OMB INFORMATION COLLECTION

SUPPORTING STATEMENT

General Licensing Provisions: Biologics License Application, Changes to
an Approved Application, Labeling, Revocation and Suspension, and Forms
FDA 356h and 2567

0910-0338

# JUSTIFICATION

## Need and Legal Basis

The Food and Drug Administration (FDA) is requesting the extension of
Office of Management and Budget (OMB) Control No. 0910-0338 and OMB
approval of the information collection provisions including Forms FDA
356h and 2567 (Tab A). The information collection provisions are listed
below (Tab B):

+----------------+--------------+--------------------------------------+
| 21 CFR Section | Category     | Description                          |
+----------------+--------------+--------------------------------------+
| 600.15(b),     | Reporting    | Requires the submission of a request |
| 610.53(d)      |              | for an exemption or modification     |
|                |              | regarding the temperature            |
|                |              | requirements during shipment and     |
|                |              | regarding dating periods,            |
|                |              | respectively, for certain biological |
|                |              | products.                            |
+----------------+--------------+--------------------------------------+
| 601.2(a),      | Reporting    | Requires manufacturers of a          |
|                |              | biological product to submit an      |
| 610.60,        |              | application with accompanying        |
| 610.61, 610.62 |              | information, including container and |
|                |              | package labeling information, to FDA |
|                |              | for approval to market a product in  |
|                |              | interstate commerce.                 |
+----------------+--------------+--------------------------------------+
| 601.5(a)       | Reporting    | Requires licensees to submit to FDA  |
|                |              | notice of its intention to           |
|                |              | discontinue manufacture of a product |
|                |              | or all products.                     |
+----------------+--------------+--------------------------------------+
| 601.6(a)       | Reporting    | Requires licensees to notify selling |
|                |              | agents and distributors upon         |
|                |              | suspension of its license, and       |
|                |              | provide FDA with records of such     |
|                |              | notification.                        |
+----------------+--------------+--------------------------------------+
| 601.12(a)(2)   | Reporting    | Requires, generally, that the holder |
|                |              | of an approved biologics license     |
|                |              | application must assess the effects  |
|                |              | of a manufacturing change before     |
|                |              | distributing a biological product    |
|                |              | made with the change.                |
+----------------+--------------+--------------------------------------+
| 601.12(a)(4)   | Reporting    | Requires applicants to promptly      |
|                |              | revise all promotional labeling and  |
|                |              | advertising to make it consistent    |
|                |              | with certain labeling changes        |
|                |              | implemented.                         |
+----------------+--------------+--------------------------------------+
| 601.12(a)(5)   | Reporting    | Requires applicants to include a     |
|                |              | list of all changes contained in the |
|                |              | supplement or annual report; for     |
|                |              | supplements, this list must be       |
|                |              | provided in the cover letter.        |
+----------------+--------------+--------------------------------------+
| 601.12         | Reporting    | Requires applicants to follow        |
| (b)(1)/(b)(3), |              | specific procedures in informing FDA |
| 601.12         |              | of each change, established in an    |
| (c)(1)/(c)(3), |              | approved license application, in the |
| 601.12(c)(5),  |              | product, production process, quality |
| and            |              | controls, equipment, facilities, or  |
| 601.1          |              | responsible personnel. The           |
| 2(d)(1)/(d)(3) |              | appropriate procedure depends on the |
|                |              | potential for the change to have a   |
|                |              | substantial, moderate, or minimal    |
|                |              | adverse effect on the identity,      |
|                |              | strength, quality, purity, or        |
|                |              | potency of the product as they may   |
|                |              | relate to the safety or              |
|                |              | effectiveness of the product.        |
+----------------+--------------+--------------------------------------+
| 601.12(b)(4)   | Reporting    | Applicants may request FDA to        |
|                |              | expedite its review of a supplement  |
|                |              | for public health reasons or if a    |
|                |              | delay in making the change described |
|                |              | in it would impose an extraordinary  |
|                |              | hardship of the applicant.           |
+----------------+--------------+--------------------------------------+
| 601.12(e)      | Reporting    | Requires applicants to submit a      |
|                |              | protocol, or change to a protocol,   |
|                |              | as a supplement requiring FDA        |
|                |              | approval before distributing the     |
|                |              | product.                             |
+----------------+--------------+--------------------------------------+
| 601.12(f)(1),  | Reporting    | Requires applicants to follow        |
| 601.12(f)(2),  |              | specific procedures in reporting     |
| 601.12(f)(3)   |              | labeling changes to FDA. The         |
|                |              | appropriate procedure depends on the |
|                |              | potential for the change to have a   |
|                |              | substantial, moderate, or minimal    |
|                |              | adverse effect on the safety or      |
|                |              | effectiveness of the product.        |
+----------------+--------------+--------------------------------------+
| 601.12(f)(4)   | Reporting    | Requires applicants to report to FDA |
|                |              | advertising and promotional labeling |
|                |              | and any changes.                     |
+----------------+--------------+--------------------------------------+
| 601.25(b)(3)   | Reporting    | Requests interested persons to       |
|                |              | submit, for review and evaluation by |
|                |              | an advisory review panel, published  |
|                |              | and unpublished data and information |
|                |              | pertinent to a designated category   |
|                |              | of biological products that have     |
|                |              | been licensed prior to July 1, 1972. |
+----------------+--------------+--------------------------------------+
| 601.26(f)      | Reporting    | Requests that licensees submit to    |
|                |              | FDA a written statement intended to  |
|                |              | show that studies adequate and       |
|                |              | appropriate to resolve questions     |
|                |              | raised about a biological product    |
|                |              | have been undertaken for a product   |
|                |              | if designated as requiring further   |
|                |              | study under the reclassification     |
|                |              | procedures.                          |
+----------------+--------------+--------------------------------------+
| 601.27(a)      | Reporting    | Requires that applications for new   |
|                |              | biological products contain data     |
|                |              | that are adequate to assess the      |
|                |              | safety and effectiveness of the      |
|                |              | biological product for the claimed   |
|                |              | indications in pediatric             |
|                |              | sub-populations, and to support      |
|                |              | dosing and administration            |
|                |              | information.                         |
+----------------+--------------+--------------------------------------+
| 601.27(b)      | Reporting    | Provides that an applicant may       |
|                |              | request a deferred submission of     |
|                |              | some or all assessments of safety    |
|                |              | and effectiveness required under     |
|                |              | 601.27(a).                           |
+----------------+--------------+--------------------------------------+

