81 FR 75130 - 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 Postmarketing Studies Status Reports

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 81, Issue 209 (October 28, 2016)

Page Range		75130-75134
FR Document		2016-26064
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.
Federal Register, Volume 81 Issue 209 (Friday, October 28, 2016)
[Federal Register Volume 81, Number 209 (Friday, October 28, 2016)]
[Notices]
[Pages 75130-75134]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2016-26064]


-----------------------------------------------------------------------

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, and Postmarketing 
Studies Status Reports

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

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 
November 28, 2016.

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.

[[Page 75131]]


FOR FURTHER INFORMATION CONTACT: FDA PRA Staff, Office of Operations, 
Food and Drug Administration, Three White Flint North, 10A63, 11601 
Landsdown St., North Bethesda, MD 20852, [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 (Pub. L. 105-115) amended the Federal Food, Drug, and Cosmetic Act 
(the 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) 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 included in the estimate under 
Sec.  601.2(a) in table 1.
    Section 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) 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) 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), (b)(3), (c)(1), (c)(3), (c)(5), (d)(1) and 
(d)(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 (b)(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), (2), and (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, 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), (2), and (3) (labeling 
supplements and annual reports) in table 1.
    Section 601.45 requires applicants of biological products for 
serious or life-threatening illnesses to submit to the Agency for 
consideration, during the pre-approval 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).
    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 subsection 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) 
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), 
(b), and (c) 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

[[Page 75132]]

requirements under Sec. Sec.  610.60 through 610.65 or 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) 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 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 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 rather 
than under this section.
    Sections 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 Sec.  601.2(a) in table 1 since 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 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 subpart H are subject 
to the postmarketing recordkeeping and safety reporting applicable to 
all approved biological products. Section 601.94 requires applicants 
under subpart H 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.  
601.91(b)(2) and Sec.  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) 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 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), 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 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(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 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(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.
    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 CDER. The application form 
serves primarily as a checklist for firms to gather and submit certain 
information to FDA. As such, the form, now entitled ``Application to 
Market a New or Abbreviated New Drug or Biologic for Human Use'' 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. The

[[Page 75133]]

estimated burden hours for nonbiological product submissions to CDER 
using FDA Form 356h are approved under OMB control number 0910-0001 (an 
estimated 3,200 submissions x24 hours = 76,800 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. 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 that the submission is complete. 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 tables 1 and 2, 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 (FY) 2015. Based on information obtained 
from FDA's database systems, there are an estimated 391 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 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 table 1, FDA is 
estimating 1 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, there were an 
estimated 11,676 submissions using Form FDA 2253 of advertising and 
promotional labeling from 114 respondents.
    Under Sec. Sec.  601.28 and 601.70(b), FDA estimates that it takes 
an applicant approximately 24 hours (8 hours per study x3 studies) 
annually to gather, complete, and submit the appropriate information 
for each postmarketing status report (approximately two to four 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). For FY 2015, there were 139 reports from 82 
respondents.
    Under Sec.  610.15(d), FDA has received no submissions since the 
implementation of the final rule in April 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 2,777 amendments to an unapproved application 
or supplement and resubmissions submitted using Form FDA 356h.
    In the Federal Register of July 11, 2016 (81 FR 44868), we 
published a 60-day notice requesting public comment on the proposed 
extension of this collection of information. No comments were received.
    FDA estimates the burden of this collection of information as 
follows:

