[Federal Register Volume 70, Number 49 (Tuesday, March 15, 2005)]
[Notices]
[Pages 12693-12697]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-5026]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2005N-0083]


Agency Information Collection Activities; Proposed Collection; 
Comment Request; General Licensing Provisions: Biologics License 
Application, Changes to an Approved Application, Labeling, Revocation 
and Suspension, and Forms FDA 356h and 2567

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing an 
opportunity for public comment on the proposed collection of certain 
information by the agency. Under the Paperwork Reduction Act of 1995 
(the PRA), Federal agencies are required to publish notice in the 
Federal Register concerning each proposed collection of information, 
including each proposed extension of an existing collection of 
information, and to allow 60 days for public comment in response to the 
notice. This notice solicits comments on the information collection 
requirements relating to the general licensing provisions regarding 
biologics license application, changes to an approved application, 
labeling, and revocation and suspension, and the use of Forms FDA 356h 
and 2567.

DATES: Submit written or electronic comments on the collection of 
information by May 16, 2005.

ADDRESSES: Submit electronic comments on the collection of information 
to: http://www.fda.gov/dockets/ecomments. Submit written comments on 
the collection of information to the Division of Dockets Management 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. All comments should be identified with the docket 
number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Jonna Capezzuto, Office of Management 
Programs (HFA-250), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-4659.

SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal 
agencies must obtain approval from the Office of Management and Budget 
(OMB) for each collection of information they conduct or sponsor. 
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR 
1320.3(c) and includes agency requests or requirements that members of 
the public submit reports, keep records, or provide information to a 
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) 
requires Federal agencies to provide a 60-day notice in the Federal 
Register concerning each proposed collection of information, including 
each proposed extension of an existing collection of information, 
before submitting the collection to OMB for approval. To comply with 
this requirement, FDA is publishing notice of the proposed collection 
of information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on these topics: (1) Whether the proposed collection 
of information is necessary for the proper performance of FDA's 
functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.

General Licensing Provisions: Biologics License Application, Changes to 
an Approved Application, Labeling, Revocation and Suspension, and Forms 
FDA 356h and 2567 (OMB Control Number 0910-0338)--Extension

    Under Section 351 of the Public Health Services Act (the PHS Act) 
(42 U.S.C. 262), 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 insure 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).

[[Page 12694]]

    Section 601.2(a) requires a manufacturer of a biological product to 
submit an application with accompanying information, including labeling 
information, to FDA for approval to market a product in interstate 
commerce. The container and package labeling requirements are provided 
under part 610 (21 CFR part 610) Sec. Sec.  610.60, 610.61, and 610.62. 
The estimate for these regulations is included in the estimate under 
Sec.  601.2(a) in table 1 of this document.
    Section 601.5(a) requires a licensee to submit to FDA notice of its 
intention to discontinue manufacture of a product or all products. 
Section 601.6(a) requires the licensee to notify selling agents and 
distributors upon suspension of its license, and provide FDA of such 
notification.
    Section 601.12 (a)(2) 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. Section 601.12(a)(4) requires, generally, that the 
applicant must promptly review all promotional labeling and advertising 
to make it consistent with any labeling changes implemented. Section 
601.12(a)(5) requires the applicant 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. The burden estimates for 
Sec.  601.12(a)(2) are included in the estimates for supplements (Sec.  
601.12(b) and (c)) and annual reports (Sec.  601.12(d)). The burden 
estimates for Sec.  601.12(a)(4) are included in the estimates under 
Sec.  601.12(f)(4) in table 1 of this document or OMB control number 
0910-0001 (expires March 31, 2005) because the required information is 
submitted with Forms FDA 2567 or 2253.
    Section 601.12(b)(1) and (b)(3), (c)(1) and (c)(3), and (c)(5), and 
(d)(1) and (d)(3) require applicants to follow specific procedures to 
inform FDA of each change, in the product, production process, quality 
controls, equipment, facilities, responsible personnel or labeling 
established in an approved license application. The 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 products as they may 
relate to the safety or effectiveness of the product. Under Sec.  
601.12(b)(4), an applicant may ask 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. The burden estimate for Sec.  601.12(b)(4) is minimal and 
included in the estimate under Sec.  601.12(b)(1) and (b)(3) in table 1 
of this document.
    Section 601.12(e) requires applicants to submit a protocol, or 
change to a protocol, as a supplement requiring FDA approval before 
distributing the product. Section 601.12(f)(1), (f)(2), and (f)(3) 
requires applicants to follow specific procedures to report labeling 
changes to FDA. Section 601.12(f)(4) requires applicants to report to 
FDA advertising and promotional labeling and any changes. Section 
601.45 requires applicants of biological products for serious or life-
threatening illnesses to submit to the agency for consideration, during 
the preapproval review period, copies of all promotional materials, 
including promotional labeling as well as advertisements.
    In addition to Sec. Sec.  601.2 and 601.12, there are other 
regulations in parts 640, 660, and 680 (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: Sec. Sec.  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 this document, the burden associated with the 
information collection requirements in these regulations is included in 
the burden estimate for Sec.  601.2 and/or Sec.  601.12. A regulation 
may be listed under more than one paragraph of Sec.  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: Sec.  640.70(a) 
for Source Plasma; Sec.  640.74(b)(3) and (b)(4) for Source Plasma 
Liquid; Sec.  640.84(a) and (c) for Albumin; Sec.  640.94(a) for Plasma 
Protein Fraction; Sec.  660.2(c) for Antibody to Hepatitis B Surface 
Antigen; Sec.  660.28(a) and (b) for Blood Grouping Reagent; Sec.  
660.35(a), (c) through (g), and (i) through (m) for Reagent Red Blood 
Cells; Sec.  660.45 for Hepatitis B Surface Antigen; and Sec.  
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 
Sec. Sec.  610.60 through 610.62 or Sec.  809.10 (21 CFR 809.10). 
Therefore, the burden estimates for these regulations is included in 
the estimate under Sec. Sec.  610.60 through 610.62 in table 1 of this 
document. The burden estimates associated with Sec.  809.10 are 
approved under OMB control number 0910-0485 (expires March 31, 2005).
    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 Sec.  601.25(b)(3), FDA estimates no 
burden for this regulation because all requested data and information 
had been submitted by 1974. Under Sec.  601.26(f), FDA estimates no 
burden for this regulation because 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 Sec.  601.12.
    Section 601.27(a) 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 subpopulations, and to support dosing and administration 
information. Section 601.27(b) provides that an applicant may request a 
deferred submission of some or all assessments of safety and 
effectiveness required under Sec.  601.27(a). Section 601.27(c) 
provides that an applicant may request a full or partial waiver of the 
requirements under Sec.  601.27(a). The estimated for Sec.  601.27(a) 
is included in the burden estimate under Sec.  601.2(a) in table 1 of 
this document since these regulations deal with information to be 
provided in an application.
    Section 601.28 requires sponsors of licensed biological products to 
submit the information in Sec.  601.28(a), (b), and (c) to the Center 
for Biologics Evaluation and Research (CBER) or Center for Drugs 
Evaluation and Research (CDER) each year, within 60 days of the 
anniversary date of approval of the license. Section 601.28(a) 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