  ------------------- ------------------------- ---------------------------------------
  601.27(c)           Reporting                 Provides that an applicant may request
                                                a full or partial waiver of the
                                                requirements under 601.27(a).

  601.28(a)           Reporting                 Requires sponsors to submit to FDA a
                                                brief summary stating whether labeling
                                                supplements for pediatric use have been
                                                submitted and whether new studies in
                                                the pediatric population to support
                                                appropriate labeling for the pediatric
                                                population have been initiated.

  601.28(b)           Reporting                 Requires sponsors to submit to FDA an
                                                analysis of available safety and
                                                efficacy data in the pediatric
                                                population and changes proposed in the
                                                labeling based on this information.

  601.28(c)           Reporting                 Requires sponsors to submit to FDA a
                                                statement on the current status of any
                                                post-marketing studies in the pediatric
                                                population performed by, on or behalf
                                                of, the applicant.

  601.33, 601.34,     Reporting                 Clarifies the information required to
  601.35                                        be submitted in an application to FDA
                                                to evaluate the safety and
                                                effectiveness of in vivo
                                                radiopharmaceuticals.

  601.45              Reporting                 Requires applicants of biological
                                                products for serious or
                                                life-threatening illnesses to submit to
                                                the agency for consideration, during
                                                the pre-approval review period, copies
                                                of all promotional materials, including
                                                promotional labeling as well as
                                                advertisements.

  601.91(b)(3)        Reporting                 Requires applicants to prepare and
                                                provide labeling with relevant
                                                information to patient or potential
                                                patients for biological products
                                                approved under the subpart when human
                                                efficacy studies are not ethical or
                                                feasible (or based on efficacy studies
                                                conducted in animals alone).

  601.93              Reporting/Recordkeeping   Provides that biological products
                                                approved under subpart H are subject to
                                                the postmarketing recordkeeping and
                                                safety reporting applicable to all
                                                approved biological products.

