Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products, 65904-65923 [2013-25956]

Download as PDF 65904 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules session). To be considered, oral comments must be presented during the transcribed portions of the public meetings. The NRC staff will also accept written comments at any time during the public meetings. Persons interested in presenting oral comments at the December 2, December 4, or December 9 public meetings are encouraged to pre-register. Persons may pre-register to present oral comments at either meeting by calling 301–287–9392 or by emailing WCRegistration@nrc.gov no later than 3 days prior to the meeting. Members of the public may also register in-person to provide oral comments at each meeting. Individual oral comments may be limited by the time available, depending on the number of persons who register. If special equipment or accommodations are needed to attend or to present information at either public meeting, then the need should be brought to the NRC’s attention no later than 10 days prior to the meeting to provide the NRC staff adequate notice to determine whether the request can be accommodated. The meeting agenda and participation details for each meeting will be available on the NRC’s Public Meeting Schedule Web site at https://www.nrc.gov/public-involve/ public-meetings/index.cfm no later than 10 days prior to each meeting. Dated at Rockville, Maryland, this 29th day of October 2013. For the Nuclear Regulatory Commission. Carrie M. Safford, Deputy Director, Waste Confidence Directorate, Office of Nuclear Material Safety and Safeguards. [FR Doc. 2013–26381 Filed 11–1–13; 8:45 am] BILLING CODE 7590–01–P Food and Drug Administration 21 CFR Parts 20, 310, 314, and 600 [Docket No. FDA–2011–N–0898] EMCDONALD on DSK67QTVN1PROD with PROPOSALS RIN 0910–AG88 Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products Food and Drug Administration, HHS. Proposed rule; request for comments. ACTION: The Food and Drug Administration (FDA or the Agency) is proposing to amend its regulations to implement certain drug shortages SUMMARY: VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 You may submit comments, identified by Docket No. FDA–2011–N– 0898 by any of the following methods, except that comments on information collection issues under the PRA must be submitted to the Office of Information and Regulatory Affairs, Office of Management and Budget (OMB) (see the ‘‘Paperwork Reduction Act of 1995’’ section). ADDRESSES: Electronic Submissions Submit electronic comments in the following way: • Federal eRulemaking Portal: https:// www.regulations.gov. Follow the instructions for submitting comments. Written Submissions: DEPARTMENT OF HEALTH AND HUMAN SERVICES AGENCY: provisions of the Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended by the Food and Drug Administration Safety and Innovation Act (FDASIA). The proposed rule would require all applicants of covered approved drugs or biological products— including certain applicants of blood or blood components for transfusion and all manufacturers of covered drugs marketed without an approved application—to notify FDA electronically of a permanent discontinuance or an interruption in manufacturing of the product that is likely to lead to a meaningful disruption in supply (or a significant disruption in supply for blood or blood components) of the product in the United States. DATES: Submit either electronic or written comments on the provisions of this proposed rule by January 3, 2014. Submit comments on the information collection requirements under the Paperwork Reduction Act of 1995 (the PRA) by December 4, 2013 (see the ‘‘Paperwork Reduction Act of 1995’’ section). Submit written submissions in the following ways: • Mail/Hand delivery/Courier (for paper or CD–ROM submissions): Division of Dockets Management (HFA– 305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Instructions: All submissions received must include the Agency name and Docket No. 2011–N–0898 for this rulemaking. All comments received may be posted without change to https:// www.regulations.gov, including any personal information provided. For additional information on submitting comments, see the ‘‘Comments’’ heading of the SUPPLEMENTARY INFORMATION section of this document. Docket: For access to the docket to read background documents or PO 00000 Frm 00015 Fmt 4702 Sfmt 4702 comments received, go to https:// www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the ‘‘Search’’ box and follow the prompts and/or go to the Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. FOR FURTHER INFORMATION CONTACT: Kalah Auchincloss, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 6208, Silver Spring, MD 20993, 301–796– 0659; or Stephen Ripley, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852– 1448, 301–827–6210. Table of Contents I. Executive Summary A. Purpose of the Proposed Rule B. Summary of the Major Provisions of the Proposed Rule C. Summary of the Costs and Benefits of the Proposed Rule II. Introduction III. Description of the Proposed Rule A. Persons Subject to the Proposed Rule B. Products Subject to the Proposed Rule C. Notification of a Permanent Discontinuance or an Interruption in Manufacturing IV. Legal Authority V. Analysis of Impacts A. Introduction B. Summary VI. Paperwork Reduction Act of 1995 VII. Federalism VIII. Environmental Impact IX. Comments X. References SUPPLEMENTARY INFORMATION: I. Executive Summary A. Purpose of the Proposed Rule FDASIA (Pub. L. 112–144) significantly amended provisions in the FD&C Act related to drug shortages. Among other things, FDASIA amended section 506C of the FD&C Act (21 U.S.C. 356c) to require all manufacturers of certain drugs to notify FDA of a permanent discontinuance or an interruption in manufacturing of these drugs 6 months in advance of the permanent discontinuance or interruption in manufacturing, or as soon practicable. FDASIA also added section 506E to the FD&C Act (21 U.S.C. 356e) requiring FDA to maintain a current list of drugs that are determined by FDA to be in shortage in the United States, and to include on that public list certain information about those shortages. Finally, FDASIA permits FDA to apply section 506C to biological products by regulation, and requires FDA to issue a final rule implementing E:\FR\FM\04NOP1.SGM 04NOP1 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules certain drug shortages provisions in FDASIA by January 9, 2014. In accordance with FDASIA, FDA is issuing this proposed rule, which we believe will improve FDA’s ability to identify potential drug shortages and to prevent or mitigate the impact of these shortages. EMCDONALD on DSK67QTVN1PROD with PROPOSALS B. Summary of the Major Provisions of the Proposed Rule The proposed rule would modify FDA’s regulations to implement sections 506C and 506E of the FD&C Act as amended by FDASIA. Proposed §§ 310.306, 314.81(b)(3)(iii) (21 CFR 314.81(b)(3)(iii)), and 600.82 would require all applicants of certain approved drugs or biological products,1 including applicants of blood or blood components for transfusion (‘‘blood or blood components’’) that manufacture a significant percentage of the U.S. blood supply, and all manufacturers of certain drugs marketed without an approved application (‘‘unapproved drug manufacturers’’), to notify FDA electronically of a permanent discontinuance or an interruption in manufacturing of the product that is likely to lead to a meaningful disruption in supply (for drugs and biological products other than blood or blood components) or a significant disruption in supply (for blood or blood components) of the product in the United States. Applicants 2 would be required to notify FDA of a permanent discontinuance or an interruption in supply if the drug or biological product is a prescription product that is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such drug used in emergency medical care or during surgery, and excluding radiopharmaceutical products (referred to in this document as ‘‘covered’’ drugs or biological products). The proposed rule would require notification to FDA at least 6 months prior to date of the permanent discontinuance or 1 As used throughout this preamble, the term ‘‘biological product’’ refers to a biological product licensed under section 351 of the Public Health Service Act, other than a biological product that also meets the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)). 2 In this document, for the sake of convenience, we collectively refer to applicants holding an abbreviated new drug application (ANDA), new drug application (NDA), or biologics license application (BLA) and unapproved drug manufacturers subject to this proposed rule as the ‘‘applicant’’ (although we recognize that an unapproved drug manufacturer is not an applicant). We may also individually refer to the ANDA, NDA, and BLA applicant or unapproved drug manufacturer as needed, if the context requires distinguishing between these entities. VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 interruption in manufacturing, or, if 6 months’ advance notice is not possible, as soon as practicable thereafter, but in no case later than 5 business days after the permanent discontinuance or interruption in manufacturing occurs. The proposed rule would also require FDA to issue a public noncompliance letter to an applicant for failure to notify FDA under the proposed rule; specify minimum information that must be included in the notification; codify FDA’s current practice of publicly disseminating information on shortages and maintaining public lists of drugs and biological products in shortage (subject to certain confidentiality protections); and define the terms, ‘‘drug shortage,’’ ‘‘biological product shortage,’’ ‘‘meaningful disruption,’’ ‘‘significant disruption,’’ ‘‘life supporting or life sustaining,’’ and ‘‘intended for use in the prevention or treatment of a debilitating disease or condition.’’ Finally, the proposed rule would include a technical revision to § 20.100 (21 CFR 20.100) (public disclosure regulations) to include a cross-reference to the disclosure provisions in in §§ 310.306, 314.81, and 600.82; and would remove § 314.91 (21 CFR 314.91) related to reducing the 6-month notification period for ‘‘good cause,’’ since it is no longer applicable under the FDASIA-revised section 506C. C. Summary of the Costs and Benefits of the Proposed Rule The proposed rule would impose annual reporting costs of up to $16,576 on those applicants affected by the rule, and up to $441,000 on FDA in review costs. Undertaking mitigation strategies, as measured by labor resources, is estimated to cost FDA between $2.44 and $7.84 million, and industry between $3.86 and $12.43 million. We also estimate annual costs for industry between $8.54 and $26.89 million associated with increasing production. Estimated total annual costs of the interactions between industry and FDA range between $14.99 and $47.62 million. Discounting over 20 years, annual quantified benefits from avoiding the purchase of alternative products, managing product shortages, and life-years gained, would range from $27.56 million to $86.77 million using a 3 percent discount rate, and from $27.50 million to $86.61 million using a 7 percent discount rate. The public health benefits, mostly nonquantified, include the value of information that would assist FDA, manufacturers, health care providers, and patients in evaluating, mitigating, and preventing shortages of drugs and biological PO 00000 Frm 00016 Fmt 4702 Sfmt 4702 65905 products that could otherwise result in delayed patient treatment or interruption in clinical trial development. II. Introduction Recent experience with shortages of drugs and biological products in the United States has shown the serious and immediate effects they can have on patients and health care providers. According to information from FDA’s drug and biological product shortages databases, the number of drug and biological product shortages quadrupled from approximately 61 in 2005 to more than 250 shortages in 2011. Although the number of drug shortages significantly decreased in 2012 to 117 shortages, drug and biological product shortages still represent an