                                                      Table 1--Estimated Annual Reporting Burden 1
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                              Number of
              21 CFR Section                 Form FDA No.      Number of    responses per   Total annual    Average burden per response     Total hours
                                                              respondents     respondent      responses                                        \10\
--------------------------------------------------------------------------------------------------------------------------------------------------------
601.2(a) \2\, 610.60 through 610.65 \3\...            356h              28           1.36              38  860..........................          32,680
601.5(a)..................................              NA              12           0.75               9  0.33 (20 minutes)............               3
601.6(a)..................................              NA               1           1                  1  0.33 (20 minutes)............               1
601.12(a)(5)..............................              NA             537          24.41          13,106  1............................          13,106
601.12(b)(1)/(b)(3)/(e) \4\...............        \2\ 356h             164           3.66             600  80...........................          48,000
601.12(c)(1)/(c)(3) \5\...................        \2\ 356h             120           4.78             574  50...........................          28,700
601.12(c)(5)..............................        \2\ 356h               7           1.14               8  50...........................             400
601.12(d)(1)/(d)(3) \6\/(f)(3) \8\........        \2\ 356h             246           3.34             822  24...........................          19,728
601.12(f)(1) \7\..........................            2253              72           1.93             139  40...........................           5,560
601.12(f)(2) \ 7\.........................            2253              60           1.82             109  20...........................           2,180
601.12(f)(4)/601.45 \9\...................            2253             114         102.42          11,676  10...........................         116,670
601.27(b).................................              NA              20          16.50             330  24...........................           7,920
601.27(c).................................              NA              12           1.08              13  8............................             104
601.70(b) and (d)/601.28..................            2252              82           1.70             139  24...........................           3,336
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             125          22.22           2,777  20...........................          55,540
                                           -------------------------------------------------------------------------------------------------------------

[[Page 75134]]

 
    Total.................................  ..............  ..............  .............  ..............  .............................         333,949
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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), (b), and (c),
  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 610.65.
\4\ The reporting requirements under Sec.  Sec.   601.12(a)(2) and (b)(4), 600.15(b), 610.9(a), 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), 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 (f)(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.

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


    Dated: October 25, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-26064 Filed 10-27-16; 8:45 am]
 BILLING CODE 4164-01-P
Federal Register / Vol. 81, No. 209 / Friday, October 28, 2016 / Notices 75131

