[Federal Register Volume 70, Number 139 (Thursday, July 21, 2005)]
[Notices]
[Pages 42068-42072]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-14330]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2005N-0083]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; 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 that a 
proposed collection of information has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995.

DATES: Fax written comments on the collection of information by August 
22, 2005.

ADDRESSES: OMB is still experiencing significant delays in the regular 
mail, including first class and express mail, and messenger deliveries 
are not being accepted. To ensure that comments on the information 
collection are received, OMB recommends that written comments be faxed 
to the Office of Information and Regulatory Affairs, OMB, Attn: Fumie 
Yokota, Desk Officer for FDA, FAX: 202-395-6974.

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: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

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).
    Section 601.2(a) requires manufacturers 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 licensees to submit to FDA notice of its 
intention to discontinue manufacture of a product or all products. 
Section 601.6(a) requires licensees to notify selling agents and 
distributors upon suspension of its license, and provide FDA with 
records 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 applicants to promptly revise 
all promotional labeling and advertising to make it consistent with 
certain labeling changes implemented. Section 601.12(a)(5) 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. 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 May 31, 2008) 
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), (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), applicants 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 on 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. 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. Section 601.12(f)(4) 
requires

[[Page 42069]]

that applicants report to FDA advertising and promotional labeling and 
any changes. Section 601.45 requires that applicants of biological 
products for serious or life-threatening illnesses 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: Sections 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: Section 
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 June 30, 2008).
    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 applicants 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 applicants may request a full or partial waiver of the 
requirements under Sec.  601.27(a). The estimate 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 the Center for Drug 
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 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, or on 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 a patient or a potential patient 
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). 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 the 
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; pending 
extension of OMB approval). 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 that 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 in 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 that manufacturers 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.
    Section 601.91(b)(2)(iii) provides that biological products 
approved under subpart H are subject to the postmarketing recordkeeping 
and safety reporting applicable to all approved biological products.
    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

[[Page 42070]]

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 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 
(expires May 31, 2008).
    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.  601.91(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 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.
    In the Federal Register of March 15, 2005 (70 FR 12693), FDA 
published a 60-day notice requesting public comment on the information 
collection provisions to which one comment was received. The comment 
was 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 comment 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.

                                 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), 610.60,     2567/356h              14               2                 28         860         24,080
 610.61, and
 610.62\2\
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601.5(a)                     NA              16               3.13              50            .33          17
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[[Page 42071]]

 
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             190               4.75             903          80         72,240
 (b)(3)\3\
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601.12(c)(1) and           356h              98               2.60             255          50         12,750
 (c)(3)\4\
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601.12(c)(5)\4\            356h              34               1.38              47          50          2,350
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601.12(d)(1) and           356h             166               1.37             227          22.5        5,107.5
 (d)(3)\5\
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601.12(e)                  356h              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)\6\            2567              15              36                540          10          5,400
 and 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) and             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.
\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.  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.
\3\.The reporting requirements under Sec.  Sec.   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 Sec.   601.12(b)(1) and (b)(3).
\4\ The reporting requirements under Sec.  Sec.   601.12(a)(2), 640.17, 640.25(c), 640.56(c), and 640.74(b)(2)
  are also included in the estimate under Sec.   601.12(c)(1) and (c)(3) or (c)(5).
\5\.The reporting requirements under Sec.   601.12(a)(2) are also included in the estimates under Sec.
  601.12(d)(1) and (d)(3).
\6\.The reporting requirements under Sec.   601.12(a)(4) are included in the estimates under Sec.   601.12(f)(4)
  or OMB control number 0910-0001 since the required information is submitted with Form FDA 2567 or 2253.

    Under table 2 of this document, 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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                               No. of         Annual Frequency     Total Annual      Hours per
     21 CFR Section        Recordkeepers      per Recordkeeping       Records         Record        Total Hours
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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.



[[Page 42072]]

    Dated: July 14, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-14330 Filed 7-20-05; 8:45 am]
BILLING CODE 4160-01-S