ongoing challenge to public health.3 Shortages can involve critical drugs used to treat cancer, to provide required parenteral nutrition, or to address other serious medical conditions and can delay or deny needed care for patients. Shortages can also result in providers prescribing second-line alternatives, which may be less effective or higher risk than firstline therapies. Preventing drug and biological product shortages is a top priority for FDA. Working closely with manufacturers and other stakeholders, FDA was able to help prevent just under 200 drug and biological product shortages in 2011 and more than 280 such shortages in 2012, using tools such as: • Working with manufacturers to resolve manufacturing and quality issues contributing to short supply. • Expediting FDA inspections and reviews of submissions from manufacturers to prevent and/or alleviate shortages. • Identifying and working with manufacturers willing to initiate or increase production to cover expected gaps in supply. • Exercising enforcement discretion in appropriate circumstances, if this would not cause undue risk to patients. In response to the increasing concerns about the impact of shortages on health care in the United States, on October 31, 2011, President Obama issued Executive Order 13588 directing FDA to ‘‘take steps that will help to prevent and reduce current and future disruptions in the supply of lifesaving medicines’’ and noting that ‘‘one important step is 3 Information on drug shortages can be found at https://www.fda.gov/drugs/drugsafety/ drugshortages/default.htm (drug shortages) and https://www.fda.gov/BiologicsBloodVaccines/ SafetyAvailability/Shortages/default.htm (biological product shortages). E:\FR\FM\04NOP1.SGM 04NOP1 65906 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules ensuring that FDA and the public receive adequate advance notice of shortages whenever possible’’ (Ref. 1 of this proposed rule). In response to the Executive Order’s directive to address the growing problem of drug shortages, FDA published an interim final rule (IFR) on December 19, 2011 (effective January 18, 2012), modifying the regulation at § 314.81 related to drug shortages (76 FR 78530). As a result of the Executive Order and IFR, early notifications to FDA of potential shortages increased from an average of 10 a month before the Executive Order to approximately 60 a month in the months after the IFR. This dramatic increase in early notifications enabled FDA to work with manufacturers to successfully prevent numerous shortages. As we stated above, FDA was able to prevent just under 200 drug and biological product shortages in 2011 and more than 280 such shortages in 2012. Moreover, the number of new drug shortages decreased from more than 250 in 2011 to 117 in 2012—a 50 percent reduction. In July 2012, FDASIA amended the FD&C Act to modify existing drug shortages requirements and to add new drug shortages provisions. This rule proposes to implement the drug shortages provisions of FDASIA, and, when final, will supersede the IFR. Although many of the issues raised by the 11 comments we received on the IFR are no longer directly applicable to this rulemaking given the changes to the underlying statute made by FDASIA, when drafting this proposed rule we considered these comments to the extent that they were applicable.4 Where appropriate, we have summarized and responded to the IFR comments in this preamble. III. Description of the Proposed Rule Section 1001 of FDASIA made substantial changes to section 506C of the FD&C Act related to reporting and addressing ‘‘permanent discontinuances’’ or ‘‘interruptions in manufacturing’’ of certain drug products. Most significantly for purposes of this proposed rule, section 506C of the FD&C Act as amended: • Requires all manufacturers of a prescription drug that is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such drug used in emergency medical care or during surgery, and excluding radiopharmaceutical products, to notify FDA of a permanent discontinuance in the manufacture of the drug or an interruption in the manufacturing of the drug that is likely to lead to a meaningful disruption in the supply of that drug in the United States at least 6 months prior to the date of the permanent discontinuance or interruption in manufacturing, or, if that is not possible, as soon as practicable. • Requires the manufacturer to include in the notification the reason for the permanent discontinuance or interruption in manufacturing. • Requires FDA to issue a letter to a ‘‘person’’ who fails to comply with the notification requirements in section 506C. • Defines the terms ‘‘drug,’’ ‘‘drug shortage,’’ and ‘‘meaningful disruption,’’ and requires FDA to define the terms ‘‘life supporting,’’ ‘‘life sustaining,’’ and ‘‘intended for use in the prevention or treatment of a debilitating disease or condition.’’ • Permits FDA to apply section 506C to biological products, including vaccines and plasma-derived products and their recombinant analogs, if FDA determines the inclusion would benefit public health, taking into account existing supply reporting programs and aiming to reduce duplicative notifications. • Requires FDA to distribute information on drug shortages to the public, to the maximum extent possible, subject to certain confidentiality protections. In addition to modifying section 506C, FDASIA added several new drug shortage-related sections to the FD&C Act, including section 506E. Section 506E of the FD&C Act requires FDA to maintain an up-to-date list of drugs that are determined by FDA to be in shortage, including the names and the National Drug Codes (NDCs) of such drugs in shortage, the name of each manufacturer of the drug, the reason for each shortage as determined by FDA (choosing from a list of reasons enumerated in the statute), and the estimated duration of each shortage. Section 506E of the FD&C Act also includes confidentiality provisions. This rule proposes to implement sections 506C and 506E of the FD&C Act by amending § 314.81(b)(3)(iii) (permanent discontinuance or interruption in manufacturing of approved prescription drugs) and § 20.100 (cross-reference to disclosure provisions); adding new § 310.306 (permanent discontinuance or interruption in manufacturing of marketed prescription unapproved new drugs) and § 600.82 (permanent discontinuance or interruption in manufacturing of prescription biological products); and removing § 314.91 (reduction in the discontinuance notification period). Table 1 compares the proposed rule to the current regulation (IFR). TABLE 1—CURRENT REGULATION (IFR) COMPARED WITH PROPOSED RULE Requirement EMCDONALD on DSK67QTVN1PROD with PROPOSALS Scope of products subject to notification requirements. Current regulation (IFR) Proposed rule § 314.81(b)(3)(iii)(a) ......................................................... § 310.306. § 314.81(b)(3)(iii)(a) and (f). § 600.82(a) and (f). All prescription drugs and biological products, including marketed unapproved prescription drugs, that are: • Life supporting, life sustaining or intended for use in the prevention or treatment of a debilitating disease or condition, including any such drug used in emergency medical care or during surgery; and • That are not radiopharmaceutical products.5 A drug product approved under an NDA or ANDA that is: • Life supporting, life sustaining or intended for use in the prevention of a serious disease or condition; and • Not originally derived from human tissue and replaced by a recombinant product. 4 The IFR comments are available electronically at https://www.regulations.gov, Docket No. FDA–2011– N–0898, or can be obtained in person at the VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. PO 00000 Frm 00017 Fmt 4702 Sfmt 4702 5 With respect to blood and blood components for transfusion, the reporting requirement applies only to an applicant that manufactures a significant percentage of the U.S. blood supply. E:\FR\FM\04NOP1.SGM 04NOP1 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules 65907 TABLE 1—CURRENT REGULATION (IFR) COMPARED WITH PROPOSED RULE—Continued Requirement What triggers notification .... Current regulation (IFR) Proposed rule § 314.81(b)(3)(iii)(a) and (d) ............................................. A ‘‘discontinuance,’’ defined as ‘‘any interruption in manufacturing . . . that could lead to a potential disruption in supply of the drug product [in the United States], whether the interruption is intended to be temporary or permanent’’. Who must notify FDA .......... § 314.81(b)(3)(iii)(a) and (d) ............................................. Applicants who are sole manufacturers of covered drugs; sole manufacturer is defined in the regulation. When to notify FDA ............ § 314.81(b)(3)(iii)(a) ......................................................... At least 6 months prior to the discontinuance. § 314.91 ........................................................................... Applicants may seek, and FDA may grant, a reduction in the 6-month notification period for ‘‘good cause.’’ How to notify FDA ............... What to include in the notification. Dissemination of information § 314.81(b)(3)(iii)(b) ......................................................... Electronically or by phone, according to instructions on FDA’s drug shortages Web page. Not specified .................................................................... § 314.81(b)(3)(iii)(c) .......................................................... EMCDONALD on DSK67QTVN1PROD with PROPOSALS FDA will publicly disclose a list of all drug products discontinued under § 314.81(b)(3)(iii)(a). Confidentiality ...................... Not specified in regulation, but information submitted to FDA under the regulation is subject to protections for trade secrets and confidential commercial and financial information where applicable. No equivalent provision ................................................... VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 PO 00000 Frm 00018 Fmt 4702 Sfmt 4702 The terms ‘‘life supporting or life sustaining’’ and ‘‘intended for use in the prevention or treatment of a debilitating disease or condition’’ are defined in the proposed rule. § 314.81(b)(3)(iii)(a) and (f). § 600.82(a)(1) and (f). For products other than blood or blood components, a ‘‘permanent discontinuance’’ or an ‘‘interruption in manufacturing that is likely to lead to a meaningful disruption in supply of the product in the United States’’; ‘‘meaningful disruption’’ is defined in the statute and the proposed rule. § 600.82(a)(2) and (f). For blood or blood components, a ‘‘permanent discontinuance’’ or an ‘‘interruption in manufacturing that is likely to lead to a significant disruption in supply of the product in the United States’’; ‘‘significant disruption’’ is defined in the proposed rule. § 314.81(b)(3)(iii)(a). § 600.82(a). All applicants for covered, approved drugs and biological products (other than blood or blood components), all applicants for blood or blood components that manufacture a significant percentage of the U.S. blood supply, and all manufacturers of covered drugs marketed without an approved application. § 314.81(b)(3)(iii)(b). § 600.82(b). • At least 6 months prior to the permanent discontinuance or interruption in manufacturing; or • If notification at least 6 months prior is impossible, ‘‘as soon as practicable,’’ which is further described in the proposed rule. • Deletes § 314.91 in its entirety, because it is no longer applicable under section 506C of the FD&C Act as amended by FDASIA. § 314.81(b)(3)(iii)(b). § 600.82(b). Electronically in a format FDA can process, review, and archive. § 314.81(b)(3)(iii)(c). § 600.82(c). • Name, NDC (or, for certain biological products, an alternative, as applicable), and applicant of the product; • Whether the notification is a permanent discontinuance or an interruption in manufacturing; • A description of the reason for the permanent discontinuance or interruption in manufacturing; and Estimated duration of the interruption in manufacturing. § 310.306(c). § 314.81(b)(3)(iii)(c). § 600.82(c). FDA will maintain public lists of drugs and biological products determined by FDA to be in shortage, including the names, NDCs (or, for certain biological products, an