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Food and Drug Administration, HHS.
The Food and Drug Administration (FDA) is announcing that a proposed collection of information has been submitted to the Office of Management and Budget (OMB) for review and clearance under the Paperwork Reduction Act of 1995.
Fax written comments on the collection of information by March 5, 2007.
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: 202-395-6974.Start Further Info
FOR FURTHER INFORMATION CONTACT:
Jonna Capezzuto, Office of the Chief Information Officer (HFA-250), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-4659.End Further Info End Preamble Start Supplemental 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 Forms FDA 456h and 2567—(OMB Control Number 0910-0338)—Extension
Under section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262), manufacturers of biological products must submit a license application for FDA review and approval before marketing a biological product in interstate commerce. Licenses may be issued only upon showing that the establishment and the products for which a license is desired meets standards prescribed in regulations designed to ensure the continued safety, purity, and potency of such products. All such licenses are issued, suspended, and revoked as prescribed by regulations in part 601 (21 CFR part 601).
Section 130(a) of the Food and Drug Administration Modernization Act (Public Law 105-115) amended the Federal Food, Drug, and Cosmetic Act (the act) by adding a new provision (section 506B of the act (21 U.S.C. 356b)) requiring reports of postmarketing studies for approved human drugs and licensed biological products. Section 506B of the 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 act, applicants that have committed to conducting 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.
Section 601.2(a) requires a manufacturer of a biological product to submit an application with accompanying information, including labeling information, to FDA for approval to market a product in interstate commerce. The container and package labeling requirements are provided under §§ 610.60, 610.61, and 610.62 (21 CFR part 610). The estimate for these regulations is included in the estimate under § 601.2(a) in table 1 of this document. Section 601.5(a) requires a licensee to submit to FDA notice of its intention to discontinue manufacture of a product or all products. Section 601.6(a) requires the licensee to notify selling agents and distributors upon suspension of its license, and provide FDA of such notification.
Section 601.12(a)(2) requires, generally, that the holder of an approved 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 review all promotional labeling and advertising to make it consistent with any labeling changes implemented. Section 601.12(a)(5) Start Printed Page 5058requires 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) (Form FDA 2567) in table 1 of this document or OMB control number 0910-0001 (expires May 31, 2008) since the required information can also be submitted with Form FDA 2253.
Section 601.12(b)(1) and (b)(3), (c)(1) and (c)(3), (c)(5), and (d)(1) and (d)(3) require applicants to follow specific procedures to inform FDA of each change, in the product, production process, quality controls, equipment, facilities, responsible personnel or labeling established in an approved license application. The appropriate procedure depends on the potential for the change to have a substantial, moderate, or minimal adverse effect on the identity, strength, quality, purity, or potency of the products as they may relate to the safety or effectiveness of the product. Under § 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 of this document.
Section 601.12(e) requires applicants to submit a protocol, or change to a protocol, as a supplement requiring FDA approval before distributing the product. Section 601.12(f)(1), (f)(2), and (f)(3) requires applicants to follow specific procedures to report labeling changes to FDA. 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 § 201.100(d)(3) (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), (f)(2), and (f)(3) (supplements and annual reports) in table 1 of this document.
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 §§ 601.2 and 601.12, there are other regulations in parts 640, 660, and 680 (21 CFR parts 640, 660, and 680) that relate to information to be submitted in a license application or supplement for certain blood or allergenic products: §§ 640.6, 640.17, 640.21(c), 640.22(c), 640.25(c), 640.56(c), 640.64(c), 640.74(a) and (b)(2), 660.51(a)(4), 680.1(b)(2)(iii), and 680.1(d). In table 1 of this document, the burden associated with the information collection requirements in these regulations is included in the burden estimate for § 601.2 and/or § 601.12. A regulation may be listed under more than one section 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: § 640.70(a) for Source Plasma; § 640.74(b)(3) and (b)(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) and (b) 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 requirements under § 610.60 through § 610.62 or § 809.10 (21 CFR 809.10). Therefore, the burden estimates for these regulations are included in the estimate under § 610.60 through § 610.62 in table 1 of this document. The burden estimates associated with § 809.10 are approved under OMB control number 0910-0485 (expires June 30, 2008).
Section 601.25(b) requests interested persons to submit, for review and evaluation by an advisory review panel, published and unpublished data and information pertinent to a designated category of biological products that have been licensed prior to July 1, 1972. Section 601.26(f) requests that licensees submit to FDA a written statement intended to show that studies adequate and appropriate to resolve questions raised about a biological product have been undertaken for a product if designated as requiring further study under the reclassification procedures. Under § 601.25(b)(3), FDA estimates no burden for this regulation since all requested data and information had been submitted by 1974. Under § 601.26(f), FDA estimates no burden for this regulation since there are no products designated to require further study and none are predicted in the future. However, based on the possible reclassification of a product, the labeling for the product may need to be revised, or a manufacturer, on its own initiative, may deem it necessary for further study. As a result, any changes to product labeling would be reported under § 601.12.