  601.94              Reporting                 Requires applicants to submit to the
                                                agency for consideration during
                                                pre-approval review period copies of
                                                all promotional materials including
                                                promotional labeling as well as
                                                advertisements.

  606.110(b)          Reporting                 Requires applicants to submit requests
                                                for approval to perform plasmapheresis
                                                of donors who do not meet certain donor
                                                requirements for the collection of
                                                plasma containing rare antibodies.

  610.11(g)(2)        Reporting                 Provides that manufacturers of certain
                                                biological products may request an
                                                exemption from the general safety test
                                                requirements.

  610.67              Reporting                 Requires certain biological products to
                                                comply with the bar code requirements
                                                at § 201.25.

  680.1(c)            Reporting                 Requires manufacturers to update
                                                annually the their license file with
                                                the list of source materials and the
                                                suppliers of the materials.

  Amendments/         Reporting                 Includes amendments to an unapproved
  Resubmissions                                 application or supplement or
                                                resubmission of a license application.

  601.91(b)(2)(iii)   Recordkeeping             Requires, in certain circumstances,
                                                postmarketing restrictions as needed to
                                                ensure the safe use of the biological
                                                products distribution conditioned on
                                                specified recordkeeping requirements.
  ------------------- ------------------------- ---------------------------------------

In addition to §§ 601.2 and 601.12, there are other regulations in 21
CFR parts 640, 660, and 680 that relate to information to be submitted
in a license application or supplement for certain blood or allergenic
products*:* §§ 640.6, 640.17, 640.21(c), 640.22(c), 640.25(c),
640.56(c), 640.64(c), 640.74(a), and (b)(2), 660.51(a)(4),
680.1(b)(2)(iii), and 680.1(d). In the table 1 of section 12 of this
document, the burden associated with the information collection
requirements in these regulations is included in the burden estimate for
§§ 601.2 and/or 601.12. A regulation may be listed under more than one
section of § 601.12 due to the type of category under which a change to
an approved application may be submitted.

There are also additional container and/or package labeling requirements
for certain licensed biological products: § 640.70(a) for Source Plasma;
§ 640.74(b)(3) and (4) for Source Plasma Liquid; § 640.84(a) and (c) for
Albumin; § 640.94(a) for Plasma Protein Fraction; § 660.2(c) for
Antibody to Hepatitis B Surface Antigen; § 660.28(a) and (b) for Blood
Grouping Reagent; § 660.35(a), (c-g), and (i-m) for Reagent Red Blood
Cells; § 660.45 for Hepatitis B Surface Antigen; and § 660.55(a) and (b)
for Anti-Human Globulin. The burden associated with the additional
labeling requirements for submission of a license application for these
certain biological products is minimal because the majority of the
burden is associated with the requirements under §§ 610.60 through
610.62 or § 809.10. Therefore, the burden estimates for these
regulations is included in the estimate under §§ 610.60 through 610.62
in table 1 of this document. The burden estimates associated with §
809.10 are approved under OMB Control No. 0910-0485 (expires June 30,
2008).

Under § 601.93, any potential postmarketing reports and/or recordkeeping
burdens would be included under the adverse experience reporting (AER)
requirements under 21 CFR part 600 (OMB Control No. 0910-0308; pending
extension of OMB approval). Therefore, any burdens associated with these
requirements would be reported under the AER information collection
requirements (OMB Control No. 0910-0308, pending extension of OMB
approval)

Under Section 351 of the Public Health Services Act (PHS Act, 42 U.S.C.
262, Tab C), manufacturers of biological products must submit a license
application for FDA review and approval before marketing a biological
product in interstate commerce. Licenses may be issued only upon showing
that the establishment and the products for which a license is desired
meets standards prescribed in regulations designed to ensure the
continued safety, purity, and potency of such products. All such
licenses are issued, suspended, and revoked as prescribed by regulations
in part 601 (21 CFR Part 601).