alternative, as applicable), and each applicant of the product (or, for marketed unapproved prescription drugs, each manufacturer of the product); the reason for the shortage; and the estimated duration of the shortage. § 314.81(b)(3)(iii)(d) § 600.82(d) Includes specific reference to protection of trade secrets and confidential commercial information submitted to FDA under the proposed rule and allows FDA to choose not to make certain other information public if it determines that would adversely affect the public health. § 20.100(c)(45). E:\FR\FM\04NOP1.SGM 04NOP1 65908 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules TABLE 1—CURRENT REGULATION (IFR) COMPARED WITH PROPOSED RULE—Continued Requirement Noncompliance ................... Current regulation (IFR) No equivalent provision ................................................... EMCDONALD on DSK67QTVN1PROD with PROPOSALS A. Persons Subject to the Proposed Rule Proposed §§ 310.306, 314.81(b)(3)(iii), and 600.82 would require notification to FDA of a permanent discontinuance or an interruption in manufacturing of a covered drug or biological product. Under the proposed rule, the following persons would be subject to these notification requirements: • All applicants with an approved NDA or ANDA for a covered drug product (proposed § 314.81(b)(3)(iii)). • All applicants with an approved BLA for a covered biological product, other than blood or blood components (proposed § 600.82(a)(1)). • Applicants with an approved BLA for blood or blood components, if the applicant is a manufacturer of a significant percentage of the U.S. blood supply (proposed § 600.82(a)(2)). • All manufacturers of a covered drug product marketed without an approved NDA or ANDA (proposed § 310.306, which applies § 314.81(b)(3)(iii) in its entirety to covered drug products marketed without an approved NDA or ANDA). Section 506C of the FD&C Act as amended by FDASIA requires a ‘‘manufacturer’’ to notify FDA of a permanent discontinuance or an interruption in manufacturing. The proposed rule would require the ANDA, NDA, or BLA applicant (for approved drugs or biological products) or the unapproved drug manufacturer (for marketed, unapproved drugs) to notify FDA of a permanent discontinuance or an interruption in manufacturing. For purposes of section 506C of the FD&C Act, under the proposed rule an ANDA, NDA, or BLA applicant would be considered the manufacturer of an approved, covered product, even if the ANDA, NDA, or BLA applicant contracts that function out to another entity. In other words, the proposed rule makes clear that for approved, covered drugs and biological products, the ANDA, NDA, or BLA applicant bears VerDate Mar<15>2010 Proposed rule 16:13 Nov 01, 2013 Jkt 232001 Cross-reference to disclosure provisions in §§ 310.306, 314.81, and 600.82. § 310.306(b). § 314.81(b)(3)(iii)(e). § 600.82(e). If an applicant of a covered drug or biological product, or manufacturer of a covered, marketed unapproved prescription drug, fails to submit a notification required under the proposed rule within the required timeframe, FDA will issue a publicly available noncompliance letter to the applicant or unapproved drug manufacturer. the responsibility for reporting to FDA a permanent discontinuance or an interruption in manufacturing, whether the product is manufactured by the applicant itself or for the applicant under contract with one or more different entities. As such, the ANDA, NDA, or BLA applicant should establish a process with any relevant contract manufacturer, active pharmaceutical ingredient (API) supplier, or other nonapplicant that ensures the applicant’s compliance with this proposed rule. For example, assume that Applicant X holds an ANDA, NDA, or BLA for a covered drug or biological product and contracts with a third party to manufacture the drug or biological product for the purposes of marketing and selling the drug or biological product in the United States. If the third party contract manufacturer experiences a manufacturing issue that results in a permanent discontinuance or an interruption in manufacturing of Applicant X’s product that would be reportable under proposed § 314.81(b)(3)(iii) or § 600.82, Applicant X, not the contract manufacturer, must notify FDA of this permanent discontinuance or interruption in manufacturing. Therefore, Applicant X should establish a process with the contract manufacturer that ensures Applicant X’s ability to timely report to FDA the permanent discontinuance or interruption in manufacturing. Section 506C(i)(3) of the FD&C Act, as amended by FDASIA, directs FDA to ‘‘take into account any supply reporting programs [for biological products] and . . . aim to reduce duplicative notification’’ in applying section 506C to biological products by regulation. Accordingly, with respect to blood or blood components, we are proposing to limit this rule only to applicants that are manufacturers of a ‘‘significant percentage of the United States blood supply.’’ As described more fully in PO 00000 Frm 00019 Fmt 4702 Sfmt 4702 sections II.B.2.c and II.C.1.b.ii, FDA believes that this approach with respect to blood or blood components will ensure that the Agency receives information that is essential to preventing shortages of these products, without being unnecessarily duplicative of existing systems or unduly burdensome to industry. For purposes of this proposed rule, FDA intends to consider an applicant that holds a BLA for blood or blood components to be a manufacturer of a ‘‘significant percentage’’ of the U.S. blood supply if the applicant manufactures 10 percent or more of the U.S. blood supply (e.g., greater than 1.5 million units of whole blood annually or approximately 125,000 units per month). B. Products Subject to the Proposed Rule 1. Prescription Drug and Biological Products That Are Life Supporting, Life Sustaining, or Intended for Use in the Prevention or Treatment of a Debilitating Disease or Condition The proposed rule would apply to all prescription drug products approved under an NDA or ANDA (proposed § 314.81(b)(3)(iii)), all marketed unapproved prescription drug products (proposed § 310.306), and all prescription biological products approved under a BLA (proposed § 600.82) that are: • Life supporting; life sustaining; or intended for use in the prevention or treatment of a debilitating disease or condition, including any such product used in emergency medical care or during surgery; and • not radiopharmaceutical products.6 FDASIA does not define the terms ‘‘life supporting,’’ ‘‘life sustaining,’’ or ‘‘intended for use in the prevention or treatment of a debilitating disease or 6 With respect to blood and blood components for transfusion, the reporting requirement applies only to an applicant that manufactures a significant percentage of the U.S. blood supply. E:\FR\FM\04NOP1.SGM 04NOP1 EMCDONALD on DSK67QTVN1PROD with PROPOSALS Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules condition,’’ but instead requires FDA to define them. Proposed §§ 314.81(b)(3)(iii)(f) and 600.82(f) would define a ‘‘life supporting or life sustaining’’ drug product as one that is ‘‘essential to, or that yields information that is essential to, the restoration or continuation of a bodily function important to the continuation of human life.’’ This definition of ‘‘life supporting’’ or ‘‘life sustaining’’ is consistent with language used to describe this term in the preamble to the final rule implementing the pre-FDASIA section 506C (72 FR 58993 at 58994 (October 18, 2007)), and in medical device regulations (see 21 CFR 821.3(g)). Under the proposed rule, ‘‘intended for use in the prevention or treatment of a debilitating disease or condition’’ would refer to ‘‘a drug product intended for use in the prevention or treatment of a disease or condition associated with mortality or morbidity that has a substantial impact on day-to-day functioning’’ (proposed §§ 314.81(b)(3)(iii)(f) and 600.82(f)). We have equated ‘‘debilitating disease or condition’’ with ‘‘serious disease or condition’’ under this proposed definition and defined it according to the definition of ‘‘serious’’ found in 21 CFR 312.300. This definition of ‘‘intended for use in the prevention or treatment of a debilitating disease or condition’’ is also consistent with our discussion of the term in the preamble to the proposed rule implementing the pre-FDASIA section 506C (65 FR 66665 at 66666 (November 7, 2000)). When defining these terms, we also took into account comments we received on the IFR, including: A request for additional clarity on how these terms relate to FDA’s use of the term ‘‘medically necessary’’ with respect to drug and biological product shortages; comments recommending that FDA interpret this terminology to require notification for ‘‘medicines at risk of being in shortage’’; and a related comment suggesting that once FDA identifies ‘‘medicines at risk of being in shortage,’’ the Agency should establish a mechanism for the purchase and storage of advance supplies of drugs on the list. According to this comment, this ‘‘government stockpile’’ could prevent shortages from occurring or mitigate the impact of an unavoidable shortage. In response to the first comment, the proposed definitions of ‘‘life supporting or life sustaining’’ and ‘‘intended for use in the prevention or treatment of a debilitating disease or condition’’ are, in important respects, different than FDA’s definition of ‘‘medically necessary’’ as used in the context of the existing Center for Drug Evaluation and Research VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 (CDER) Manual of Policies and Procedures (MAPP) on drug shortages (CDER MAPP 6003.1) (Ref. 2 of this proposed rule). FDA considers a product to be medically necessary under this internal MAPP if ‘‘there is no other adequately available drug product that is judged by medical staff to be an appropriate substitute’’ (Ref. 2 of this proposed rule). Under this proposed rule, the applicant would be required to notify FDA of a permanent discontinuance or an interruption in manufacturing of a drug or biological product that is life supporting, life sustaining, or intended for use in the prevention or treatment of debilitating disease or condition, whether or not the product is considered medically necessary under the MAPP. Under the MAPP, FDA uses the definition of medically necessary to prioritize the Agency’s response to specific shortages or potential shortages and to allocate resources appropriately. In response to the second group of comments, the proposed rule does not define either ‘‘life supporting or life sustaining’’ or ‘‘intended for use in the prevention or treatment of debilitating disease or condition’’ to mean ‘‘medicines at risk of being in shortage,’’ because shortages are often triggered by factors related to manufacturing and product quality that cannot be anticipated in advance, making it difficult, if not impossible, to accurately predict drugs or biological products that are vulnerable to shortage. This suggested interpretation of these terms would also be inconsistent with the statutory text, which defines drugs subject to the notification provisions by their uses, and contains separate language to explain when risks to supply require a notification. Finally, in response to the suggestion to create a national stockpile of drugs and biological products vulnerable to shortage, FDA concludes that this is beyond the scope of the current proposal, which is to implement amended sections 506C and 506E of the FD&C Act. We are interested in comments on the definitions of ‘‘life supporting or lifesustaining’’ and ‘‘intended for use in the prevention or treatment of a debilitating disease or condition.’’ FDA believes these definitions are consistent with the industry’s (and Agency’s) current understanding of the terms, and that more information rather than less is essential for resolving drug shortages. However, we are specifically interested in comments on whether these definitions might unintentionally broaden the scope of reporting to such an extent that the Agency is ‘‘over- PO 00000 Frm 00020 Fmt 4702 Sfmt 4702 65909 notified,’’ particularly in the context of the requirement for applicants to notify FDA of a meaningful disruption in the manufacturer’s supply, without regard to the market as a whole (see section III.C.1. for further discussion on meaningful disruption in supply). 