[Federal Register Volume 67, Number 110 (Friday, June 7, 2002)]
[Notices]
[Pages 39406-39409]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-14390]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 01N-0587]


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY:  The Food and Drug Administration (FDA) is announcing that the 
proposed collection of information listed below has been submitted to 
the Office of Management and Budget (OMB) for review and clearance 
under the Paperwork Reduction Act of 1995.

DATES:  Submit written comments on the collection of information by 
July 8, 2002.

ADDRESSES:  Submit written comments on the collection of information to 
the Office of Information and Regulatory Affairs, OMB, New Executive 
Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: 
Stuart Shapiro, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT:  JonnaLynn P. Capezzuto, Office of 
Information Resources Management (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 Forms FDA 356h and 2567; and 
Revocation and Suspension (OMB Control Number 0910-0338)--Extension

    Under section 351 of the Public Health Service 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 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). 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 21 CFR 610.60, 610.61, 
and 610.62. Section 601.12(a) provides the general requirements for 
submitting a change to an approved application. Section 601.12(b), (c), 
and (d) requires applicants to follow specific procedures in informing 
FDA of each change, established in an approved license application, in 
the product, production process, quality controls, equipment, 
facilities, or responsible personnel. The appropriate procedure depends 
on the potential for the change to have a substantial, moderate, 
minimal, or no adverse effect on the safety or effectiveness of the 
product. 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 in reporting 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 to submit to the agency for consideration, 
during the preapproval review period, copies of all promotional 
materials, including promotional labeling as well as advertisements. 
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). Section 601.28 requires sponsors of 
licensed biological products to submit the information in section

[[Page 39407]]

601.28(a), (b), and (c) to the Center for Biologics Evaluation and 
Research (CBER) 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, 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. In addition to Secs. 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: 
Secs. 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), 660.51(a)(4), and 
680.1(b)(2)(iii). In table 1 of this document, the burden associated 
with the information collection requirements in these regulations is 
included in the burden estimate for Secs. 601.2 and 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. In addition, the burden associated with 
the information collection requirements in Sec. 601.27(a) and 
Secs. 601.33 through 601.35 is included in the burden estimate for 
Sec. 601.2 since these regulations deal with information to be provided 
in an application. Sections 600.15(b) (21 CFR 600.15(b)) and Sec.  
610.53(d) (21 CFR 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 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. 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 with records of such notification. Section 680.1(c) 
requires manufacturers to update annually the list of source materials 
and the suppliers of the materials. 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 Center for Drug Evaluation and Research (CDER). The application 
form serves primarily as a checklist for firms to gather and submit to 
the agency studies and data that have been completed. 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 the agency 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 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 Form FDA 
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 and 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. 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 in fiscal year (FY) 2000, or the number of 
submissions received in FY 2000. Based on information obtained from 
CBER's database system, there are an estimated 350 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) 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 Secs. 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. In FY 2000, CBER received 4,302 
submissions of advertising and promotional labeling from 117 
manufacturers. FDA estimates that approximately 36 percent of those 
submissions were received with Form FDA 2567 resulting in an estimated 
1,549 submissions by 42 manufacturers. The burden hours for the 
remaining submissions received using Form FDA 2253 are reported under 
OMB control number 0910-0376. Under Secs. 600.15(b) and 610.53(d), FDA 
receives very few requests for an exemption or modification to the 
requirements, therefore, FDA has estimated one respondent per year in 
table 1 of this document to account for the rare

[[Page 39408]]