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). Section 601.27(c) provides that an applicant may request a full or partial waiver of the requirements under § 601.27(a). The burden estimates for § 601.27(a) are included in the burden estimate under § 601.2(a) in table 1 of this document, since these regulations deal with information to be provided in an application.
Section 601.28 requires sponsors of licensed biological products to submit the information in § 601.28(a), (b), and (c) to the Center for Biologics Evaluation and Research (CBER) or the Center for Drug Evaluation and Research (CDER) each year, within 60 days of the anniversary date of approval of the license. Section 601.28(a) requires sponsors to submit to FDA a brief summary stating whether labeling supplements for pediatric use have been submitted and whether new studies in the pediatric population to support appropriate labeling for the pediatric population have been initiated. Section 601.28(b) requires sponsors to submit to FDA an analysis of available safety and efficacy data in the pediatric population and changes proposed in the labeling based on this information. Section 601.28(c) requires sponsors to submit to FDA a statement on the current status of any postmarketing studies in the pediatric population performed by, or on behalf of, the applicant. 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 Start Printed Page 5059application to FDA to evaluate the safety and effectiveness of in vivo radiopharmaceuticals. The burden estimates for §§ 601.33 through 601.35 are included in the burden estimate under § 601.2(a) in table 1 of this document, 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 (approved under OMB control number 0910-0001). Under § 601.70(d), two copies of the annual report shall be submitted to FDA.
Section 601.91(b)(2)(iii) requires, in certain circumstances, postmarketing restrictions as needed to ensure the safe use of the biological products distribution conditioned on specified recordkeeping requirements. Section 601.91(b)(3) requires applicants to prepare and provide labeling with relevant information to patient or potential patient for biological products approved under the subpart 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 this subpart are subject to the postmarketing recordkeeping and safety reporting applicable to all approved biological products. Section 601.94 requires applicants under this subpart to submit to the agency for consideration during preapproval review period copies of all promotional materials including promotional labeling as well as advertisements. Under § 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; expires May 31, 2005). Therefore, any burdens associated with these requirements would be reported under the AER information collection requirements (OMB control number 0910-0308).
Section 610.11(g)(2) provides that a manufacturer of certain biological products may request an exemption from the general safety test (GST) requirements contained in this subpart. Under § 610.11(g)(2), FDA requires only those manufacturers of biological products requesting an exemption from the GST to submit additional information as part of a license application or supplement to an approved license application. Therefore, the burden estimate for § 610.11(g)(2) is included in the estimate under §§ 601.2(a) and 601.12(b) in table 1 of this document.
Section 610.67 requires certain biological products to comply with the bar code requirements at § 201.25 (21 CFR 201.25). Section 201.25 is approved under OMB control number 0910-0537 (expires February 28, 2007).
Section 680.1(c) requires manufacturers to update annually their license file with the list of source materials and the suppliers of the materials.
Sections 600.15(b) and 610.53(d) require the submission of a request for an exemption or modification regarding the temperature requirements during shipment and from dating periods, respectively, for certain biological products. Section 606.110(b) requires the submission of a request for approval to perform plasmapheresis of donors who do not meet certain donor requirements for the collection of plasma containing rare antibodies. Under §§ 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 of this document.
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. The checklist helps to ensure that the application is complete and contains all the necessary information, so that delays due to lack of information may be eliminated. The form provides key information to FDA for efficient handling and distribution to the appropriate staff for review. The estimated burden hours for submissions to CDER using Form FDA 356h are reported under OMB control number 0910-0001.
Form FDA 2567 “Transmittal of Labels and Circulars” is used by manufacturers of licensed biological products to submit labeling (e.g., circulars, package labels, container labels, etc.) and labeling changes for FDA review and approval. The labeling information is submitted with the form for license applications, supplements, or as part of an annual report. Form FDA 2567 is also used for the transmission of advertisements and promotional labeling. Form FDA 2567 serves as an easy guide to assure that the manufacturer has provided the information required for expeditious handling of their labeling by CBER. For advertisements and promotional labeling, manufacturers of licensed biological products may submit to CBER either Form FDA 2567 or 2253. Form FDA 2253 was previously used only by drug manufacturers regulated by CDER. In August 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.
