[Federal Register Volume 85, Number 12 (Friday, January 17, 2020)]
[Notices]
[Pages 3053-3057]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-00729]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-0578]


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, Postmarketing Studies 
Status Reports, and Form FDA 356h

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or we) 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 
February 18, 2020.

ADDRESSES: 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: FDA Desk Officer, 
Fax: 202-395-7285, or emailed to [email protected]. All 
comments should be identified with the OMB control number 0910-0338. 
Also include the FDA docket number found in brackets in the heading of 
this document.

FOR FURTHER INFORMATION CONTACT: Domini Bean, Office of Operations, 
Food and Drug Administration, Three White Flint North, 10A-12M, 11601 
Landsdown St., North Bethesda, MD 20852, 301-796-5733, 
[email protected].

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, 
Postmarketing Studies Status Reports, and Form FDA 356h

OMB Control Number 0910-0338--Extension

    Under section 351 of the Public Health Services 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 130(a) of the Food and Drug Administration Modernization 
Act of 1997 (Pub. L. 105-115) amended the Federal Food, Drug, and 
Cosmetic Act (FD&C Act) by adding a new provision (section 506B of the 
FD&C Act (21 U.S.C. 356b)) requiring reports of postmarketing studies 
for approved human drugs and licensed biological products. Section 506B 
of the FD&C Act provides FDA with additional authority to monitor the 
progress of postmarketing studies that applicants have made a 
commitment to conduct and requires the Agency to make publicly 
available information that pertains to the status of these studies. 
Under section 506B(a) of the FD&C Act, applicants that have committed 
to conduct a postmarketing study for an approved human drug or licensed 
biological product must submit to FDA a status report of the progress 
of the study or the reasons for the failure of the applicant to conduct 
the study. This report must be submitted within 1 year after the U.S. 
approval of the application and then annually until the study is 
completed or terminated.
    A summary of the collection of information requirements follows:
    Section 601.2(a) (21 CFR 601.2(a)) requires a manufacturer of a 
biological product to submit an application on forms prescribed for 
such purposes with accompanying data and information, including certain 
labeling information, to FDA for approval to market a product in 
interstate commerce. The container and package labeling requirements 
are provided under Sec. Sec.  610.60 through 610.65 (21 CFR 610.60 
through 610.65). The estimate for these regulations is

[[Page 3054]]

