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, 75130-75134 [2016-26064]

Download as PDF 75130 Dated: October 24, 2016. Leslie Kux, Associate Commissioner for Policy. [FR Doc. 2016–26066 Filed 10–27–16; 8:45 am] Food and Drug Administration [Docket No. FDA–2013–N–0578] BILLING CODE 4164–01–C mstockstill on DSK3G9T082PROD with NOTICES DEPARTMENT OF HEALTH AND HUMAN SERVICES 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. The Food and Drug Administration (FDA or we) is SUMMARY: VerDate Sep<11>2014 18:12 Oct 27, 2016 Jkt 241001 PO 00000 Frm 00105 Fmt 4703 Sfmt 4703 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 oira_ submission@omb.eop.gov. 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. E:\FR\FM\28OCN1.SGM 28OCN1 EN28OC16.037</GPH> Federal Register / Vol. 81, No. 209 / Friday, October 28, 2016 / Notices Federal Register / Vol. 81, No. 209 / Friday, October 28, 2016 / Notices FDA PRA Staff, Office of Operations, Food and Drug Administration, Three White Flint North, 10A63, 11601 Landsdown St., North Bethesda, MD 20852, PRAStaff@fda.hhs.gov. 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 mstockstill on DSK3G9T082PROD with NOTICES FOR FURTHER INFORMATION CONTACT: VerDate Sep<11>2014 18:12 Oct 27, 2016 Jkt 241001 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 §§ 610.60 through 610.65 (21 CFR 610.60 through 610.65). The estimate for these regulations is included in the estimate under § 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 § 601.12(a)(2) are included in the estimates for supplements (§§ 601.12(b) and (c)) and annual reports (§ 601.12(d)). The burden estimates for § 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 § 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 § 601.12(b)(4) is minimal and included in the estimate under § 601.12(b)(1) and (b)(3) in table 1. Section 601.12(e) requires applicants to submit a protocol, or change to a PO 00000 Frm 00106 Fmt 4703 Sfmt 4703 75131 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 § 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 §§ 601.2(a) and 601.12(f). The burden estimate for § 601.14 is minimal and included in the estimate under §§ 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 lifethreatening 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 §§ 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: §§ 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 §§ 601.2 and/or 601.12. A regulation may be listed under more than one subsection of § 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: § 640.74(b)(3) and (4) for Source Plasma Liquid; § 640.84(a) and (c) for Albumin; § 640.94(a) for Plasma Protein Fraction; § 660.2(c) for Antibody to Hepatitis B Surface Antigen; § 660.28(a), (b), and (c) for Blood Grouping Reagent; § 660.35(a), (c through g), and (i through m) for Reagent Red Blood Cells; § 660.45 for Hepatitis B Surface Antigen; and § 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 E:\FR\FM\28OCN1.SGM 28OCN1 mstockstill on DSK3G9T082PROD with NOTICES 75132 Federal Register / Vol. 81, No. 209 / Friday, October 28, 2016 / Notices requirements under §§ 610.60 through 610.65 or 21 CFR 809.10. Therefore, the burden estimates for these regulations are included in the estimate under §§ 610.60 through 610.65 in table 1. The burden estimates associated with § 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 § 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 § 601.27(a) with adequate justification. The burden estimates for § 601.27(a) are included in the burden estimate under § 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 § 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 § 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 §§ 601.33 through 601.35 are included in the burden estimate under VerDate Sep<11>2014 18:12 Oct 27, 2016 Jkt 241001 § 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 § 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 § 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 § 601.91(b)(3) is included in the estimate under §§ 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 § 610.9(a) is included in the estimate under §§ 601.2(a) and 601.12(b) and (c) in table 1. Under § 610.15(d), the Director of CBER or the Director of CDER may PO 00000 Frm 00107 Fmt 4703 Sfmt 4703 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 § 601.12; therefore, the burden estimate for § 640.120 is included in the estimate under § 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 §§ 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 §§ 600.15(b), 610.53(d), and 606.110(b) are included in the estimates under § 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 E:\FR\FM\28OCN1.SGM 28OCN1 Federal Register / Vol. 81, No. 209 / Friday, October 28, 2016 / Notices 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 ×24 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 §§ 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 §§ 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). 75133 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 §§ 601.28 and 601.70(b), FDA estimates that it takes an applicant approximately 24 hours (8 hours per study ×3 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 § 601.70(d). For FY 2015, there were 139 reports from 82 respondents. Under § 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 § 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 60day 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 mstockstill on DSK3G9T082PROD with NOTICES 21 CFR Section Form FDA No. 601.2(a) 2, 610.60 through 610.65 3 ... 601.5(a) .............................................. 601.6(a) .............................................. 601.12(a)(5) ....................................... 601.12(b)(1)/(b)(3)/(e) 4 ...................... 601.12(c)(1)/(c)(3) 5 ............................ 601.12(c)(5) ....................................... 601.12(d)(1)/(d)(3) 6/(f)(3) 8 ................ 601.12(f)(1) 7 ...................................... 601.12(f)(2) 7 ................................ 601.12(f)(4)/601.45 9 .......................... 