Under table 1 of this document, the number of respondents is based on the estimated annual number of manufacturers that submitted the required information to FDA or the number of submissions FDA received. Based on information obtained from FDA's database systems, there are an estimated 306 licensed biologics manufacturers. However, not all manufacturers will have any submissions in a given year and some may have multiple submissions. The total annual responses are based on the estimated number of submissions (i.e., license applications, labeling and other supplements, protocols, advertising and promotional labeling, notifications) for a particular product received annually by FDA. Based on previous estimates, the rate of submissions is not expected to change significantly in the next few years. The hours per response are based on information provided by industry and past FDA experience with the various submissions or notifications. The hours per response include the time estimated to prepare the various submissions or notifications to FDA, and, as applicable, the time required to fill out the appropriate form and collate the documentation. Additional information regarding these estimates is provided as follows 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 Start Printed Page 5060and a complex application or supplement.
Under § 601.6(a), the total annual responses are based on FDA estimates that establishments may notify an average of 20 selling agents and distributors of such suspension, and provide FDA of such notification. The number of respondents is based on the estimated annual number of suspensions of a biologic license.
Under §§ 601.12(f)(4) and 601.45, manufacturers of biological products may use either Form FDA 2567 or Form FDA 2253 to submit advertising and promotional labeling. Based on information obtained from FDA's database system, there were an estimated 3,600 submissions of advertising and promotional labeling in fiscal year 2004. FDA estimates that approximately 15 percent of those submissions were received with Form FDA 2567 resulting in an estimated 540 submissions. The burden hours for the remaining submissions received using Form FDA 2253 are reported under OMB control number 0910-0001.
Under § 601.70(b), FDA estimates that it takes an applicant approximately 24 hours (8 hours per study x 3) 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). Under §§ 601.91 through 601.94, FDA expects to receive very few applications of this nature; however, for calculation purposes, FDA is estimating the annual submission of one application. Under §§ 601.93(b)(3) and 601.94, FDA estimates 240 hours for a manufacturer of a new biological product to develop patient labeling, and to submit the appropriate information and promotional labeling to FDA. The majority of the burden for developing the patient labeling is included under the reporting requirements for § 601.94, therefore minimal burden is calculated for providing the guide to patients under § 601.91(b)(3).
There were also 3,540 amendments to an unapproved application or supplement and 23 resubmissions (total of 3,563 submissions) submitted using Form FDA 356h.
In the Federal Register of November 2, 2006 (71 FR 64536), FDA published a 60-day notice requesting public comment on the information collection provisions. No comments were received.
|21 CFR Section||Form FDA No.||No. of Respondents||Annual Frequency per Response||Total Annual Responses||Hours per Response||Total Hours|
|601.2(a)2, 610.60, 610.61, and 610.623||2567/356h||14||2||28||860||24,080|
|601.28(a), (b), and (c)||NA||44||3.27||144||33.5||4,824|
|601.70(b) and (d)||2252||19||1.58||30||24||720|
|Start Printed Page 5061|
|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, 610.11(g)(2), 640.17, 640.25(c), 640.56(c), 640.74(b)(2), 660.51(a)(4), and 680.1(b)(2)(iii) are included in the estimate under § 601.2(a).|
|3 The reporting requirements under §§ 640.70(a), 640.74(b)(3) and (4), 640.84(a) and (c), 640.94(a), 660.2(c), 660.28(a) and (b), 660.35(a), (c-g), and (i-m), 660.45, and 660.55(a) and (b) are included under §§ 610.60 through 610.62.|
|4 The reporting requirements under §§ 600.15(b), 610.11(g)(2), 610.53(d), 606.110(b), 640.6, 640.17, 640.21(c), 640.22(c), 640.25(c), 640.56(c), 640.64(c), 640.74(a) and (b)(2), and 680.1(d) are included in the estimate under § 601.12(b)|
|5 The reporting requirements under §§ 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 § 601.14 is included in the estimate under § 601.12(f)(1) and (f)(2).|
|7 The reporting requirement under § 601.14 is included in the estimate under § 601.12(f)(3).|
Under Table 2, the estimated recordkeeping burden of 1 hour is based on previous estimates for the recordkeeping requirements associated with the AER system.
|21 CFR Section||No. of Recordkeepers||Annual Frequency per Recordkeeping||Total Annual Records||Hours per Record||Total Hours|
|1 There are no capital costs or operating and maintenance costs associated with this collection of information.|
Dated: January 26, 2007.
Assistant Commissioner for Policy.
[FR Doc. E7-1741 Filed 2-1-07; 8:45 am]
BILLING CODE 4160-01-S