included in the estimate under Sec.  601.2(a) in table 1.
    Section 601.5(a) (21 CFR 601.5(a)) requires a manufacturer to 
submit to FDA notice of its intention to discontinue manufacture of a 
product or all products. Section 601.6(a) (21 CFR 601.6(a) requires the 
manufacturer to notify selling agents and distributors upon suspension 
of its license, and provide FDA of such notification.
    Section 601.12(a)(2) (21 CFR 601.12((a)(2)) requires, generally, 
that the holder of an approved biologics license application (BLA) 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 revise 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. 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 601.12(f)(4) in table 1.
    Sections 601.12(b)(1) and (3), (c)(1), (3), and (5), and (d)(1) and 
(3) require applicants to follow specific procedures to submit 
information to FDA of any changes, in the product, production process, 
quality controls, equipment, facilities, or responsible personnel 
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 (3) in table 1.
    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) through (3) requires 
applicants to follow specific procedures to report certain labeling 
changes to FDA. Section 601.12(f)(4) requires applicants to report to 
FDA advertising and promotional labeling and any changes.
    Under Sec.  601.14 (21 CFR 601.14), the content of labeling 
required in 21 CFR 201.100(d)(3) must be in electronic format and in a 
form that FDA can process, review, and archive. This requirement is in 
addition to the provisions of Sec. Sec.  601.2(a) and 601.12(f). The 
burden estimate for Sec.  601.14 is minimal and included in the 
estimate under Sec. Sec.  601.2(a) (BLAs) and 601.12(f)(1) through (3) 
(labeling supplements and annual reports) in table 1.
    Section 601.45 (21 CFR 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 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 as follows: 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), and 680.1(b)(2)(iii) and (d) (21 
CFR 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) and 
(d)).
    In table 1, the burden associated with the information collection 
requirements in the applicable regulations is included in the burden 
estimate for Sec. Sec.  601.2 and/or 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 including: Sec.  
640.74(b)(3) and (4) for Source Plasma Liquid; Sec.  640.84(a) and (c) 
(21 CFR 640.84(a) and (c)) for Albumin; Sec.  640.94(a) (21 CFR 
640.94(a)) for Plasma Protein Fraction; Sec.  660.2(c) (21 CFR 
660.2(c)) for Antibody to Hepatitis B Surface Antigen; Sec.  660.28(a) 
through (c) (21 CFR 660.28(a) through (c)) for Blood Grouping Reagent; 
Sec.  660.35(a) through (d) (21 CFR 660.35(a) through (d)) for Reagent 
Red Blood Cells; Sec.  660.45 (21 CFR 660.45) for Hepatitis B Surface 
Antigen; and Sec.  660.55(a) and (b) (21 CFR 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 610.65 
or Sec.  809.10 (21 CFR 809.10). Therefore, the burden estimates for 
these regulations are included in the estimate under Sec. Sec.  610.60 
through 610.65 in table 1. The burden estimates associated with Sec.  
809.10 are approved under OMB control number 0910-0485.
    Section 601.27(a) (21 CFR 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) until after 
licensing the product for use in adults. Section 601.27(c) provides 
that an applicant may request a full or partial waiver of the 
requirements under Sec.  601.27(a) with adequate justification. The 
burden estimates for Sec.  601.27(a) are included in the burden 
estimate under Sec.  601.2(a) in table 1 because these regulations deal 
with information to be provided in an application.
    Section 601.28 (21 CFR 601.28) requires sponsors of licensed 
biological products to submit the information in Sec.  601.28(a) 
through (c) to the Center for Biologics Evaluation and Research (CBER) 
or to 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, on or behalf of, the applicant. If 
the postmarketing studies were required or agreed to, the status of 
these studies is to be reported under Sec.  601.70 (21 CFR 601.70) 
rather than under this section.
    Sections 601.33 through 601.35 (21 CFR 601.33 through 601.35) 
clarify the information to be submitted in an application to FDA to 
evaluate the safety and effectiveness of radiopharmaceuticals intended 
for in vivo administration for diagnostic and monitoring use. The 
burden estimates for Sec. Sec.  601.33 through 601.35 are included in 
the burden estimate under

[[Page 3055]]