FOR FURTHER INFORMATION CONTACT: FDA prescribed for such purposes with protocol, as a supplement requiring
PRA Staff, Office of Operations, Food accompanying data and information, FDA approval before distributing the
and Drug Administration, Three White including certain labeling information, product. Section 601.12(f)(1), (2), and
Flint North, 10A63, 11601 Landsdown to FDA for approval to market a product (3) requires applicants to follow specific
St., North Bethesda, MD 20852, in interstate commerce. The container procedures to report certain labeling
PRAStaff@fda.hhs.gov. and package labeling requirements are changes to FDA. Section 601.12(f)(4)
SUPPLEMENTARY INFORMATION: In provided under §§ 610.60 through requires applicants to report to FDA
compliance with 44 U.S.C. 3507, FDA 610.65 (21 CFR 610.60 through 610.65). advertising and promotional labeling
has submitted the following proposed The estimate for these regulations is and any changes.
collection of information to OMB for included in the estimate under Under § 601.14, the content of
review and clearance. § 601.2(a) in table 1. labeling required in 21 CFR
General Licensing Provisions: Section 601.5(a) requires a 201.100(d)(3) must be in electronic
Biologics License Application, Changes manufacturer to submit to FDA notice of format and in a form that FDA can
to an Approved Application, Labeling, its intention to discontinue manufacture process, review, and archive. This
Revocation and Suspension, of a product or all products. Section requirement is in addition to the
Postmarketing Studies Status Reports, 601.6(a) requires the manufacturer to provisions of §§ 601.2(a) and 601.12(f).
and Form FDA 356h OMB Control notify selling agents and distributors The burden estimate for § 601.14 is
Number 0910–0338—Extension upon suspension of its license, and minimal and included in the estimate
provide FDA of such notification. under §§ 601.2(a) (BLAs) and
Under Section 351 of the Public
Section 601.12(a)(2) requires, 601.12(f)(1), (2), and (3) (labeling
Health Services Act (42 U.S.C. 262),
generally, that the holder of an supplements and annual reports) in
manufacturers of biological products approved Biologics License Application table 1.
must submit a license application for (BLA) must assess the effects of a Section 601.45 requires applicants of
FDA review and approval before manufacturing change before biological products for serious or life-
marketing a biological product in distributing a biological product made threatening illnesses to submit to the
interstate commerce. Licenses may be with the change. Section 601.12(a)(4) Agency for consideration, during the
issued only upon showing that the requires, generally, that the applicant pre-approval review period, copies of all
establishment and the products for must promptly revise all promotional promotional materials, including
which a license is desired meets labeling and advertising to make it promotional labeling as well as
standards prescribed in regulations consistent with any labeling changes advertisements.
designed to ensure the continued safety, implemented. Section 601.12(a)(5) In addition to §§ 601.2 and 601.12,
purity, and potency of such products. requires the applicant to include a list there are other regulations in 21 CFR
All such licenses are issued, suspended, of all changes contained in the parts 640, 660, and 680 that relate to
and revoked as prescribed by supplement or annual report; for information to be submitted in a license
regulations in part 601 (21 CFR part supplements, this list must be provided application or supplement for certain
601). in the cover letter. The burden estimates blood or allergenic products as follows:
Section 130(a) of the Food and Drug for § 601.12(a)(2) are included in the §§ 640.6; 640.17; 640.21(c); 640.22(c);
Administration Modernization Act (Pub. estimates for supplements (§§ 601.12(b) 640.25(c); 640.56(c); 640.64(c); 640.74(a)
L. 105–115) amended the Federal Food, and (c)) and annual reports and (b)(2); 660.51(a)(4); and
Drug, and Cosmetic Act (the FD&C Act) (§ 601.12(d)). The burden estimates for 680.1(b)(2)(iii) and (d).
by adding a new provision (section § 601.12(a)(4) are included in the In table 1, the burden associated with
506B of the FD&C Act (21 U.S.C. 356b)) estimates under 601.12(f)(4) in table 1. the information collection requirements
requiring reports of postmarketing Sections 601.12(b)(1), (b)(3), (c)(1), in the applicable regulations is included
studies for approved human drugs and (c)(3), (c)(5), (d)(1) and (d)(3) require in the burden estimate for §§ 601.2
licensed biological products. Section applicants to follow specific procedures and/or 601.12. A regulation may be
506B of the FD&C Act provides FDA to submit information to FDA of any listed under more than one subsection
with additional authority to monitor the changes, in the product, production of § 601.12 due to the type of category
progress of postmarketing studies that process, quality controls, equipment, under which a change to an approved
applicants have made a commitment to facilities, or responsible personnel application may be submitted.
conduct and requires the Agency to established in an approved license There are also additional container
make publicly available information application. The appropriate procedure and/or package labeling requirements
that pertains to the status of these depends on the potential for the change for certain licensed biological products
studies. Under section 506B(a) of the to have a substantial, moderate, or including: § 640.74(b)(3) and (4) for
FD&C Act, applicants that have minimal adverse effect on the identity, Source Plasma Liquid; § 640.84(a) and
committed to conduct a postmarketing strength, quality, purity, or potency of (c) for Albumin; § 640.94(a) for Plasma
study for an approved human drug or the products as they may relate to the Protein Fraction; § 660.2(c) for Antibody
licensed biological product must submit safety or effectiveness of the product. to Hepatitis B Surface Antigen;
to FDA a status report of the progress of Under § 601.12(b)(4), an applicant may § 660.28(a), (b), and (c) for Blood
the study or the reasons for the failure ask FDA to expedite its review of a Grouping Reagent; § 660.35(a), (c
of the applicant to conduct the study. supplement for public health reasons or through g), and (i through m) for
This report must be submitted within 1 if a delay in making the change Reagent Red Blood Cells; § 660.45 for
year after the U.S. approval of the described in it would impose an Hepatitis B Surface Antigen; and
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application and then annually until the extraordinary hardship of the applicant. § 660.55(a) and (b) for Anti-Human
study is completed or terminated. The burden estimate for § 601.12(b)(4) is Globulin. The burden associated with
A summary of the collection of minimal and included in the estimate the additional labeling requirements for
information requirements follows: under § 601.12(b)(1) and (b)(3) in table submission of a license application for
Section 601.2(a) requires a 1. these certain biological products is
manufacturer of a biological product to Section 601.12(e) requires applicants minimal because the majority of the
submit an application on forms to submit a protocol, or change to a burden is associated with the