2. Biological Products Section 506C of the FD&C Act, as amended, states that for purposes of this section the term ‘‘drug’’ does not include biological products as defined in section 351(i) of the Public Health Service Act, unless the Secretary of Health and Human Services (the Secretary) applies section 506C to such products by regulation. Section 506C(i)(3) of the FD&C Act provides that FDA may, by regulation, apply section 506C to biological products, ‘‘including plasma products derived from human plasma protein and their recombinant analogs’’ if ‘‘the Secretary determines that such inclusion would benefit the public health,’’ taking into account ‘‘any [existing] supply reporting programs’’ and aiming to reduce ‘‘duplicative notification.’’ Additionally, FDA may apply section 506C of the FD&C Act to vaccines, but the Secretary must determine whether notification of a vaccine shortage to the Centers for Disease Control and Prevention (CDC) under its ‘‘vaccine shortage notification program’’ could satisfy a vaccine manufacturer’s obligation to notify FDA of a permanent discontinuance or an interruption in manufacturing under section 506C. We are proposing to apply section 506C of the FD&C Act to all biological products, including recombinant therapeutic proteins, monoclonal antibody products, vaccines, allergenic products, plasma-derived products and their recombinant analogs, blood or blood components, and cellular and gene therapy products. Like drug shortages, shortages of biological products can have serious negative consequences for patients who rely on these products for their treatment. For example, recent shortages of biological products such as agalsidase beta (Fabrazyme), peginterferon alfa-2a (Pegasys), and BCG 7 Live (Intravesical) (TheraCys) have adversely affected patient care. Fabrazyme is indicated for the treatment of Fabry’s disease, a life shortening, inherited disease caused by a deficiency of alpha-galactosidase A, an enzyme needed to metabolize lipids. The Fabrazyme shortage resulted from contamination at the manufacturing 7 BCG is an attenuated live culture preparation of the Bacillus of Calmette and Guerin (BCG) strain of Mycobaterium bovis. E:\FR\FM\04NOP1.SGM 04NOP1 EMCDONALD on DSK67QTVN1PROD with PROPOSALS 65910 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules plant and led to rationing of the product at one-third the recommended dose for current patients using the drug. As a result of the reduced doses, some patients reported a progression of Fabry’s disease, including serious adverse events affecting the heart, central nervous system, and kidneys. Similarly, shortages of the antiviral drug Pegasys and the bladder cancer biological drug TheraCys threatened the timely treatment of patients with debilitating diseases, interrupting the continuity (and potentially undercutting the effectiveness) of treatment for patients prescribed these medications as well as preventing new patients from obtaining these medications. Early notification of a permanent discontinuance or an interruption in the manufacturing of biological products would allow FDA to address, prevent, or mitigate a shortage of these products, greatly benefiting the public health. In addition, for the reasons described in this document, we have determined that requiring manufacturers of biological products to notify FDA under this proposed rule would not duplicate the existing reporting programs of which we are aware. a. Plasma-derived products and their recombinant analogs. As stated previously, we are proposing to apply section 506C of the FD&C Act to all biological products, including plasma products derived from human plasma protein and their recombinant analogs (referred to in this document as plasmaderived products and their recombinant analogs). With respect to plasmaderived products and their recombinant analogs, FDA recognizes that the Plasma Protein Therapeutics Association (PPTA) has developed a voluntary data system that captures the distribution and supply of five plasma product groups in the United States: PlasmaDerived Factor VIII, Recombinant Factor VIII, Immune Globulin (Ig), Albumin 5%, and Albumin 25%. The PPTA, in consultation with a third party, voluntarily submits a monthly report to FDA of aggregate distribution data for these five product groups. This information provides a picture of the total supply and distribution of these five products in any given month as compared to the last 12 months (see, e.g., https://www.pptaglobal.org/ UserFiles/file/Sept2012PDfviii.pdf). (FDA has verified the Web sites in this document but is not responsible for any subsequent changes to the Web sites after this document publishes in the Federal Register.) FDA recognizes and greatly appreciates the efforts by PPTA to provide plasma product supply VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 information to FDA and the public. However, in addition to the PPTA system, for several reasons we believe that it would benefit the public health for the Agency to receive direct notification under this proposed rule from all manufacturers of these products. First, the PPTA system does not include all plasma-derived products and their recombinant analogs. FDA has approved many plasma-derived products (and their recombinant analogs) that are not included in the PPTA monthly report, but that would be subject to this proposed rule, such as Rho(D) Immune Globulin and Hepatitis B Immune Globulin; Coagulation Factor VIIa (Recombinant); and Coagulation Factor IX. Second, the product distribution data is submitted to PPTA (and subsequently to FDA) on a voluntary basis; reporting under this proposed rule would be mandatory. Finally, the PPTA data is aggregate distribution data derived from historical supply and demand. Unlike the notifications proposed under this rule, it is not real-time data, nor does it capture the types of circumstances that would be considered a ‘‘permanent discontinuance’’ or an ‘‘interruption in manufacturing’’ under this proposed rule. Rather, as described previously, the PPTA data provides a snapshot of current aggregate supply as compared to historical supply. It is not intended to identify circumstances that could lead to a future permanent discontinuance or an interruption in manufacturing of all plasma-derived products and their recombinant analogs. Because the PPTA program, although helpful, does not serve the same purpose as notification under this proposed rule, including plasmaderived products and their recombinant analogs in this rulemaking will not duplicate the PPTA system. FDA believes that including these products within the scope of the proposed rule is essential to FDA’s efforts to identify permanent discontinuances and interruptions in manufacturing of these products, and consequently, essential to our efforts to address, prevent, or mitigate shortages of these products. b. Vaccines. We are proposing to apply section 506C of the FD&C Act to all biological products, including vaccines. Under section 506C(i)(3)(B) of the FD&C Act, if FDA applies section 506C to vaccines, the Secretary must specifically consider whether the notification requirement may be satisfied by submitting a notification to CDC under CDC’s ‘‘vaccine shortage notification program.’’ CDC contracts with vaccine manufacturers as part of the Vaccines PO 00000 Frm 00021 Fmt 4702 Sfmt 4702 for Children (VFC) program.8 FDA recognizes that CDC includes language in its contracts with vaccine manufacturers requiring the manufacturer to notify CDC of vaccine supply issues that could affect the manufacturer’s ability to fulfill its contract with CDC.9 Only certain vaccines are included under the existing CDC program, and thus, only manufacturers of certain vaccines are obligated to provide notification of supply issues to CDC. Based on information from CDC, FDA estimates that approximately 30 percent of vaccines licensed in the United States are not subject to CDC notification, including vaccines for rabies, yellow fever, and typhoid. Moreover, even for the vaccines that are subject to CDC notification, the information collected is not adequate for purposes of this rule, because the existing CDC program does not require vaccine manufacturers to provide notice 6 months in advance of a permanent discontinuance or interruption in manufacturing. Early notice of permanent discontinuances and interruptions is critically important to the prevention of drug shortages. Although FDA and its HHS partners work together closely on vaccine supply issues, and the current framework for CDC notification is useful for contractual purposes, FDA believes including vaccines within the scope of this rulemaking is necessary to fully support FDA’s efforts to identify, address, prevent, or mitigate a vaccine shortage and would not be duplicative of existing notification systems. c. Blood or blood components for transfusion. We are proposing to apply section 506C of the FD&C Act to blood 8 The VFC program is a federally funded program that provides vaccines at no cost to children and adults who might not otherwise be vaccinated because of inability to pay. VFC was created by the Omnibus Budget Reconciliation Act of 1993 as a new entitlement program to be a required part of each state’s Medicaid plan. CDC buys vaccines at a discount from the manufacturers and distributes them to awardees—i.e., State health departments and certain local and territorial public health Agencies—who in turn distribute them at no charge to those private physicians’ offices and public health clinics registered as VFC providers. (See https://www.cdc.gov/vaccines/programs/vfc/ index.html.) 9 The Biomedical Advanced Research and Development Authority (BARDA), which is responsible for the procurement of certain vaccines related to medical countermeasures, also includes similar language in its procurement contracts. Contracts for the procurement of medical countermeasures against chemical, biological, nuclear, and radiological threat agents (e.g. smallpox and anthrax vaccines) are administered by BARDA, part of the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services (HHS). (See https://www.hhs.gov/aspr.) E:\FR\FM\04NOP1.SGM 04NOP1 EMCDONALD on DSK67QTVN1PROD with PROPOSALS Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules or blood components, but in a more limited manner than for other biological products. The proposed rule would require blood or blood component applicants (i.e., blood collection establishments subject to licensure) that manufacture a significant percentage of the U.S. blood supply to notify FDA of a permanent discontinuance or an interruption in manufacturing that is likely to lead to a ‘‘significant disruption’’ in the applicant’s supply of blood or blood components. As described more fully in sections II.A and II.C.1.b.ii, the proposed rule is intended to require reporting of largescale, permanent discontinuances, or interruptions in manufacturing of blood or blood components. The proposed rule would ensure that FDA receives information essential to the Agency in preventing, mitigating, or addressing shortages of blood or blood components, while avoiding duplication with existing programs that monitor local and regional supplies of blood or blood components by ABO blood group. We are aware of two significant efforts to monitor local and regional supplies of blood or blood components. i. America’s Blood Centers and the Blood Availability and Safety Information System. America’s Blood Centers (ABC) is a network of nonprofit community blood centers in North America. ABC members operate more than 600 blood collection sites in 45 states and provide blood or blood components to more than 3,500 hospitals and health care facilities. ABC also maintains a voluntary supply monitoring program for blood and blood components. Information on local and regional blood supply is provided weekly to ABC members nationwide through a newsletter, and online (see https://www.americasblood.org/ stoplight.aspx). In addition, ABC and certain other large licensed blood establishments provide voluntary, daily blood supply reports to HHS, which