601.27(b) ............................................ 601.27(c) ............................................ 601.70(b) and (d)/601.28 ................... 610.15(d) ............................................ 680.1(c) .............................................. 680.1(b)(3)(iv) .................................... Amendments/Resubmissions ............ VerDate Sep<11>2014 18:12 Oct 27, 2016 Jkt 241001 Number of respondents 356h NA NA NA 2 356h 2 356h 2 356h 2 356h 2253 2253 2253 NA NA 2252 NA NA NA 356h PO 00000 Frm 00108 Number of responses per respondent 28 12 1 537 164 120 7 246 72 60 114 20 12 82 1 9 1 125 Fmt 4703 1.36 0.75 1 24.41 3.66 4.78 1.14 3.34 1.93 1.82 102.42 16.50 1.08 1.70 1 1 1 22.22 Sfmt 4703 Total annual responses Average burden per response 38 9 1 13,106 600 574 8 822 139 109 11,676 330 13 139 1 9 1 2,777 E:\FR\FM\28OCN1.SGM 860 ....................... 0.33 (20 minutes) 0.33 (20 minutes) 1 ........................... 80 ......................... 50 ......................... 50 ......................... 24 ......................... 40 ......................... 20 ......................... 10 ......................... 24 ......................... 8 ........................... 24 ......................... 1 ........................... 2 ........................... 2 ........................... 20 ......................... 28OCN1 Total hours 10 32,680 3 1 13,106 48,000 28,700 400 19,728 5,560 2,180 116,670 7,920 104 3,336 1 18 2 55,540 75134 Federal Register / Vol. 81, No. 209 / Friday, October 28, 2016 / Notices TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1—Continued Form FDA No. 21 CFR Section Total ............................................ Number of respondents Number of responses per respondent Total annual responses Average burden per response ........................ ........................ ........................ ........................ .............................. Total hours 10 333,949 1 There are no capital costs or operating and maintenance costs associated with this collection of information. 2 The reporting requirements under §§ 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 § 601.2(a). 3 The reporting requirements under §§ 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 §§ 610.60 through 610.65. 4 The reporting requirements under §§ 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 § 601.12(b). 5 The reporting requirements under §§ 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 § 601.12(c). 6 The reporting requirement under § 601.12(a)(2) is included in the estimate under § 601.12(d). 7 The reporting requirement under § 601.14 is included in the estimate under § 601.12(f)(1) and (f)(2). 8 The reporting requirement under §§ 601.12(a)(4) and 601.14 is included in the estimate under § 601.12(f)(3). 9 The reporting requirement under § 601.94 is included in the estimate under § 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 Number of respondents 21 CFR Section 601.6(a) ...................................................................... Annual disclosures per respondent 1 Total annual disclosures 20 Average burden per disclosure 20 0.33 Total hours 2 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 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2013–N–0796] Agency Information Collection Activities; Proposed Collection; Comment Request; Testing Communications on Medical Devices and Radiation-Emitting Products AGENCY: Food and Drug Administration, HHS. ACTION: Notice. The Food and Drug Administration (FDA) is announcing an opportunity for public comment on the proposed collection of certain information by the Agency. Under the Paperwork Reduction Act of 1995 (the PRA), Federal Agencies are required to publish notice in the Federal Register concerning each proposed collection of information, including each proposed extension of an existing collection of information, and to allow 60 days for mstockstill on DSK3G9T082PROD with NOTICES SUMMARY: VerDate Sep<11>2014 18:12 Oct 27, 2016 Jkt 241001 public comment in response to the notice. This notice solicits comments on communication studies involving medical devices and radiation-emitting products regulated by FDA. This information will be used to explore concepts of interest and assist in the development and modification of communication messages and campaigns to fulfill the Agency’s mission to protect the public health. DATES: Submit either electronic or written comments on the collection of information by December 27, 2016. ADDRESSES: You may submit comments as follows: Electronic Submissions Submit electronic comments in the following way: • Federal eRulemaking Portal: http:// www.regulations.gov. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to http:// www.regulations.gov will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else’s Social Security number, or PO 00000 Frm 00109 Fmt 4703 Sfmt 4703 confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on http://www.regulations.gov. • If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see ‘‘Written/Paper Submissions’’ and ‘‘Instructions’’). Written/Paper Submissions Submit written/paper submissions as follows: • Mail/Hand delivery/Courier (for written/paper submissions): Division of Dockets Management (HFA–305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. • For written/paper comments submitted to the Division of Dockets Management, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in ‘‘Instructions.’’ Instructions: All submissions received must include the Docket No. FDA– 2013–N–0796 for ‘‘Agency Information Collection Activities; Proposed E:\FR\FM\28OCN1.SGM 28OCN1

Agencies

[Federal Register Volume 81, Number 209 (Friday, October 28, 2016)]
[Notices]
[Pages 75130-75134]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-26064]


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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, 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 oira_submission@omb.eop.gov. 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, PRAStaff@fda.hhs.gov.

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