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requirements under §§ 610.60 through § 601.2(a) in table 1 since these approve, as appropriate, a
610.65 or 21 CFR 809.10. Therefore, the regulations deal with information to be manufacturer’s request for exceptions or
burden estimates for these regulations provided in an application. alternatives to the regulation for
are included in the estimate under Section 601.70 (b) requires each constituent materials. Manufacturers
§§ 610.60 through 610.65 in table 1. The applicant of a licensed biological seeking approval of an exception or
burden estimates associated with product to submit annually a report to alternative must submit a request in
§ 809.10 are approved under OMB FDA on the status of postmarketing writing with a brief statement describing
control number 0910–0485. studies for each approved product the basis for the request and the
Section 601.27(a) requires that application. Each annual postmarketing supporting data.
applications for new biological products status report must be accompanied by a Section 640.120 requires licensed
contain data that are adequate to assess completed transmittal Form FDA 2252 establishments to submit a request for
the safety and effectiveness of the (Form FDA 2252 approved under OMB an exception or alternative to any
biological product for the claimed control number 0910–0001). Under requirement in the biologics regulations
indications in pediatric subpopulations, § 601.70(d), two copies of the annual regarding blood, blood components, or
and to support dosing and report shall be submitted to FDA. blood products. For licensed
administration information. Section Sections 601.91 through 601.94 establishments, a request for an
601.27(b) provides that an applicant concern biological products for which exception or alternative must be
may request a deferred submission of human efficacy studies are not ethical or submitted in accordance with § 601.12;
some or all assessments of safety and feasible. Section 601.91(b)(2) requires, therefore, the burden estimate for
effectiveness required under § 601.27(a) in certain circumstances, such § 640.120 is included in the estimate
until after licensing the product for use postmarking restrictions as are needed under § 601.12(b) in table 1.
in adults. Section 601.27(c) provides to ensure the safe use of the biological Section 680.1(c) requires
that an applicant may request a full or product. Section 601.91(b)(3) requires manufacturers to update annually their
partial waiver of the requirements under applicants to prepare and provide license file with the list of source
§ 601.27(a) with adequate justification. labeling with relevant information to materials and the suppliers of the
The burden estimates for § 601.27(a) are patients or potential patients for materials. Section 680.1(b)(3)(iv)
included in the burden estimate under biological products approved under part requires manufacturers to notify FDA
§ 601.2(a) in table 1 since these 601, subpart H, when human efficacy when certain diseases are detected in
regulations deal with information to be studies are not ethical or feasible (or source materials.
provided in an application. based on evidence of effectiveness from Sections 600.15(b) and 610.53(d) (21
Section 601.28 requires sponsors of studies in animals). Section 601.93 CFR 610.53(d)) require the submission
licensed biological products to submit provides that biological products of a request for an exemption or
the information in § 601.28(a), (b), and approved under subpart H are subject to modification regarding the temperature
(c) to the Center for Biologics Evaluation the postmarketing recordkeeping and requirements during shipment and from
and Research (CBER) or to the Center for safety reporting applicable to all dating periods, respectively, for certain
Drug Evaluation and Research (CDER) approved biological products. Section biological products. Section 606.110(b)
each year, within 60 days of the 601.94 requires applicants under (21 CFR 606.110(b)) requires the
anniversary date of approval of the subpart H to submit to the Agency for submission of a request for approval to
license. Section 601.28(a) requires consideration during preapproval perform plasmapheresis of donors who
sponsors to submit to FDA a brief review period copies of all promotional do not meet certain donor requirements
summary stating whether labeling materials including promotional for the collection of plasma containing
supplements for pediatric use have been labeling as well as advertisements. rare antibodies. Under §§ 600.15(b),
submitted and whether new studies in Under § 601.91(b)(2) and § 601.93, any 610.53(d), and 606.110(b), a request for
the pediatric population to support potential postmarketing reports and/or an exemption or modification to the
appropriate labeling for the pediatric recordkeeping burdens would be requirements would be submitted as a
population have been initiated. Section included under the adverse experience supplement. Therefore, the burden
601.28(b) requires sponsors to submit to reporting (AER) requirements under 21 hours for any submissions under
FDA an analysis of available safety and CFR part 600 (OMB control number §§ 600.15(b), 610.53(d), and 606.110(b)
efficacy data in the pediatric population 0910–0308). Therefore, any burdens are included in the estimates under
and changes proposed in the labeling associated with these requirements § 601.12(b) in table 1.
based on this information. Section would be reported under the AER In July 1997, FDA revised Form FDA
601.28(c) requires sponsors to submit to information collection requirements 356h ‘‘Application to Market a New
FDA a statement on the current status of (OMB control number 0910–0308). The Drug, Biologic, or an Antibiotic Drug for
any postmarketing studies in the burden estimate for § 601.91(b)(3) is Human Use’’ to harmonize application
pediatric population performed by, on included in the estimate under procedures between CBER and CDER.
or behalf of, the applicant. If the §§ 610.60 through 610.65. The application form serves primarily as
postmarketing studies were required or Section 610.9(a) requires the a checklist for firms to gather and
agreed to, the status of these studies is applicant to present certain information, submit certain information to FDA. As
to be reported under § 601.70 rather in the form of a license application or such, the form, now entitled
than under this section. supplement to the application, for a ‘‘Application to Market a New or
Sections 601.33 through 601.35 clarify modification of any particular test Abbreviated New Drug or Biologic for
the information to be submitted in an method or manufacturing process or the Human Use’’ helps to ensure that the
mstockstill on DSK3G9T082PROD with NOTICES