maintains a system called the Blood Availability and Safety Information System (BASIS) (see https:// www.usbloodreport.net/About.aspx). Certain sentinel hospitals also voluntarily provide inventory reports to the BASIS system, and these data are compiled into a weekly status report on blood supplies, stratified by ABO blood group. Upon request, FDA receives BASIS reports from HHS. The ABC and BASIS systems monitor the supply and demand of blood or blood components on a daily and weekly basis, and in the event of a national disaster. In other words, ABC and BASIS are tools for local blood centers and hospitals to track their day- VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 to-day inventory of blood or blood components. Unlike the notifications required under this proposed rule, ABC and BASIS are not designed to predict large-scale or nationwide disruptions in the supply of blood or blood components. Moreover, ABC and BASIS are voluntary systems; the proposed rule would require mandatory reporting. ii. Task Force. Also critical to the management of the national blood supply is the coordinating function of the Interorganizational Task Force on Domestic Disasters and Acts of Terrorism (Task Force), which is managed by the AABB (formerly the American Association of Blood Banks). The Task Force was formed in January 2002 to help make certain that blood collection efforts resulting from domestic disasters and acts of terrorism are managed properly, and to deliver clear and consistent messages to the public regarding the status of the U.S. blood supply. The Task Force is comprised of representatives from blood establishments, trade associations, commercial entities, and liaisons from governmental Agencies (including FDA), who work together to ensure that adequate blood inventories are in place at all times. In addition, the Task Force operates a system for assessing the need for collections and transportation of blood components, should a disaster or act of terrorism occur. Again, the Task Force efforts, although critical to public health, are focused on inventory management and are not intended to predict large-scale disruptions in the supply of blood or blood components. The Task Force coordinates the movement of blood throughout the United States and appeals to the public for blood donations, but it is not sufficient for FDA in the context of predicting a permanent discontinuance or an interruption in manufacturing of these products that would have a large-scale impact. In short, although the information already available to FDA from the ABC, BASIS, and Task Force programs is useful, the existing frameworks are voluntary, do not result in a direct notification from an applicant to FDA, and, as explained previously, only capture short-term, day-to-day supply and distribution information. In addition, in contrast to this proposed rule, the existing systems are not equipped to predict large-scale, significant disruptions of blood or blood components. Accordingly, FDA has determined that including blood or blood components within the scope of this rule would benefit the public health, providing information that is PO 00000 Frm 00022 Fmt 4702 Sfmt 4702 65911 essential to FDA’s efforts to address shortages of these products. However, recognizing that the existing ABC, BASIS, and Task Force programs do provide certain information concerning the supply of blood or blood components, we have limited the proposed reporting requirements to apply only to applicants of blood or blood components that manufacture a significant percentage of the U.S. blood supply, and only to a permanent discontinuance of manufacture or an interruption in manufacturing that is likely to lead to a ‘‘significant disruption’’ in supply of that blood or blood component, as further described in sections II.A and II.C.1. d. Distribution reports (for all biological products). Under § 600.81 (21 CFR 600.81), applicants are required to submit to the Center for Biologics Evaluation and Research (CBER) or CDER, information about the quantity of product distributed under the biologics license, including the quantity distributed to distributors. As part of this safety reporting requirement, manufacturers provide distribution data to FDA every 6 months or at other intervals as may be required by FDA. Although distribution reports submitted by applicants are helpful in the analysis of safety reporting data, particularly for newly approved products, these reports do not include information about a permanent discontinuance or an interruption of the manufacture of a biological product that is likely to lead to a meaningful disruption in the supply of that product. Furthermore, the production cycles of biological products vary widely (e.g., some are manufactured once a year, some are manufactured every other year, and some are manufactured more or less frequently), such that any distribution data received from the manufacturer at 6-month intervals for such products will not be current. Therefore, FDA has determined that the reporting requirements under § 600.81 do not constitute a duplicate supply reporting program. In summary, we are proposing to apply section 506C of the FD&C Act to all biological products. For the reasons discussed in this document, FDA finds that this inclusion would benefit the public health by facilitating prompt FDA action to address, prevent, or mitigate drug shortages, without duplicating existing reporting programs or creating redundant reporting. With respect to vaccines, for the reasons already described, we have determined that notification to CDC is not sufficient for purposes of reporting to FDA under E:\FR\FM\04NOP1.SGM 04NOP1 65912 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules section 506C of the FD&C Act and may not replace section 506C notifications. 3. Scope of the Term ‘‘Product’’ For purposes of this proposed rule, ‘‘product’’ refers to a specific strength, dosage form, or route of administration of a drug or biological product. For example, if Applicant X experiences an interruption in manufacturing of the 50milligram (mg) strength of a drug product that would be subject to proposed § 314.81(b)(3)(iii), but the 100 mg strength continues to be manufactured without delay, under the proposed rule, Applicant X must notify FDA of the interruption in manufacturing of the 50 mg strength if the interruption is likely to lead to a meaningful disruption in the applicant’s supply of the 50 mg strength. Recent experience has shown that the permanent discontinuance or interruption in manufacturing of a specific strength, dosage form, or route of administration of a drug or biological product can have a significant impact on the targeted needs of particular patients (e.g., although the 100 mg tablet from Applicant X is available, it may not be split in half easily for a patient that is prescribed the 50 mg strength). Moreover, shortages of a specific strength, dosage form, or route of administration may lead to a shortage of another strength, dosage form, or route of administration of the product, exacerbating patient difficulties in acquiring the product. Obtaining this information is consistent with the emphasis in the IFR on the importance of notifying FDA of permanent or temporary interruptions in supply of a specific strength, dosage form, or route of administration of covered products (76 FR 78530 at 78533), and with the general support for this approach we received in comments on the IFR. C. Notification of a Permanent Discontinuance or an Interruption in Manufacturing EMCDONALD on DSK67QTVN1PROD with PROPOSALS 1. Notification a. Permanent discontinuance. Section 506C of the FD&C Act requires manufacturers to notify FDA of a permanent discontinuance of manufacture of a covered drug. Proposed §§ 314.81(b)(3)(iii) and 600.82 would require the applicant to report all permanent discontinuances of covered drugs and biological products to FDA. For purposes of this rule, we are interpreting a permanent discontinuance to be a decision by the applicant for business or other reasons to cease manufacturing and distributing the product indefinitely. VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 b. Interruption in manufacturing. In addition to permanent discontinuances, section 506C of the FD&C Act requires manufacturers to notify FDA of an interruption in manufacturing of a covered drug that is likely to lead to a meaningful disruption in supply of that drug in the United States. The statute defines ‘‘meaningful disruption’’ to mean ‘‘a change in production that is reasonably likely to lead to a reduction in the supply of a drug by a manufacturer that is more than negligible and affects the ability of the manufacturer to fill orders or meet expected demand for its product; and does not include interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time’’ (emphasis added). i. Drugs and biological products other than blood or blood components. Proposed §§ 314.81(b)(3)(iii)(a) and 600.82(a)(1) would require the applicant for a product other than blood or blood components to report to FDA an interruption in manufacturing of the drug or biological product that is likely to lead to a meaningful disruption in supply of that drug or biological product in the United States. Proposed §§ 314.81(b)(3)(iii)(f) and 600.82(f) would adopt the statutory definition of meaningful disruption in supply. Consistent with the statutory definition of meaningful disruption, the proposed rule would require an applicant to report an interruption in manufacturing likely to lead to a meaningful disruption in its own supply of a covered drug or biological product. In other words, when evaluating whether an interruption in manufacturing is reportable to FDA under this proposed rule, rather than considering the potential impact of the interruption on the market as a whole, the relevant question (regardless of how large or small the applicant’s market share may be) is whether the interruption is likely to lead to a reduction in the applicant’s supply of a covered drug or biological product that is more than negligible, and affects the ability of the applicant to fill its own orders or meet the expected demand of its clients for the covered product. Consistent with the statute, the proposed rule would not require an applicant to predict the market-wide impact of its own interruption in manufacturing, which can be difficult to accurately assess and could lead to inconsistent interpretation of the regulation, less accurate predictions, PO 00000 Frm 00023 Fmt 4702 Sfmt 4702 and under- or reporting, as suggested by multiple comments on the IFR. Under the proposed rule, reportable discontinuances or interruptions in manufacturing of a covered drug or biological product would include: • A business decision to permanently discontinue manufacture of a covered drug or biological product. • A delay in acquiring APIs or inactive ingredients that is likely to lead to a meaningful disruption in the applicant’s supply of a covered drug or biological product while alternative API suppliers are located. • Equipment failure or contamination affecting the quality of a covered drug or biological product that necessitates an interruption in manufacturing while the equipment is repaired or the contamination issue is addressed and that is likely to lead to a meaningful disruption in the applicant’s supply of the product. • Manufacturing shutdowns for maintenance or other routine matters, if the shutdown extends for longer than anticipated or otherwise is likely to lead to a meaningful disruption in the applicant’s supply of a covered drug or biological product. • A merger of firms or transfer of an application for a covered drug or biological product to a new firm, if the merger or transfer is likely to lead to a meaningful disruption in the applicant’s supply of the product. • An interruption in manufacturing (e.g., contamination of a manufacturing line) that in the applicant’s view may not meaningfully disrupt the marketwide supply of the covered drug or biological product (for example, because the applicant holds only a small share of the market for the product), but that the applicant determines is likely to lead to a meaningful disruption in its own supply of the covered