under OMB No.0910-0291, Tab C) or the Vaccine Adverse Experience
Reporting System Form (VAERS-1, Tab D). Section 321 of the National
Childhood Vaccine Injury Act (NCVIA, Tab E) specifically addresses the
waiver of paperwork reduction in the implementation of this statute. 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 pre-approved by MedWatch or VAERS.

The general recordkeeping provisions under § 600.12 require
manufacturers 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.

**2. [How, By Whom, and the Purpose for Collecting This
Information]{.underline}**

The primary purpose of FDA's AER system is to flag 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. 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 increase public health protection because
such information enables FDA to recommend important changes to the
product's labeling (such as adding a new warning) and, when necessary,
to initiate removal of a biological product from the market and to
ensure that the manufacturer has taken adequate corrective action, if
necessary. The semiannual distribution report allows FDA to see the
quantity, the lot number, and the dosage of different products. 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 assuring accountability and traceability in each step from the
manufacture to distribution and recall of products and by enabling 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 Technology to Reduce Burden on the Public]{.underline}**

Most of the information required under the AER regulations is to be
submitted using FDA Form 3500A or VAERS-1. Both versions of the forms
and instructions are available on the internet. The forms can 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.

Licensed manufacturers may use computers, tapes, microfiche or microfilm
in lieu of hard copy records for the purpose of maintaining records.
Computers may be used for filing distribution records. FDA is not aware
of any other improved technology to reduce the burden.

**4. [Identification and Use of Duplicate Information]{.underline}**

FDA is the only agency that requests this information. The required
information is not available from any other source.

**5. [FDA's Efforts to Reduce Burden on Small Business ]{.underline}**

FDA believes that the regulations should apply equally to all
enterprises. While FDA does not believe it can apply different standards
with respect to statutory requirements, FDA does provide special help to
small businesses. The Center for Biologics Evaluation and Research
(CBER), Office of Communication, Training, and Manufacturers Assistance,
provides assistance to small businesses concerning FDA's regulatory
requirements.

**6. [Impact of Not Collecting This Information or Collecting
Information Less Frequently]{.underline}**

Less frequent data collection would delay identification of biological
products believed responsible for adverse reactions including permanent
injuries and fatalities. Appropriate FDA action such as withdrawal from
the market or changes in labeling would also be delayed. However, FDA is
preparing to issue a proposed rule that would amend the expedited and
periodic safety reporting regulations for human drugs and biological
products to revise certain reporting formats as recommended by the
International Conference on Harmonization (ICH), to revise current
reporting requirements, to revise certain reporting time frames, and to
make other revisions to the regulations to enhance the quality of
suspected adverse drug reaction reports received by FDA.

There are no technical or legal obstacles to reducing the burden.

**7. [Special Circumstances That Occur When Collecting This
Information]{.underline}**

The licensed manufacturers are required to submit to FDA a 15-day Alert
report for each serious and unexpected adverse experience. This
requirement enables FDA to promptly investigate and, when necessary,
initiate corrective action to protect the public from potential adverse
product interactions.

**8. [Identification of Outside FDA Sources]{.underline}**

In accordance with 5 CFR 1320.8(d), a 60-day notice for public comment
on the information collection provisions was published in the **Federal
Register** of October 4, 2002 (67 FR 62249, Tab F). No comments were
received from the public*.*

**9. [Payment or Gifts Offered to Respondents]{.underline}**

FDA has not provided and has no intention to provide any payment or gift
to respondents.

**10. [Method of Ensuring Respondent Confidentiality ]{.underline}**

The confidentiality of information received by FDA is consistent with
the Freedom of Information Act (FOIA) and the agency's regulations under
21 CFR Part 20 which prohibit FDA from releasing to the public the names
of patients, individual reporters, health care practitioners, hospitals,
and any geographical identifiers. Such information is deleted from any
information released by FDA under FOIA and FDA regulations.

**11. [Use of Sensitive Questions]{.underline}**

Questions of a sensitive nature are not applicable to this information
collection.

**12. [Burden Hours and Costs Associated With This Information
Collection]{.underline}**

The estimated annual burden for this information collection is 576,593
hours.

  -------------- ------------- ----------- ----------- ----------- -----------
  Estimated                                                        
  Annual                                                           
  Reporting                                                        
  Burden                                                           

  21 CFR Section No. of        Annual      Total       Hours per   Total Hours
                 Respondents   Frequency   Annual      Response    
                               per         Responses               
                               Response                            

  600.80(c)(1) & 95            146.72      13,938      1           13,938
  600.80(e)                                                        

  600.80(c)(2)   95            106.34      10,102      28          282,856

  600.81         95            3.57        339         1           339

  600.90         12            1           12          1           12

  TOTAL                                                            297,145
  -------------- ------------- ----------- ----------- ----------- -----------

Respondents to this collection of information are manufacturers of
biological products. The number of respondents is based on the estimated
number of manufacturers that submitted the required information to FDA
in 2000 and 2001. Based on information obtained from CBER's database
system, there were approximately 95 licensed manufacturers. This number
excludes those manufacturers who produce blood and blood components and
in-vitro diagnostic licensed products because they are specifically
exempt from the regulations. However, not all manufacturers may have any
submissions in a given year and some may have multiple submissions. The
total annual responses are based on the estimated number of submissions
received annually by FDA. There were an estimated 13,938 15-day Alert
reports, 10,102 periodic reports, and 339 distribution reports submitted
to FDA. The number of 15-day Alert reports for postmarketing studies
under § 600.80 (e) was minimal and is included in the total number of
15-day Alert reports. FDA received an average of 12 waiver requests
under § 600.90, of which 11 were approved for exemption of the AER
requirements. The hours per response are based on FDA's 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.