instance in which a request may be made. Under Sec. 601.25(b)(3), FDA 
estimates no burden for this regulation since all requested data and 
information had been submitted by 1974. Under Sec. 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 
Sec. 601.12. Under Sec. 601.6(a), the total annual responses is based 
on FDA estimates that establishments may notify an average of 20 
selling agents and distributors of such suspension and provide FDA with 
the records of such notification. The number of respondents is based on 
the estimated annual number of suspensions by FDA of a biologics 
license. There were also 1,585 amendments to an unapproved application 
or supplement and 21 resubmissions (total of 1,606 submissions) 
submitted in FY 2000 using Form FDA 356h.
    One letter of comment was received in response to the 60-day notice 
on the information collection in which we received one comment on the 
proposed information collection.
    The comment stated that we should revise various regulations to 
harmonize regulations between CBER and CDER. The comment cited many 
specific provisions, with none of the cited provisions being affected 
by the proposed information collection, and recommended specific 
changes to those provisions. For example, the comment asked that we 
delete Sec. 610.12 (21 CFR 610.12) regarding sterility for bulk 
materials, that we revise 21 CFR 610.11, Sec. 610.12, and 21 CFR 610.13 
and 610.30 to delete references to specific tests, and that we redefine 
``manufacturer'' in 21 CFR 600.3(t). The comment also asked us to 
address ``outdated'' safety reporting regulations; to permit multiple 
product facilities (citing 21 CFR 600.11(e)(3)); and to expedite 
followup actions after inspections.
    The comment's suggested regulatory revisions pertain to provisions 
or matters that are outside the scope of the proposed information 
collection. Consequently, we decline to adopt the comment's 
recommendations.
    The comment relevant to the information collection in the 60-day 
notice stated that Form FDA 2567 is only used to submit labels to CBER 
and that CDER does not use this form. The comment stated that the 
requirement to use only one form for one Center imposes an additional 
burden (but did not describe the additional burden), and suggested that 
CBER and CDER use the same form or not use the form at all.
    We are considering whether to retain Form FDA 2567 for labeling 
purposes, but because the issue of eliminating the form is complex, we 
won't have a decision on the matter before the OMB approval expires. 
Therefore, we are renewing the form until a final decision is reached 
on the use of the form. Manufacturers already have the option of 
submitting to CBER and CDER Form FDA 2253 for the submission of 
advertising and promotional labeling. However, any additional burden of 
submitting the form with a biologics license application is minimal 
because the time required to complete this form is estimated to average 
10 minutes.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1.--Estimated Annual Reporting Burden\1\
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             Form
  21 CFR      FDA   No. of Respondents   Annual Frequency per    Total Annual     Hours per       Total Hours
  Part\2\     No.                              Response            Responses      Response
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601.2(a),   2567           22                     3.64               80           1,600         128,000
 610.60,     and
 610.61,     356h
 and
 610.62
601.12(b)(  356h          168                     4.98              837              80          66,960
 1) and
 (b)(3)
601.12(c)(  356h          119                     6.63              789              50          39,450
 1) and
 (c)(3)
601.12(c)(  356h           58                     3.52              204              50          10,200
 5)
601.12(d)   356h           83                     1.72              143              10           1,430
601.12(e)   356h           70                     1                  70              20           1,400
601.12(f)(  2567           37                     2.08               77              40           3,080
 1)
601.12(f)(  2567           45                     1                  45              20             900
 2)
601.12(f)(  2567           20                     1                  20              10             200
 3)
601.12(f)(  2567           42                    36.88            1,549              10          15,490
 4) and
 601.45
600.15(b)   356h            1                     1                   1               8               8
610.53(d)   356h            1                     1                   1               8               8
601.25(b)(  NA              0                     0                   0               0               0
 3)
601.26(f)   NA              0                     0                   0               0               0
601.27(b)   NA              5                     1                   5              24             120
601.27(c)   NA              3                     1.33                4               8              32
601.28(a)   NA             69                     1                  69               8             552
601.28(b)   NA             69                     1                  69              24           1,656
601.28(c)   NA             69                     1                  69               1.5           103.5
601.5(a)    NA             25                     1                  25                .33            8.25
601.6(a)    NA              2                    21                  42                .33           14
680.1(c)    NA             10                     1                  10               2              20
Amendments  356h          350                     4.59            1,606              20          32,120
 and
 Resubmiss
 ions
  Total                                                                                         301,751.75
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ The reporting requirement under Secs.  601.27(a), 601.33, 601.34, 601.35, and 680.1(b)(2)(iii) is included
  in the estimate under Sec.  601.2(a). The reporting requirement under Secs.  640.6, 640.17, 640.21(c),
  640.22(c), 640.25(c), 640.56(c), 640.64(c), and 640.72(a) and (b)(2) is included in the estimate under Sec.
  601.12(b). The reporting requirement under Secs.  640.25(c) and 640.56(c) is also included in the estimate
  under Sec.  601.12(c)(3).



[[Page 39409]]

    Dated: May 31, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-14390 Filed 6-6-02; 8:45 am]
BILLING CODE 4160-01-S