[[Page 12695]]

pediatric population have been initiated. Section 601.28(b) 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. Section 601.28(c) requires sponsors to 
submit to FDA a statement on the current status of any postmarketing 
studies in the pediatric population performed by, on or behalf of, the 
applicant.
    Sections 601.33 through 601.35 clarify the information to be 
submitted in an application to FDA to evaluate the safety and 
effectiveness of in vivo radiopharmaceuticals. The burden estimates for 
Sec. Sec.  601.33 through 601.35 are included in the burden estimate 
under Sec.  601.2(a) in table 1 of this document since these 
regulations deal with information to be provided in an application.
    Section 601.91(b)(3) requires applicants to prepare and provide 
labeling with relevant information to patient or potential patient for 
biological products approved under the subpart when human efficacy 
studies are not ethical or feasible (or based on evidence of 
effectiveness from studies in animals). Section 601.93 provides that 
biological products approved under this subpart are subject to the 
postmarketing recordkeeping and safety reporting applicable to all 
approved biological products. Section 601.94 requires applicants under 
this subpart to submit to the agency for consideration during 
preapproval review period copies of all promotional materials including 
promotional labeling as well as advertisements. Under Sec.  601.93, any 
potential postmarketing reports and/or recordkeeping burdens would be 
included under the adverse experience reporting (AER) requirements 
under part 600 (21 CFR part 600) (OMB control number 0910-0308; expires 
May 31, 2005). Therefore, any burdens associated with these 
requirements would be reported under the AER information collection 
requirements (OMB control number 0910-0308).
    Section 610.11(g)(2) provides a manufacturer of certain biological 
products may request an exemption from the general safety test (GST) 
requirements contained in this subpart. Under Sec.  610.11(g)(2), FDA 
requires only those manufacturers of biological products requesting an 
exemption from the GST to submit additional information as part of a 
license application or supplement to an approved license application. 
Therefore, the burden estimate for Sec.  610.11(g)(2) is included in 
the estimate under Sec. Sec.  601.2(a) and 601.12(b) in table 1 of this 
document.
    Section 610.67 requires certain biological products to comply with 
the bar code requirements at Sec.  201.25 (21 CFR 201.25). Section 
201.25 is approved under OMB control number 0910-0537 (expires February 
28, 2007).
    Section 680.1(c) requires manufacturers to update annually their 
license file with the list of source materials and the suppliers of the 
materials.
    Sections 600.15(b) and 610.53(d) require the submission of a 
request for an exemption or modification regarding the temperature 
requirements during shipment and from dating periods, respectively, for 
certain biological products. Section 606.110(b) requires the submission 
of a request for approval to perform plasmapheresis of donors who do 
not meet certain donor requirements for the collection of plasma 
containing rare antibodies. Under Sec. Sec.  600.15(b), 610.53(d), and 
606.110(b), a request for an exemption or modification to the 
requirements would be submitted as a supplement. Therefore, the burden 
hours for any submissions under Sec. Sec.  600.15(b), 610.53(d), and 
606.110(b) are included in the estimates under Sec.  601.12(b) in table 
1 of this document.
    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 CBER and the CDER. The application form 
serves primarily as a checklist for firms to gather and submit certain 
information 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 to CDER using FDA Form 356h are reported under OMB control 
number 0910-0001.
    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 was previously used only by drug manufacturers regulated 
by 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 the submission is complete.
    Under table 1 of this document, 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 FDA 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 (i.e., 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 Sec. Sec.  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 Sec.  601.6(a), the total annual responses are based on FDA 
estimates