application to FDA to evaluate the conditions which it is conducted under application is complete and contains all
safety and effectiveness of the biologics regulations. The burden the necessary information, so that
radiopharmaceuticals intended for in estimate for § 610.9(a) is included in the delays due to lack of information may
vivo administration for diagnostic and estimate under §§ 601.2(a) and 601.12(b) be eliminated. In addition, the form
monitoring use. The burden estimates and (c) in table 1. provides key information to FDA for
for §§ 601.33 through 601.35 are Under § 610.15(d), the Director of efficient handling and distribution to
included in the burden estimate under CBER or the Director of CDER may the appropriate staff for review. The

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Federal Register / Vol. 81, No. 209 / Friday, October 28, 2016 / Notices 75133

estimated burden hours for The total annual responses are based on Based on information obtained from
nonbiological product submissions to the estimated number of submissions FDA’s database system, there were an
CDER using FDA Form 356h are (i.e., license applications, labeling and estimated 11,676 submissions using
approved under OMB control number other supplements, protocols, Form FDA 2253 of advertising and
0910–0001 (an estimated 3,200 advertising and promotional labeling, promotional labeling from 114
submissions ×24 hours = 76,800 hours). notifications) for a particular product respondents.
For advertisements and promotional received annually by FDA. The hours Under §§ 601.28 and 601.70(b), FDA
labeling (e. g., circulars, package labels, per response are based on information estimates that it takes an applicant
container labels, etc.) and labeling provided by industry and past FDA approximately 24 hours (8 hours per
changes, manufacturers of licensed experience with the various study ×3 studies) annually to gather,
biological products may submit to CBER submissions or notifications. The hours complete, and submit the appropriate
or CDER Form FDA 2253. In August of per response include the time estimated information for each postmarketing
1998, FDA revised and harmonized to prepare the various submissions or status report (approximately two to four
Form FDA 2253 so the form may be notifications to FDA, and, as applicable, studies per report) and the accompanied
used to transmit specimens of the time required to fill out the transmittal Form FDA 2252. Included in
promotional labeling and appropriate form and collate the these 24 hours is the time necessary to
advertisements for biological products documentation. Additional information prepare and submit two copies of the
as well as for prescription drugs and regarding these estimates is provided as annual progress report of postmarketing
antibiotics. The revised, harmonized necessary. studies to FDA under § 601.70(d). For
form updates the information about the Under §§ 601.2 and 601.12, the FY 2015, there were 139 reports from 82
estimated hours per response are based respondents.
types of promotional materials and the
on the average number of hours to Under § 610.15(d), FDA has received
codes that are used to clarify the type of
submit the various submissions. The no submissions since the
advertisement or labeling submitted,
estimated average number of hours is implementation of the final rule in April
clarifies the intended audience for the
based on the range of hours to complete
advertisements or promotional labeling 2011. Therefore, FDA is estimating one
a very basic application or supplement
(e.g., consumers, professionals, news respondent and one annual request to
and a complex application or
services), and helps ensure that the account for a possible submission to
supplement.
submission is complete. Form FDA 2253 Under section 601.6(a), the total CBER or CDER of a request for an