Sec.  601.2(a) in table 1 because these regulations deal with 
information to be provided in an application.
    Section 601.70(b) requires each applicant of a licensed biological 
product to submit annually a report to FDA on the status of 
postmarketing studies for each approved product application. Each 
annual postmarketing status report must be accompanied by a completed 
transmittal Form FDA 2252 (Form FDA 2252 approved under OMB control 
number 0910-0001). Under Sec.  601.70(d), two copies of the annual 
report shall be submitted to FDA.
    Sections 601.91 through 601.94 (21 CFR 601.91 through 601.94) 
concern biological products for which human efficacy studies are not 
ethical or feasible. Section 601.91(b)(2) requires, in certain 
circumstances, such postmarking restrictions as are needed to ensure 
the safe use of the biological product. Section 601.91(b)(3) requires 
applicants to prepare and provide labeling with relevant information to 
patients or potential patients for biological products approved under 
part 601, subpart H, 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 part 601, subpart H are subject to the postmarketing 
recordkeeping and safety reporting applicable to all approved 
biological products. Section 601.94 requires applicants under part 601, 
subpart H 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. Sec.  
601.91(b)(2) and 601.93, any potential postmarketing reports and/or 
recordkeeping burdens would be included under the adverse experience 
reporting (AER) requirements under 21 CFR part 600 (OMB control number 
0910-0308). Therefore, any burdens associated with these requirements 
would be reported under the AER information collection requirements 
(OMB control number 0910-0308). The burden estimate for Sec.  
601.91(b)(3) is included in the estimate under Sec. Sec.  610.60 
through 610.65.
    Section 610.9(a) (21 CFR 610.9(a)) requires the applicant to 
present certain information, in the form of a license application or 
supplement to the application, for a modification of any particular 
test method or manufacturing process or the conditions under which it 
is conducted under the biologics regulations. The burden estimate for 
Sec.  610.9(a) is included in the estimate under Sec. Sec.  601.2(a) 
and 601.12(b) and (c) in table 1.
    Under Sec.  610.15(d) (21 CFR 610.15(d)), the Director of CBER or 
the Director of CDER may approve, as appropriate, a manufacturer's 
request for exceptions or alternatives to the regulation for 
constituent materials. Manufacturers seeking approval of an exception 
or alternative must submit a request in writing with a brief statement 
describing the basis for the request and the supporting data.
    Section 640.120 (21 CFR 640.120) requires licensed establishments 
to submit a request for an exception or alternative to any requirement 
in the biologics regulations regarding blood, blood components, or 
blood products. For licensed establishments, a request for an exception 
or alternative must be submitted in accordance with Sec.  601.12; 
therefore, the burden estimate for Sec.  640.120 is included in the 
estimate under Sec.  601.12(b) in table 1.
    Section 680.1(c) requires manufacturers to update annually their 
license file with the list of source materials and the suppliers of the 
materials. Section 680.1(b)(3)(iv) requires manufacturers to notify FDA 
when certain diseases are detected in source materials.
    Sections 600.15(b) and 610.53(b) (21 CFR 600.15(b) and 610.53(b)) 
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) (21 CFR 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(b), 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.
    Form FDA 356h, ``Application to Market a New or Abbreviated New 
Drug or Biologic for Human Use,'' is used for the applicable 
submissions to both CBER and CDER. The application form serves 
primarily as a checklist for firms to gather and submit certain 
information to FDA and 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. In addition, the form provides key 
information to FDA for efficient handling and distribution to the 
appropriate staff for review. FDA estimates an average of 24 hours to 
complete the application form, which is included in the average burden 
per response. The estimated burden hours for nonbiological product 
submissions to CDER using Form FDA 356h are approved under OMB control 
number 0910-0001 (an estimated 16,650 submissions x 24 hours = 399,600 
hours).
    For advertisements and promotional labeling (e.g., circulars, 
package labels, container labels, etc.) and labeling changes, 
manufacturers of licensed biological products may submit to CBER or 
CDER Form FDA 2253. Form FDA 2253 can also be submitted electronically. 
Form FDA 2253 is approved under OMB control number 0910-0001.
    Respondents to this collection of information are manufacturers of 
biological products. Under table 1, the numbers of respondents are 
based on the estimated annual number of manufacturers that submitted 
the required information to FDA or the number of submissions FDA 
received in fiscal year 2018. Based on information obtained from FDA's 
database systems, there are an estimated 424 licensed biologics 
manufacturers. 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. 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 section 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. In

[[Page 3056]]

table 1, FDA is estimating one in case a suspension occurs.
    Under Sec. Sec.  601.12(f)(4) and 601.45, manufacturers of 
biological products may use Form FDA 2253 to submit advertising and 
promotional labeling (which can include multiple pieces). Based on 
information obtained from FDA's database system, the estimate is based 
on the number of submissions received using Form FDA 2253 for 
advertising and promotional labeling.
    Under Sec. Sec.  601.28 and 601.70(b), FDA estimates that it takes 
an applicant approximately 24 hours (8 hours per study x 3 studies) 
annually to gather, complete, and submit the appropriate information 
for each postmarketing status report (approximately 2 to 4 studies per 
report) and the accompanied transmittal Form FDA 2252. Included in 
these 24 hours is the time necessary to prepare and submit two copies 
of the annual progress report of postmarketing studies to FDA under 
Sec.  601.70(d).
    Under Sec.  610.15(d), FDA has received no submissions since the 
implementation of the final rule (``Revision of the Requirements for 
Constituent Materials'') in April 2011 (76 FR 20513, April 13, 2011). 
Therefore, FDA is estimating one respondent and one annual request to 
account for a possible submission to CBER or CDER of a request for an 
exception or alternative for constituent materials under Sec.  
610.15(d).
    There were a total of 3,398 amendments to an unapproved application 
or supplement and resubmissions submitted using Form FDA 356h.
    In the Federal Register of September 19, 2019 (84 FR 49310), we 
published a 60-day notice requesting public comment on the proposed 
collection of information. No comments were received.
    We estimate the burden of this collection of information as 
follows:

                                                     Table 1--Estimated Annual Reporting Burden \1\
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                                                                             Number of                                                           Total
             21 CFR section                Form FDA No.      Number of     responses per   Total annual       Average burden per response        hours
                                                            respondents     respondent       responses                                            \10\
--------------------------------------------------------------------------------------------------------------------------------------------------------
601.2(a) ,\2\ 610.60 through 610.65 \3\.            356h              36            1.28              46  860................................     39,560
601.5(a)................................              NA               8            1.13               9  0.33 (20 minutes)..................          3
601.6(a)................................              NA               1               1               1  0.33 (20 minutes)..................          1
601.12(a)(5)............................              NA             430           4.158           1,788  1..................................      1,788
601.12(b)(1) and (3) and (e) \4\........        \2\ 356h             166           4.843             804  80.................................     64,320
601.12(c)(1) and (3) \5\................        \2\ 356h             149            4.58             682  50.................................     34,100
601.12(c)(5)............................        \2\ 356h               7            1.14               8  50.................................        400
601.12(d)(1) and (3) \6\ and (f)(3) \8\.        \2\ 356h             245           3.575             876  24.................................     21,024
601.12(f)(1) \7\........................            2253              65           3.169             206  40.................................      8,240
601.12(f)(2) \7\........................            2253              43            2.05              88  20.................................      1,760
601.12(f)(4)/601.45 \9\.................            2253             134          145.86          19,545  10.................................    195,450
601.27(b)...............................              NA              12            1.08              13  24.................................        312
601.27(c)...............................              NA               2               1               2  8..................................         16
601.70(b) and (d)/601.28................            2252              65           3.169             206  24.................................      4,944
610.15(d)...............................              NA               1               1               1  1..................................          1
680.1(c)................................              NA               9               1               9  2..................................         18
680.1(b)(3)(iv).........................              NA               1               1               1  2..................................          2
Amendments/Resubmissions................            356h             136          24.985           3,398  20.................................     67,960
                                         ---------------------------------------------------------------------------------------------------------------
    Total...............................  ..............  ..............  ..............  ..............  ...................................    439,899
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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.   601.14, 601.27(a), 601.33, 601.34, 601.35, 610.9(a), 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).
\3\ The reporting requirements under Sec.  Sec.   601.93(b)(3), 640.74(b)(3) and (4), 640.84(a) and (c), 640.94(a), 660.2(c), 660.28(a) through (c),
  660.35(a) through (d), 660.45, and 660.55(a) and (b) are included under Sec.  Sec.   610.60 through 610.65.
\4\ The reporting requirements under Sec.  Sec.   601.12(a)(2) and (b)(4), 600.15(b), 610.9(a), 610.53(b), 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), 640.120, and 680.1(d) are included in the estimate under Sec.   601.12(b).
\5\ The reporting requirements under Sec.  Sec.   601.12(a)(2), 610.9(a), 640.17, 640.25(c), 640.56(c), and 640.74(b)(2) are included in the estimate
  under Sec.   601.12(c).
\6\ The reporting requirement under Sec.   601.12(a)(2) is included in the estimate under Sec.   601.12(d).
\7\ The reporting requirement under Sec.   601.14 is included in the estimate under Sec.   601.12(f)(1) and (2).
\8\ The reporting requirement under Sec.  Sec.   601.12(a)(4) and 601.14 is included in the estimate under Sec.   601.12(f)(3).
\9\ The reporting requirement under Sec.   601.94 is included in the estimate under Sec.   601.45.
\10\ The numbers in this column have been rounded to the nearest whole number.


                                               Table 2--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                   Number of
                21 CFR section                    Number of     disclosures per    Total annual       Average burden per disclosure      Total hours \2\
                                                 respondents       respondent      disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
601.6(a).....................................               1               20               20   0.33 (20 minutes)....................               7
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\ The number in this column has been rounded to the nearest whole number.

    Our estimated burden for the information collection reflects an 
overall increase of 105,948 hours and a corresponding decrease of 2,671 
responses. We attribute this adjustment in the total hours to an 
increase in the number of submissions we have received under Sec. Sec.  
601.12(b)(1) and (3), (e), and (f)(4), and 601.45 over the last

[[Page 3057]]

few years. We attribute the decrease in total annual responses to a 
decrease in responses received under Sec. Sec.  601.12(a)(5) and 
601.27(b) over the last few years.

    Dated: January 8, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-00729 Filed 1-16-20; 8:45 am]
BILLING CODE 4164-01-P