[[Page 12696]]

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 Sec. Sec.  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 number 0910-0376.
    Under Sec. Sec.  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 
Sec. Sec.  601.93(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 Sec.  601.94, therefore 
minimal burden is calculated for providing the guide to patients under 
Sec.  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.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1.--Estimated Annual Reporting Burden\1\
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                    Form FDA      No. of     Annual Frequency   Total Annual       Hours per
 21 CFR Section       No.      Respondents     per Response       Responses         Response        Total Hours
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601.2(a),           2567/356h           14               2              28                860          24,080
 610.60, 610.61,
 and 610.62
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601.5(a)                   NA           16               3.13           50                   .33           17
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601.6(a)                   NA            1              21              21                   .33            7
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601.12(a)(5)               NA          190              15.7         2,983                  1           2,983
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601.12(b)(1) and      356h\2\          190               4.75          903                 80          72,240
 (b)(3)
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601.12(c)(1) and      356h\2\           98               2.60          255                 50          12,750
 (c)(3)
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601.12(c)(5)          356h\2\           34               1.38           47                 50           2,350
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601.12(d)(1) and      356h\2\          166               1.37          227                 22.5         5,107.5
 (d)(3)
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601.12(e)             356h\2\           14               1.43           20                120           2,400
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601.12(f)(1)             2567           12               1              12                 40             480
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601.12(f)(2)             2567           10               1              10                 20             200
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601.12(f)(3)             2567           70               1.43          100                 10           1,000
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601.12(f)(4),            2567           15              36             540                 10           5,400
 601.45
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601.25(b)(3)               NA            0               0               0                  0               0
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601.26(f)                  NA            0               0               0                  0               0
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601.27(b)                  NA            3               1               3                 24              72
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601.27(c)                  NA            7               1               7                  8              56
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601.28(a)                  NA           44               3.27          144                  8           1,152
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601.28(b)                  NA           44               3.27          144                 24           3,456
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601.28(c)                  NA           44               3.27          144                  1.5           216
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601.91(b)(3),              NA            1               1               1                240             240
 601.94
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610.67                     NA          174              31           5,400                 24         129,600
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680.1(c)                   NA           10               1              10                  2              20
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Amendments/              356h          306              11.6         3,563                 20          71,260
 resubmissions
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Total             ...........  ...........  .................  ..............  .................      335,086.5
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

[[Page 12697]]

 
\2\ The reporting requirements under Sec.  Sec.   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 Sec.
    601.2(a). The reporting requirements under Sec.   600.15(b), 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 Sec.   601.12(b). The reporting requirement under Sec.  Sec.   640.17, 640.25(c),
  640.56(c), and 640.74(b)(2) is also included in the estimate under Sec.   601.12(c). The reporting
  requirements under Sec.  Sec.   640.70(a), 640.74(b)(3) and (b)(4); 640.84(a) and (c); 640.94(a), 660.2(c),
  660.28(a) and (b); 660.35(a), (c) through (g), and (i) through (m); 660.45, and 660.55(a) and (b) are included
  under Sec.  Sec.   610.60 through 610.62.

    Under Table 2, the estimated recordkeeping burden of 1 hour is 
based on previous estimates for the recordkeeping requirements 
associated with the AER system.

                               Table 2.--Estimated Annual Recordkeeping Burden\1\
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                                                      Annual
         21 CFR Section           No. of Record-   Frequency per   Total Annual      Hours per      Total Hours
                                      keepers     Record-keeping      Records         Record
----------------------------------------------------------------------------------------------------------------
601.91(b)(2)(iii)                              1               1               1               1               1
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


    Dated: March 9, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-5026 Filed 3-14-05; 8:45 am]
BILLING CODE 4160-01-S