In July 1997, FDA revised Form FDA 356h \"Application to Market a New
Drug, Biologic, or an Antibiotic Drug for Human Use\" to harmonize
application procedures between Center for Biologics Evaluation and
Research (CBER) and the Center for Drugs Evaluation and Research (CDER).
The application form serves primarily as a checklist for firms to gather
and submit to FDA. The checklist helps to ensure that the application is
complete and contains all the necessary information, so that delays due
to lack of information may be eliminated. The form provides key
information to FDA for efficient handling and distribution to the
appropriate staff for review. The estimated burden hours for submissions
using FDA Form 356h to CDER are reported under OMB Control No. 0910-0001
(expires May 31, 2008.)

Form FDA 2567 \"Transmittal of Labels and Circulars\" is used by
manufacturers of licensed biological products to submit labeling (e.g.,
circulars, package labels, container labels, etc.) and labeling changes
for FDA review and approval. The labeling information is submitted with
the form for license applications, supplements, or as part of an annual
report. Form FDA 2567 is also used for the transmission of
advertisements and promotional labeling. Form FDA 2567 serves as an easy
guide to assure that the manufacturer has provided the information
required for expeditious handling of their labeling by CBER. For
advertisements and promotional labeling, manufacturers of licensed
biological products may submit to CBER either Form FDA 2567 or 2253.
Form FDA 2253 (approved under OMB Control No. 0910-0376, expires May 31,
2008) was previously used only by drug manufacturers regulated by the
CDER. In August of 1998, FDA revised and harmonized Form FDA 2253 so the
form may be used to transmit specimens of promotional labeling and
advertisements for biological products as well as for prescription drugs
and antibiotics. The revised, harmonized form updates the information
about the types of promotional materials and the codes that are used to
clarify the type of advertisement or labeling submitted; clarifies the
intended audience for the advertisements or promotional labeling (e.g.,
consumers, professionals, news services); and helps ensure that the
submission is complete.

## Information Users

FDA has the responsibility to ensure the safety, purity, potency, and
effectiveness of biological products. The PHS Act and FDA regulations
require manufacturers to submit a license application for review and
approval prior to marketing a biological product in interstate commerce.
In addition, manufacturers must submit to FDA advertising and
promotional labeling. Manufacturers are also required to submit changes,
including labeling, changes to an approved application, as well as
advertising and promotional labeling changes. The information submitted
to FDA in a biologics license application (BLA), supplement to an
approved application, or other similar submission is used to determine
if a product is safe, effective, and not misbranded under prescribed,
recommended, or suggested conditions of use. The recordkeeping
requirements serve preventative and remedial purposes to ensure safe use
of the biological products. Without this and other information, FDA
could not monitor industry procedures and discharge its statutory
responsibility for protecting the nation's health.

## Improved Information Technology

One of FDA's continuing objectives is to improve the speed and quality
of its review and approval programs. In order to reach a decision to
approve an application, the agency must evaluate all information and
data provided by applicants on the safety, purity, potency, and efficacy
of the proposed product. To make the review process more efficient for
industry and FDA, CBER is utilizing electronic information systems
technology. CBER currently accepts the submission of electronic license
applications. FDA believes the increased use of computer assisted
license applications will enhance the timeliness, effectiveness, and
efficiency of the review process and reduce burdensome, nonessential
hard-copy handling and storage. FDA is not aware of any other improved
technology to reduce the burden.

## Duplication of Similar Information

FDA is the only agency that requires the filing of an application for
the marketing of biological product for human use, any changes to an
approved application, and other required information. No other component
of the agency or other government agencies requires similar information
or data to be filed. This information is not available from any other
source.

## Small Businesses

FDA believes that its duty requires the equal application of the
regulations 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 Communications, Training, and
Manufacturers Assistance provides assistance to small businesses subject
to FDA's regulatory requirements.

## Less Frequent Collection

Manufacturers are required to submit applications for approval of
biological products prior to marketing such products in interstate
commerce. In addition, manufacturers are required to submit a supplement
to an approved application prior to implementing a change or in an
annual report, depending on the significance of the change. Less
frequent collection of this and other information will not provide the
necessary information needed by FDA to properly evaluate the safety,
purity, potency, and effectiveness of a biological product.

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

## Special Circumstances

An applicant may be required to submit to FDA proprietary trade secret
or other confidential information when submitting a license application,
or change to an approved application. FDA has instituted security
measures to protect confidential information received from manufacturers
and will, to the extent permitted by law, protect the information. In
addition, certain changes to an approved application are required to be
submitted each time a change is made. This information is necessary for
FDA to ensure that the proposed changes do not have an adverse effect on
the strength, quality, purity, or potency as they may relate to the
safety and effectiveness of a product.

