[Federal Register: March 15, 2005 (Volume 70, Number 49)]
[Notices]
[Page 12693-12697]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr15mr05-98]
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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
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601.91(b)(2)(iii) 1 1 1 1 1
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\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