can also be submitted electronically. annual responses are based on FDA exception or alternative for constituent
Form FDA 2253 is approved under OMB estimates that establishments may notify materials under § 610.15(d).
control number 0910–0001. an average of 20 selling agents and There were a total of 2,777
Respondents to this collection of distributors of such suspension, and amendments to an unapproved
information are manufacturers of provide FDA of such notification. The application or supplement and
biological products. Under tables 1 and number of respondents is based on the resubmissions submitted using Form
2, the numbers of respondents are based estimated annual number of FDA 356h.
on the estimated annual number of suspensions of a biologic license. In In the Federal Register of July 11,
manufacturers that submitted the table 1, FDA is estimating 1 in case a 2016 (81 FR 44868), we published a 60-
required information to FDA or the suspension occurs. day notice requesting public comment
number of submissions FDA received in Under §§ 601.12(f)(4) and 601.45, on the proposed extension of this
fiscal year (FY) 2015. Based on manufacturers of biological products collection of information. No comments
information obtained from FDA’s may use Form FDA 2253 to submit were received.
database systems, there are an estimated advertising and promotional labeling FDA estimates the burden of this
391 licensed biologics manufacturers. (which can include multiple pieces). collection of information as follows:

TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1
Number of
Number of Total annual Average burden
21 CFR Section Form FDA No. responses per Total hours 10
respondents responses per response
respondent

601.2(a) 2, 610.60 through 610.65 3 ... 356h 28 1.36 38 860 ....................... 32,680
601.5(a) .............................................. NA 12 0.75 9 0.33 (20 minutes) 3
601.6(a) .............................................. NA 1 1 1 0.33 (20 minutes) 1
601.12(a)(5) ....................................... NA 537 24.41 13,106 1 ........................... 13,106
601.12(b)(1)/(b)(3)/(e) 4 ...................... 2 356h 164 3.66 600 80 ......................... 48,000
601.12(c)(1)/(c)(3) 5 ............................ 2 356h 120 4.78 574 50 ......................... 28,700
601.12(c)(5) ....................................... 2 356h 7 1.14 8 50 ......................... 400
601.12(d)(1)/(d)(3) 6/(f)(3) 8 ................ 2 356h 246 3.34 822 24 ......................... 19,728
601.12(f)(1) 7 ...................................... 2253 72 1.93 139 40 ......................... 5,560
601.12(f)(2) 7 ................................ 2253 60 1.82 109 20 ......................... 2,180
601.12(f)(4)/601.45 9 .......................... 2253 114 102.42 11,676 10 ......................... 116,670
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601.27(b) ............................................ NA 20 16.50 330 24 ......................... 7,920
601.27(c) ............................................ NA 12 1.08 13 8 ........................... 104
601.70(b) and (d)/601.28 ................... 2252 82 1.70 139 24 ......................... 3,336
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 125 22.22 2,777 20 ......................... 55,540

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Document Created: 2018-02-13 16:40:07
Document Modified: 2018-02-13 16:40:07
Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Notices
Action		Notice.
Dates		Fax written comments on the collection of information by November 28, 2016.
Contact		FDA PRA Staff, Office of Operations, Food and Drug Administration, Three White Flint North, 10A63, 11601 Landsdown St., North Bethesda, MD 20852, [email protected]
FR Citation		81 FR 75130
DEPARTMENT OF HEALTH AND HUMAN SERVICESFood and Drug Administration

Federal Register Volume 81, Issue 209 (October 28, 2016)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