## *Federal Register* Notice/Outside Consultation

In accordance with 5 CFR 1320.8(d), FDA published a notice in the
Federal Register of March 15, 2005 (70 FR 12693), Tab D) providing for a
60-day comment period on the information collection. We received one
comment in response to whether the proposed collection of information is
necessary for the proper performance of FDA's functions, including
whether the information will have practical utility. The comment
generally stated an opinion that the information collection program is
not necessary, does not protect Americans, and is costly without
justification. The commenter did not request any action nor did they
provide data to support a change to the information collection
requirements.

Information collection is a statutory requirement under the Paperwork
Reduction Act of 1995 (44 U.S.C. 3501-3520). FDA cannot abolish or
modify the information collection requirements provided in the
regulations (5 CFR 1320.3(c)) unless the statute is changed. Changing
the statute is beyond FDA's authority and control.

## Payment/Gift to Respondent

No payment or gift was provided to respondents.

## Confidentiality

The confidentiality of information received by FDA would be consistent
with the Freedom of Information Act and the agency's regulations under
21 CFR Part 20 and 21 CFR 601.51. Manufacturers submitting an
application for FDA approval to market a biological product in
interstate commerce, or any changes to an approved application, may be
required to include proprietary or trade information in a license
application submitted for FDA approval. However, such proprietary or
trade information is deleted from any information released by FDA under
the Freedom of Information Act and FDA regulations.

## Sensitive Questions

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

## Burden Estimate (Total Hours and Wages)

The total annual estimated burden imposed by this collection of
information is 335,087.5 hours.

Table 1. -- Estimated Annual Reporting Burden

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

  601.2(a), 610.60, 610.61,  2567/356h   14            2           28          860        24,080
  and 610.62 ^1^                                                                          

  601.5(a)                   NA          16            3.13        50          .33        17

  601.6(a)                   NA          1             21          21          .33        7

  601.12(a)(5)               NA          190           15.7        2,983       1          2,983

  601.12(b)(1)/(b)(3) ^2^    356h        190           4.75        903         80         72,240

  601.12(c)(1)/(c)(3) ^3^    356h        98            2.60        255         50         12,750

  601.12(c)(5) ^3^           356h        34            1.38        47          50         2,350

  601.12(d)(1)/(d)(3) ^4^    356h        166           1.37        227         22.5       5,107.5

  601.12(e)                  356h        14            1.43        20          120        2,400

  601.12(f)(1)               2567        12            1           12          40         480

  601.12(f)(2)               2567        10            1           10          20         200

  601.12(f)(3)               2567        70            1.43        100         10         1,000

  601.12(f)(4) ^5^/601.45    2567        15            36          540         10         5,400

  601.27(b)                  NA          3             1           3           24         72

  601.27(c)                  NA          7             1           7           8          56

  601.28(a)                  NA          44            3.27        144         8          1,152

  601.28(b)                  NA          44            3.27        144         24         3,456

  601.28(c)                  NA          44            3.27        144         1.5        216

  601.91(b)(3), 601.94       NA          1             1           1           240        240

  610.67                     NA          174           31          5,400       24         129,600

  680.1(c)                   NA          10            1           10          2          20

  Amendments/Resubmissions   356h        306           11.6        3,563       20         71,260

  Total                                                                                   335,086.5
  -------------------------- ----------- ------------- ----------- ----------- ---------- -----------

^1^ The reporting requirements under §§ 601.27(a), 601.33, 601.34,
601.35, 610.11(g)(2), 640.17, 640.25(c), 640.56(c), 640.74(b)(2),
660.51(a)(4), and 680.1(b)(2)(iii) are included in the estimate under §
601.2(a). The reporting requirements under §§ 640.70(a), 640.74(b)(3)
and (4), 640.84(a) and (c), 640.94(a), 660.2(c), 660.28(a) and (b),
660.35(a), (c-g), and (i-m), 660.45, and 660.55(a) and (b) are included
under §§ 610.60 through 610.62.