  --------------- --------------- --------------- ----------- --------- ---------
  Estimated                                                             
  Annual                                                                
  Recordkeeping                                                         
  Burden                                                                

  21 CFR Section  No. of          Annual          Total       Hours per Total
                  Recordkeepers   Frequency of    Annual      Record    Hours
                                  Recordkeeping   Records               

  600.12          111             60.78           6,747       32        215,904

  600.12(b)(2)    329             5.00            1,646       24        39,504

  600.80(i)       95              253.05          24,040      1         24,040

  TOTAL                                                                 279,448
  --------------- --------------- --------------- ----------- --------- ---------

The number of respondents is based on the number of manufacturers
subject to those regulations. Based on information obtained from CBER's
database system, there were approximately 329 licensed manufacturers of
biological products. However, the number of recordkeepers listed for §
600.12(a)-(e) excluding (b)(2) is estimated to be 111. This number
excludes manufacturers of blood and blood components because their
burden hours for recordkeeping have been reported under § 606.160 in OMB
Control No. 0910-0116. The total annual records is based on the annual
average of lots released (6,747), number of recalls made (1,646), and
total number of AER reports received (24,040) in 2000 and 2001. The
hours per record are based on FDA's experience.

### Cost to Respondents

The estimated annualized cost to the respondents is \$21,196,069. This
cost is based on an average pay rate of \$45.00 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 \$28
per hour for a mid-level professional who has the training and skills to
handle the various recordkeeping requirements. This salary estimate
includes benefits but no overhead costs.

+-----------------+-----------------+-----------------+-----------------+
| Cost to         |                 |                 |                 |
| Respondents     |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Activity        | Number of Hours | Cost per Hour   | Total Cost      |
+-----------------+-----------------+-----------------+-----------------+
| # Reporting     | 297,145         | \$45            | \$13,371,525    |
+-----------------+-----------------+-----------------+-----------------+
| # Recordkeeping | 279,448         | \$28            | \$7,824,544     |
+-----------------+-----------------+-----------------+-----------------+
| # TOTAL         |                 |                 | \$21,196,069    |
+-----------------+-----------------+-----------------+-----------------+

**13. [Annual Cost Estimate to Respondents]{.underline}**

There are no capital and start-up, or operation, maintenance and
purchase costs associated with

the collection of information requirements.

**14. [Annual Cost Estimate to FDA]{.underline}**

The estimated annual cost to FDA is \$4,427,461. This figure is based on
a GS-6/5 Consumer Safety Technician, at a pay rate of \$17 per hour, who
is responsible for triage of the report. This figure is also based on a
GS-13/5 Consumer Safety Officer, at a pay rate of \$40 per hour, who is
responsible for reviewing the reports.

+------------+--------------+-----------------+------------+----------+
| Annual     |              |                 |            |          |
| Cost to    |              |                 |            |          |
| FDA        |              |                 |            |          |
+------------+--------------+-----------------+------------+----------+
| Activity   | Number of    | Hours per       | Cost per   | Total    |
|            | Reports      | Report          | Hour       | Cost     |
+------------+--------------+-----------------+------------+----------+
| Report     | 297,145      | 0.1             | \$17       | \        |
| Triage     |              |                 |            | $505,147 |
+------------+--------------+-----------------+------------+----------+
| Report     | 297,145      | 0.33            | \$40       | \$3      |
| Review     |              |                 |            | ,922,314 |
+------------+--------------+-----------------+------------+----------+
| # TOTAL    |              |                 |            | \$4      |
|            |              |                 |            | ,427,461 |
+------------+--------------+-----------------+------------+----------+

**15. [Changes from Previous Approval]{.underline}**

The estimated total annual burden for the AER information collection
requirements was 268,803 hours in 2000. The current increase to 576,593
burden hours is mostly attributed to the increased number of total
annual responses under § 600.80(c)(1), and the increase in the revised
estimated hours per response under § 600.80(c)(2).

**16. [Publishing the Results of This Information
Collection]{.underline}**

There are no results to publish for this information collection.

**17. [Reason for Not Displaying the OMB Approval Date]{.underline}**

FDA is not seeking approval to exempt display of the expiration date for
OMB approval.

**18. [Explanations to Section 19, "Certification for Paperwork
Reduction Act Submissions"]{.underline}**

There are no exceptions to Item 19 of OMB Form 83-I.