^2^ The reporting requirements under §§ 600.15(b), 601.12(a)(2),
601.12(b) (4), 610.11(g)(2), 610.53(d), 606.110(b), 640.6, 640.17,
640.21(c), 640.22(c), 640.25(c), 640.56(c), 640.64(c), 640.74(a) and
(b)(2), and 680.1(d) are included in the estimate under §§
601.12(b)(1)/(b)(3).

^3^ The reporting requirements under §§ 601.12(a)(2), 640.17, 640.25(c),
640.56(c), and 640.74(b)(2) are also included in the estimate under §§
601.12(c)(1)/(c)(3) or (c)(5).

^4^ The reporting requirements under § 601.12(a)(2) are also included in
the estimates under §§ 601.12(d)(1)/(d)(3).

^5.^The reporting requirements under § 601.12(a)(4) are included in the
estimates under 601.12(f)(4) or OMB Control No. 0910-0001 since the
required information is submitted with Forms FDA 2567 or 2253.

The number of respondents is based on the estimated annual number of
manufacturers that submitted the required information to FDA or the
number of submissions received. Based on information obtained from
CBER\'s database system, there are 306 licensed biologics manufacturers.
However, not all manufacturers will 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 (e.g., license
applications, labeling and other supplements, protocols, advertising and
promotional labeling, notifications) for a particular product received
annually by FDA. Based on previous estimates, the rate of submissions is
not expected to change significantly in the next few years. The hours
per response are based on information provided by industry and past FDA
experience with the various submissions or notifications. The hours per
response include the time estimated to prepare the various submissions
or notifications to FDA, and, as applicable, the time required to fill
out the appropriate form and collate the documentation. Additional
information regarding these estimates is provided below as necessary.

Under §§ 601.2 and 601.12, the estimated hours per response are based on
the average number of hours to submit the various submissions. The
estimated average number of hours is based on the range of hours to
complete a very basic application or supplement and a complex
application or supplement.

Under § 601.6(a), the total annual responses are based on FDA estimates
that establishments may notify an average of 20 selling agents and
distributors of such suspension, and provide FDA of such notification.
The number of respondents is based on the estimated annual number of
suspensions of a biologic license.

Under §§ 601.12(f)(4) and 601.45, manufacturers of biological products
may use either Form FDA 2567 or Form FDA 2253 to submit advertising and
promotional labeling. Based on information obtained from CBER's database
system, there were an estimated 3,600 submissions of advertising and
promotional labeling in fiscal year 2004. FDA estimates that
approximately 15 percent of those submissions were received with Form
FDA 2567 resulting in an estimated 540 submissions. The burden hours for
the remaining submissions received using Form FDA 2253 are reported
under OMB Control No. 0910-0376.

Under §§ 601.91 through 601.94, FDA expects to receive very few
applications of this nature; however, for calculation purposes, FDA is
estimating the submission of one application annually. Under §§
601.91(b)(3) and 601.94, FDA estimates 240 hours for a manufacturer of a
new biological product to develop patient labeling, and to submit the
appropriate information and promotional labeling to FDA. The majority of
the burden for developing the patient labeling is included under the
reporting requirements for § 601.94, therefore minimal burden is
calculated for providing the guide to patients under § 601.91(b)(3).

There were also 3,540 amendments to an unapproved application or
supplement and 23 resubmissions (total of 3,563 submissions) submitted
using Form FDA 356h.

^Table\ 2.\ -\ Estimated\ Annual\ Recordkeeping\ Burden^

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

  601.91(b)(2)(iii)   1               1               1           1           1
  ------------------- --------------- --------------- ----------- ----------- -----------

The estimated recordkeeping burden of 1 hour is based on previous
estimates for the recordkeeping requirements associated with the AER
system.

[Cost to Respondents]{.underline}

The estimated annual cost to respondents is \$14,075,331.00.

  ----------------- ----------------- ----------------- -----------------
  Activity          No. of Hours      Cost per Hour     Total Cost

  Reporting         335,086.5         \$42.00           \$14,073,633.00

  Reporting         24                \$69.00           \$1,656.00

  Recordkeeping     1                 \$42.00           \$42
  ----------------- ----------------- ----------------- -----------------

The cost estimate is based on a regulatory affairs specialist, at a pay
rate of \$42.00/hour, who would be responsible for filling out the form,
and preparing an application, supplement, or other similar submission
and recordkeeping. The cost estimate is also based on a medical director
at a pay rate of \$69.00/hour who would be responsible for the preparing
notification to FDA of discontinuance of a product(s), and notification
to industry of a license suspension (50 notices of products(s)
discontinuance and 21 notices of license suspension with an average of
20 minutes per notification). The estimated average hourly pay rate
includes benefits but no overhead costs.

FDA is estimating the operating costs for postage and handling
associated with the submissions sent to FDA.

  ------------------- ----------------- ------------------- ---------------
  Activity            No. of            Average Cost per    Total Cost
                      Submissions       Submission          

  Postage and         3,563             \$120.00            \$427,560.00
  Handling                                                  
  ------------------- ----------------- ------------------- ---------------

Based on our burden estimates, there were 3,563 submissions sent to FDA.
FDA estimates that most of the application, supplements, and other
submissions are submitted from industry to FDA/CBER by private courier.
Submissions in this information collection package can range from a
regular letter to several boxes of data with the majority of supplements
received containing less than a box of data. Based on past FDA
experience, FDA estimates that an average of 1 box of data is submitted
to FDA taking into account the various submissions. FDA estimates that
each box weighs approximately 20 pounds. Based on cost estimates of a
major private courier, the cost for a 20 lb. box shipped Standard
Overnight is \$120.00; this shipping cost is based on an average
distance within the continental U.S.

## Capital Costs (Maintenance of Capital Costs)

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

## Cost to Federal Government

The estimated annualized cost to the Federal Government is
\$15,854,325.6. This estimate is based on full-time equivalents (FTEs)
associated with the review of license applications including
supplemental applications or other similar submissions. The amount of
time and expense incurred by the Federal government is due to the review
of all material submitted with an application, supplement, or other
similar submission. This information is essential to determine the
safety and effectiveness of products in support of FDA's mission to
protect the public health. This information may include clinical data,
safety updates, samples submitted for evaluation by the agency, case
report tabulations, case report forms, and patient information. In
addition, the estimate is based on the number of FTEs associated with
the processing of license revocations and suspensions, and advertising
and promotional labeling. The estimated average annual salary for CBER
reviewers is \$110,176 that includes benefits but no overhead costs.

  --------------------------- ------------- --------------------- ----------------
  Activity                    Number of     Average Annual        Total Cost
                              FTEs          Reviewer Salary       

  Application/Supplement      103.3         \$110,176             \$11,381,180
  Review                                                          

  License Processing          36.1          \$110,176             \$3,977,353.6

  Advertisement/Promotional   4.5           \$110,176             \$495,792
  Labeling                                                        

  Total                                                           \$15,854,325.6
  --------------------------- ------------- --------------------- ----------------

## Program or Burden Changes

The burden estimate for 0910-0338 was 301,751.75. The overall increase
in burden to 335,087.5 is attributed to the consolidation of several OMB
packages: 0910-0423 (biologics regulations only), 0910-0504, 0910-0527,
and 0910-0538 (biologics regulations only).

Section 601.25(b) requests interested persons to submit, for review and
evaluation by an advisory review panel, published and unpublished data
and information pertinent to a designated category of biological
products that have been licensed prior to July 1, 1972. Section
601.26(f) requests that licensees submit to FDA a written statement
intended to show that studies adequate and appropriate to resolve
questions raised about a biological product have been undertaken for a
product if designated as requiring further study under the
reclassification procedures. Under § 601.25(b)(3), FDA estimates no
burden for this regulation since all requested data and information had
been submitted by 1974. Under section 601.26(f), FDA estimates no burden
for this regulation since there are no products designated to require
further study and none are predicted in the future. However, based on
the possible reclassification of a product, the labeling for the product
may need to be revised, or a manufacturer, on its own initiative, may
deem it necessary for further study. As a result, any changes to product
labeling would be reported under § 601.12. Since there is no further
burden, we will no longer request OMB approval for these two
regulations.

## Publication and Tabulation Dates

There are no tabulated results to publish for this information
collection.

## Display of OMB Approval Date

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

## Exceptions to "Certification for Paperwork Reduction Act Submissions"

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