product. Conversely, an applicant would not be required under the proposed rule to notify FDA if an interruption in manufacturing is not likely to lead to a meaningful disruption in the applicant’s supply of the drug or biological product. For example, FDA would not need to be notified in the following circumstances: • A scheduled shutdown of an applicant’s manufacturing facility for routine maintenance, if the shutdown is anticipated and planned for in advance; and therefore, is not expected to lead to a meaningful disruption in the applicant’s supply of a covered drug or biological product. • An unexpected power outage that results in an unscheduled interruption in manufacturing of a covered drug or biological product, if the applicant expects to resume normal operations E:\FR\FM\04NOP1.SGM 04NOP1 EMCDONALD on DSK67QTVN1PROD with PROPOSALS Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules within a relatively short timeframe and does not expect to experience a meaningful disruption in its supply of the covered drug or biological product. In either of these circumstances, if the interruption in manufacturing subsequently appears likely to lead to a meaningful disruption in the applicant’s supply of the covered drug or biological product, then it would become a reportable interruption in manufacturing under this proposed rule and the applicant would be required to notify FDA. The list of examples described in this document is intended to assist industry in understanding what would (or would not) be required to be reported under amended section 506C of the FD&C Act, but it is not exhaustive. The proposed rule would require any permanent discontinuance or any interruption in manufacturing that is likely to lead to a meaningful disruption in the applicant’s supply of a covered drug or biological product to be reported to FDA, even if not specifically described in this preamble. ii. Blood or blood components for transfusion. Proposed § 600.82(a)(2) would require an applicant that manufactures a significant percentage of the U.S. blood supply to report to FDA an interruption in manufacturing of a blood or blood component that is likely to lead to a ‘‘significant disruption’’ in supply of that product in the United States. As we discussed in section II.A, an applicant that manufactures 10 percent or more of the U.S. blood supply (e.g., greater than 1.5 million units of whole blood annually or approximately 125,000 units per month), would be considered to manufacture a significant percentage of the U.S. blood supply for purposes of this proposed rule. Proposed § 600.82(f) defines ‘‘significant disruption’’ to mean ‘‘a change in production that is reasonably likely to lead to a reduction in the supply of blood or blood components by a manufacturer that substantially affects the ability of the manufacturer to fill orders or meet expected demand for its product; and does not include interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time.’’ This definition of significant disruption closely follows, but is not identical to, the statutory and regulatory definition of meaningful disruption. For purposes of the proposed rule, FDA intends to consider an interruption in manufacturing that leads to a reduction of 20 percent or more of an VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 applicant’s own supply of blood or blood components over a one-month period to ‘‘substantially affect’’ the ability of the applicant to fill orders or meet expected demand; accordingly, such an interruption would be considered a ‘‘significant disruption’’ in supply. Again, when determining when an interruption in manufacturing is likely to lead to a significant disruption in supply, the blood or blood component applicant should not consider the market as a whole, but rather, should consider only its own supply of product. The proposed definition of ‘‘significant disruption’’ (interpreted to mean affecting 20 percent or more of an individual applicant’s supply over a one-month period) as applied to blood or blood components, in combination with the limitation of the proposed rule only to applicants of blood or blood components that manufacture a significant percentage (10 percent or more) of the nation’s blood supply, is intended to avoid duplication with existing programs to monitor the daily and weekly distribution of blood or blood components described in section II.B.2.c. As described in that section, in general, existing programs maintained by ABC, BASIS, and the Task Force monitor and resolve temporary, local shortfalls of a particular ABO blood group or a particular blood component. Accordingly, the definition of ‘‘significant disruption’’ is intended to capture events that are likely to precipitate large-scale disruptions in an applicant’s blood supply, and that are unlikely to be identified and corrected by the existing ABC, BASIS, and Task Force programs. The additional limitation of the proposed rule to applicants that manufacture a significant percentage of the nation’s blood supply further ensures that reporting to FDA will not unnecessarily duplicate reporting to the ABC, BASIS, and Task Force systems, but still allows FDA to receive information that is essential to the Agency in preventing large-scale shortages of these products. Under the proposed rule, circumstances that would trigger notification to FDA of a permanent discontinuance or an interruption in manufacturing of blood or blood components would include the following examples. We recognize that, with the exception of the first example of a permanent discontinuance, the following interruptions are unlikely to be reasonably anticipated 6 months in advance. In that case they would be reportable as soon as practicable, but in no case later than 5 business days after PO 00000 Frm 00024 Fmt 4702 Sfmt 4702 65913 the interruption in manufacturing occurs: • A business decision by an applicant that manufactures 10 percent or more of the nation’s blood supply to permanently discontinue manufacture of blood or blood components; • A computer system failure that causes an applicant of a blood establishment that collects 10 percent or more of the nation’s blood supply to be unable to label blood for 2 weeks, resulting in a 20 percent monthly shortfall of blood for that applicant; • An issue with blood collection bags, such that they are unavailable, causing an applicant that manufactures 10 percent or more of the nation’s blood supply to experience a 20 percent monthly shortfall in normal production for that applicant; • An issue with apheresis collection devices that causes an applicant of a blood establishment that collects 10 percent or more of the nation’s blood supply to be unable to collect platelets by apheresis, resulting in a 20 percent monthly shortfall in platelet supply for that applicant; • An explosion or fire that damages a large testing laboratory that performs blood testing for an applicant that manufactures 10 percent or more of the nation’s blood supply, resulting in a 20 percent monthly shortfall of blood or blood components for that applicant. Conversely, a covered blood or blood component applicant would not be required under the proposed rule to notify FDA if an interruption in manufacturing is not likely to lead to a significant disruption in the applicant’s supply of blood or blood components. For example, FDA would not need to be notified if a covered blood or blood component applicant experiences a temporary drop in blood donations at one of its local blood donation centers, such that it is unable to fully supply its hospital customers with blood for several days, provided the donation center quickly returns to its normal donation and supply levels and the dip in blood donations is not likely to lead to a 20 percent decrease in the applicant’s overall supply of blood over a one-month period. We expect that this type of situation would be identified and resolved through the ABC, BASIS, and Task Force systems (e.g., these systems would identify the issue and locate temporary, alternative blood supplies for the applicant’s customers). If such an event does lead to a significant disruption in a covered applicant’s supply of blood or blood components, it would need to be reported to FDA under the proposed rule. E:\FR\FM\04NOP1.SGM 04NOP1 EMCDONALD on DSK67QTVN1PROD with PROPOSALS 65914 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules Again, the list of examples described in this document is intended to assist industry in understanding what must be reported under amended section 506C of the FD&C Act, but the list is not exhaustive. The proposed rule would require any permanent discontinuance or any interruption in manufacturing that is likely to lead to a significant disruption (as defined by the proposed rule) in a covered applicant’s supply of blood or blood components to be reported to FDA, even if not specifically discussed in this preamble. c. Consideration of comments to the IFR. Several comments on the IFR suggested alternative ways of defining circumstances that must be reported to FDA under pre-FDASIA section 506C of the FD&C Act. We have considered whether these may be relevant to amended section 506C of the FD&C Act. For example, one comment suggested that historical supply and demand should be considered when determining whether to notify FDA under section 506C of the FD&C Act. Specifically, the comment suggested that notification should only be required if an interruption in manufacturing is expected to affect the supply of the product based on ‘‘historical inventory levels and other factors.’’ Another comment suggested that an applicant should be required to report to FDA only after the disruption in supply occurs, for example when it is ‘‘unable to ship 90 percent or more of its full quantity of [covered] product as reasonably ordered by its customers for more than 4 weeks.’’ In other words, the applicant should report to FDA if it experiences a 10 percent reduction in supply for a 4-week period. A third comment suggested that notification should be required when an event causes an applicant to predict that patients will be unable to obtain a covered product for a certain, extended period of time (e.g., at the point when an applicant projects that it will be unable to ship the drug or biological product to customers for 8 weeks). Although we agree that it could be appropriate to consider historical supply and demand or shipping schedules in deciding whether a notification would be required under this proposed rule, we decline to limit the term ‘‘interruption in manufacturing that is likely to lead to a meaningful disruption in supply’’ to consideration only of such factors, and we decline to define the requirement by codifying a preset, numerical threshold. The purpose of FDASIA, and this proposed rule, is to improve FDA’s ability to prevent or mitigate the impact of drug and biological product shortages by VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 broadening the scope of information that the Agency receives regarding permanent discontinuances and interruptions in manufacturing. If reportable circumstances are limited to situations in which a manufacturer is unable to ship a certain percentage of historic demand for a certain period time, or unable to ship at all for a certain period of time, some circumstances that could lead to a shortage may not be reported to FDA, putting the Agency at a disadvantage in addressing those situations. For example, if notification under this proposed rule is triggered only by the inability of an applicant to ship at least 90 percent of its full quantity of a particular drug product as reasonably ordered by its customers for more than 4 weeks (10 percent reduction in supply), if an applicant were able to ship 92 percent of its supply (i.e., it experiences an 8 percent reduction in supply), the interruption would not be reportable to FDA. Yet this interruption in manufacturing may still have an impact on a patient’s ability to obtain the product and could still lead to a product shortage that is ‘‘more than negligible.’’ Instead, this proposed rule defines ‘‘meaningful disruption in supply’’ consistent with the statutory text, and this preamble provides examples of reportable interruptions in manufacturing as illustrations for industry. An applicant may, at its discretion, analyze historical supply and demand and estimate shipping schedules to help determine whether an interruption in manufacturing is likely to lead to a meaningful disruption in supply, but the applicant should not substitute a rigid calculation for a full consideration of all circumstances applicable to determining whether the change in production is reasonably likely to lead to a reduction in supply that is more than negligible and that affects the manufacturer’s ability to fill orders or meet expected demand for its product. 2. Timing and Submission of Notification a. Timing of notification. Section 506C of the FD&C Act requires notification to FDA ‘‘(1) at least 6 months prior to the date of the permanent discontinuance or interruption [in manufacturing]; or (2) if compliance with paragraph (1) is not possible, as soon as practicable.’’ Consistent with the statute, proposed §§ 314.81(b)(3)(iii)(b) and 600.82(b) would require an applicant to notify FDA of a permanent discontinuance or an interruption in manufacturing at PO 00000 Frm 00025 Fmt 4702 Sfmt 4702 least 6 months in advance of the date of the permanent discontinuance or interruption in manufacturing; or, if 6 months’ advance notice is not possible, as soon as practicable thereafter, but in no case later than 5 business days after the permanent discontinuance or interruption in manufacturing occurs. The Agency’s most powerful tool for addressing drug and biological product shortages is early notification, which provides lead time for FDA to work with manufacturers and other stakeholders to prevent a shortage or to mitigate the impact of an unavoidable shortage. As such, we expect that applicants would provide 6 months’ advance notice whenever possible. In particular, FDA believes that an applicant will generally know of a permanent discontinuance at least 6 months in advance, and in that case the applicant would be required to provide notification of a permanent discontinuance to FDA at least 6 months in advance. We understand that an applicant may not reasonably be able to anticipate certain interruptions in manufacturing that are likely to lead to a meaningful disruption in supply 6 months in advance. For example, if an applicant discovers fungal contamination that requires an immediate, temporary shutdown of its manufacturing plant for a covered product, the applicant will not be able to provide FDA with 6 months’ advance notice of the interruption in manufacturing. Instead, the proposed rule would require the applicant to notify FDA ‘‘as soon as practicable,’’ but in no case more than 5 business days after the interruption in manufacturing occurs. In this example, the applicant would need to notify FDA as soon as it reasonably anticipates that an interruption in manufacturing caused by fungal contamination is likely to result in a meaningful disruption in supply of the applicant’s product. The applicant should not wait until it or its manufacturer begins rejecting or delaying fulfillment of orders for the product from available inventory (i.e., the applicant should not wait until the interruption in manufacturing actually begins to disrupt supply and affect patient access to the product). In our experience, even if it is not possible for an applicant to notify the Agency before a permanent discontinuance or an interruption in manufacturing occurs, it should generally be possible for the applicant to provide notice within a day or two, and it should always be possible for the applicant to notify the Agency no later than 5 days after the permanent discontinuance or interruption occurs, even in the event of a natural disaster E:\FR\FM\04NOP1.SGM 04NOP1 EMCDONALD on DSK67QTVN1PROD with PROPOSALS Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules or some other catastrophic incident. Accordingly, the 5-day provision in our proposal represents a date certain after which FDA would be able to take action under section 506C(f) of the FD&C Act against an applicant for failure to comply with the notification requirements (see section II.C.5 of this document for further discussion of the consequences of failure to notify FDA). Additionally, an applicant that could have notified the Agency before five days had passed, but waited until the end of the 5-day period would be in violation of the proposed regulation. Consistent with the statutory intent, whenever possible, applicants would be required to provide us with advance notice, whether 6 months’ advance notice, or ‘‘as soon as practicable’’ thereafter (e.g., 3 months’ advance notice). b. Submission of notification. Proposed §§ 314.81(b)(3)(iii)(b) and 600.82(b) would require an applicant to notify FDA of a permanent discontinuance or an interruption in manufacturing electronically in a format FDA can process, review, and archive. Applicants must email notifications to drugshortages@fda.hhs.gov (for products regulated by CDER) or cbershortage@fda.hhs.gov (for products regulated by CBER). In the future, the Agency may consider creating an electronic notification portal linked to the Agency’s internal drug shortages database to facilitate submission of these notifications. Unless and until this portal is created, however, email notifications will be used. c. Reduction in notification period for ‘‘good cause’’. Under the pre-FDASIA section 506C(b), a manufacturer could seek, and FDA could grant, a reduction in the required 6-month advance notification period for ‘‘good cause.’’ The statute listed several reasons that would constitute ‘‘good cause,’’ including when continuing to manufacture the product for the full 6month notification period could cause a public health problem or result in substantial economic or legal hardship for the manufacturer. The regulation at § 314.91 implemented the pre-FDASIA section 506C(b). Because section 506C of the FD&C Act as amended by FDASIA does not include an option for formally seeking a reduction in the 6-month advance notification period based on ‘‘good cause,’’ this rule proposes to eliminate § 314.91 in its entirety. 3. Contents of the Notification Proposed §§ 314.81(b)(3)(iii)(c) and 600.82(c) would require an applicant to include the following items in VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 notifications submitted under section 506C(a) of the FD&C Act: • The name of the drug or biological product subject to the notification, including the NDC for the drug or biological product (or, for a biological product that does not have an NDC, an alternative standard for identification and labeling that has been recognized as acceptable by the Center Director); • The name of the applicant of the drug or biological product; • Whether the notification relates to a permanent discontinuance of the drug or biological product or an interruption in manufacturing of the drug or biological product; • A description of the reason for the permanent discontinuance or interruption in manufacturing; and • The estimated duration of the interruption in manufacturing. FDA is proposing to require applicants to include the minimum information listed in this document in the initial notification to assist the Agency in complying with section 506E of the FD&C Act, which requires FDA to maintain a publicly available list of drugs in shortage, as described in section II.C.4 of this document. We recognize that the duration of an interruption in manufacturing can be difficult to accurately predict. The applicant should provide FDA with its best estimate of the expected duration of the interruption in manufacturing. If, after the initial notification is submitted, the estimated duration changes, the applicant should notify FDA of the new expected duration of the interruption in manufacturing so that FDA can respond appropriately. In addition, the applicant should include a detailed, factual description of the reason for the shortage in the notification to assist FDA in responding to the notification. In addition to the proposed required elements of the notification, applicants are encouraged to include any other information in the notification that may be helpful to the Agency in working with the applicant to resolve the permanent discontinuance or interruption in manufacturing. Such information could include the applicant’s market share, inventory on hand or in distribution channels, allocation procedures and/or plans for releasing available product, copies of communications to patients and providers regarding the shortage (e.g., Dear Healthcare Professional letters), or initial proposals to prevent or mitigate the shortage. As appropriate, the Agency will also follow up with the applicant after the notification is submitted to obtain additional information and to work with the applicant to facilitate PO 00000 Frm 00026 Fmt 4702 Sfmt 4702 65915 resolution of any shortage or potential shortage. 4. Public Lists of Products in Shortage Section 506E of the FD&C Act requires FDA to maintain a publicly available list of drugs (and biological products, if FDA applies section 506C to biological products by regulation) that are determined by FDA to be in shortage, including providing the names and NDCs of the drugs, the name of each manufacturer of the drug, the reason(s) for the shortage, and the estimated duration of the shortage. Section 506C(h)(2) of the FD&C Act defines ‘‘drug shortage’’ to mean ‘‘a period of time when the demand or projected demand for the drug within the United States exceeds the supply of the drug.’’ For purposes of section 506E of the FD&C Act, under the proposed rule, the ANDA, NDA, or BLA applicant would be considered the manufacturer of an approved drug or biological product, even if the ANDA, NDA, or BLA applicant contracts that function out to another entity. Section 506E of the FD&C Act further requires FDA to include on the drug shortages list the reason for the shortage, choosing from the following statutory list of categories: • Requirements relating to complying with current good manufacturing practices (CGMPs); • Regulatory delay; • Shortage of an active ingredient; • Shortage of an inactive ingredient component; • Discontinuation of the manufacture of the drug; • Delay in shipping of the drug; and • Demand increase in the drug. Consistent with the statute, and with FDA’s current practice, under proposed §§ 310.306(b), 314.81(b)(3)(iii)(d), and 600.82(d), FDA would maintain publicly available lists of drugs and biological products that are determined by FDA to be in shortage, whether or not FDA has received a notification under this proposed rule concerning the product in shortage. Proposed §§ 314.81(b)(3)(iii)(f) and 600.82(f) adopt the statutory definition of drug shortage (substituting ‘‘biological product shortage’’ for ‘‘drug shortage’’ in § 600.82(f)). Under the proposed rule, the shortages lists would include the following required statutory elements for drugs or biological products in shortage: Names and NDCs (or the alternative standard for certain biological products) of the drugs or biological products, names of each applicant, reason for each shortage, and estimated duration of each shortage. E:\FR\FM\04NOP1.SGM 04NOP1 EMCDONALD on DSK67QTVN1PROD with PROPOSALS 65916 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules If FDA has received a notification under the proposed rule for the drug or biological product, FDA would consider the reason for the shortage supplied by the applicant in its notification, and, where applicable, other relevant information before the Agency, in determining how to categorize the reason for the shortage under the proposed rule. Consistent with the statute, the Agency, not the applicant, would be responsible for determining which categorical reason best fits a particular situation. FDA would generally choose the categorical reason that best fits the applicant’s supplied description. To facilitate FDA’s determination of the categorical reason for the shortage, under the proposed rule we would expect applicants to supply as many details and facts as possible concerning the reason for the permanent discontinuance or interruption in manufacturing when submitting a 506C notification. This information would also assist FDA in responding quickly to the notification. FDA works proactively with applicants and others experiencing issues that could lead to a product shortage. We are committed to working with industry to address any underlying quality or manufacturing issues, and we seek to avoid shutdowns and long-term interruptions in supply whenever possible to ensure continued patient access to vital safe and effective drugs and biological products. If FDA has not received a notification under the proposed rule, but becomes aware of a shortage through other means, FDA would consider information before the Agency when determining and choosing the reason for the shortage to be included on the public list. In addition to the list of statutory reasons for the shortage that FDA may choose from, we are also proposing to add an eighth category, entitled ‘‘Other reason.’’ We are proposing to add this category because the Agency believes that some quality or manufacturing problems that result in a shortage may not fit into any of the listed categories in the statute (e.g., not all quality concerns are the result of noncompliance with CGMPs). The Agency would only choose ‘‘Other reason’’ if none of the other listed reasons is applicable. For example, an interruption in manufacturing as a result of a natural disaster or other catastrophic loss would fall into the ‘‘Other reason’’ category. Moreover, as described in this document, although FDA may choose the ‘‘Other reason’’ category, the public shortages list would also include a brief summary of the VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 reason for the shortage submitted by the applicant, thus providing additional information to the public on the cause of the shortage. As noted previously, the proposed rule would codify, consistent with FDASIA, FDA’s current practice of maintaining public lists of drugs and biological products in shortage, available on FDA’s Web site at https:// www.fda.gov/drugs/drugsafety/ drugshortages/default.htm (drug shortages) and https://www.fda.gov/ BiologicsBloodVaccines/ SafetyAvailability/Shortages/ default.htm (biological product shortages). FDA’s current drug shortages list was reorganized after the enactment of FDASIA to begin implementing revised section 506E of the FD&C Act. The drug shortages list now includes six categories of information about each drug product on the list: Company (manufacturer of product and contact information); Product (name, strength, formulation, dosage, and NDC); Availability and Estimated Shortage Duration; Related Information (includes applicant’s submitted description of reason for shortage); Shortage Reason (FDA-determined reason for the shortage, chosen from the list in proposed §§ 314.81(b)(3)(iii)(d)); and Date Updated (last date FDA updated the information for that particular product). The biological product shortage list includes similar information in fields for Product Name, Reason for Shortage, and Status. In reformatting and revising the drug shortages list and drafting this proposed rule, we considered several comments on the IFR and other suggestions from stakeholders to improve the Agency’s public communication about shortages. We agree that communication between FDA and interested stakeholders, including industry, providers (such as physicians, pharmacists, and nurses), and patients, is an essential component of preventing and mitigating both drug and biological product shortages. FDA updates the drug and biological product shortages lists regularly, and strives to communicate in ‘‘real-time’’ so that patients and providers have the most current data available for planning purposes. Moreover, consistent with section 506D(d) of the FD&C Act, FDA is encouraging patients, providers, pharmacists, and other nonapplicants to communicate with the Agency about potential shortages or disruptions in supply via one of the following email addresses: drugshortages@fda.hhs.gov or cbershortage@fda.hhs.gov. FDA is already in frequent contact with third PO 00000 Frm 00027 Fmt 4702 Sfmt 4702 parties to collect and disseminate shortage-related information, and we hope the availability of these dedicated email addresses will further facilitate communication. We are continuing to work diligently to improve our drug and biological product shortages Web sites and to consider new methods for communicating with all stakeholders about shortages. We appreciate suggestions on how to do this more effectively. 5. Confidentiality and Disclosure In general, as required by section 506C(c) and 506E of the FD&C Act, and as described in this document, FDA will publicly disclose, to the maximum extent possible, information on drug shortages, including information provided by applicants in a notification of a permanent discontinuance or an interruption in manufacturing. Proposed §§ 314.81(b)(3)(iii)(d) and 600.82(d) contain an exception to these provisions, stating that FDA may choose not to make information collected under the authority of this proposed rule available to the public on the drug or biological product shortages lists or under its general obligation to disseminate drug shortage information under section 506C(c) of the FD&C Act if the Agency determines that disclosure of such information would adversely affect the public health (such as by increasing the possibility of hoarding or other disruption of the availability of the drug or biological product to patients). These proposed provisions closely track the statutory language in sections 506C(c)(3) and 506E(c)(3) of the FD&C Act. In addition, proposed §§ 310.306(c), 314.81(b)(3)(iii)(d), and 600.82(d) state that FDA will not provide on the public drug or biological product shortages lists or under section 506C(c) of the FD&C Act, information that is protected by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4), including trade secrets and commercial or financial information that is considered confidential or privileged under 21 CFR 20.61. These proposed provisions would ensure appropriate protection for commercial and trade secret information protected by other Federal law and are consistent with the statutory language in sections 506C(d) and 506E(c)(2) of the FD&C Act, which clarify that the information provisions in sections 506C and 506E do not alter or amend 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4). Additionally, by reference to section 506E of the FD&C Act, the Agency’s obligation to disseminate to the public, to the maximum extent possible, drug shortage information under section 506C(c) does not alter or E:\FR\FM\04NOP1.SGM 04NOP1 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules EMCDONALD on DSK67QTVN1PROD with PROPOSALS amend the protections afforded by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4). FDA is also proposing a technical amendment to § 20.100 to include a cross-reference to §§ 310.306, 314.81, and 600.82. Proposed § 20.100 describes, by cross-reference to other regulations, the rules on public availability of certain specific categories of information. One comment on the IFR expressed concern that FDA had not discussed how the Agency would preserve the confidentiality of proprietary information reported to FDA in the context of (pre-FDASIA) section 506C notifications. The comment was specifically concerned that as FDA attempts to mitigate a potential drug shortage by contacting manufacturers to increase production, it might reveal confidential information, even if the interruption in manufacturing by the original manufacturer is only temporary. Proposed §§ 314.81(b)(3)(iii)(d) and 600.82(d) are intended to make clear that FDA will adhere to applicable laws to protect trade secrets and confidential commercial information as it works to mitigate or prevent a shortage. 6. Failure To Notify Proposed §§ 310.306(b), 314.81(b)(iii)(3)(e), and 600.82(e) would require FDA to issue a noncompliance letter to an applicant (or, for a covered, unapproved drug, to a manufacturer) who fails to submit a section 506C notification as required under proposed §§ 314.81(b)(iii)(3)(a) and 600.82(a) within the timeframe stated in proposed §§ 314.81(b)(iii)(3)(b) and 600.82(b). Consistent with the statute, as proposed in this rule, failure to notify FDA would include failure to timely notify FDA. For example, if FDA discovers that an applicant did not notify FDA of the permanent discontinuance of a covered drug or biological product 6 months in advance, even though the applicant anticipated the permanent discontinuance 6 months in advance, FDA would issue a noncompliance letter under this proposed rule. Similarly, if FDA determines that an applicant experienced a reportable interruption in manufacturing that it could not reasonably anticipate 6 months in advance, but the applicant failed to notify FDA ‘‘as soon as practicable,’’ the proposed rule would require FDA to issue a noncompliance letter. Refer to section II.C.2.a of this document for a discussion of the required timing for section 506C notifications. As required by statute, the proposed rule would provide the applicant with 30 days from the date of issuance of the VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 noncompliance letter to respond to the letter. The applicant’s response must set forth the basis for noncompliance and provide the required notification with the required information. Under the proposed rule, not later than 45 days after the date of issuance of the letter, FDA would make the letter and the applicant’s response public, after appropriate redaction to protect any trade secret or confidential commercial information. FDA would not make the letter and the applicant’s response public if FDA determines, based on the applicant’s response, that the applicant had a reasonable basis for not notifying FDA as required. IV. Legal Authority FDA is amending its regulations to implement sections 506C and 506E of the FD&C Act (21 U.S.C. 356c and 356e) as amended by FDASIA. FDA’s authority for this rule also derives from section 701(a) of the FD&C Act (21 U.S.C. 371(a)). V. Analysis of Impacts A. Introduction FDA has examined the impacts of the proposed rule under Executive Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 U.S.C. 601–612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104–4). Executive Orders 12866 and 13563 direct Agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety, and other advantages; distributive impacts; and equity). OMB has determined that this proposed rule may be an economically significant regulatory action as defined by Executive Order 12866. The Regulatory Flexibility Act requires Agencies to analyze regulatory options that would minimize any significant impact of a rule on small entities. The estimated per notification cost for small business entities, $224, represents a small percentage of average annual sales (up to 0.10 percent), for all entities covered by the proposed rule. Although the final rule does not require specific mitigation strategies, for firms that choose to implement mitigation or prevention strategies, there could be additional costs of $112,000 associated with labor resources. For pharmaceutical companies with fewer than 20 workers, these could be 2 to 7.8 percent of average annual sales. In FDA’s experience, 4–5 small business PO 00000 Frm 00028 Fmt 4702 Sfmt 4702 65917 entities per year have been affected by a shortage. For these companies, the average annual sales was $17.54 million, and the estimated costs of implementing mitigation or prevention strategies would represent less than 0.64 percent of their average annual sales. The Agency anticipates that the proposed rule will not have a significant economic impact on a substantial number of small entities, and seeks comments on its Initial Regulatory Flexibility Analysis. Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires that Agencies prepare a written statement, which includes an assessment of anticipated costs and benefits, before proposing ‘‘any rule that includes any Federal mandate that may result in the expenditure by State, local, and tribal governments, in the aggregate, or by the private sector, of $100,000,000 or more (adjusted annually for inflation) in any one year.’’ The current threshold after adjustment for inflation is $141 million, using the most current (2012) Implicit Price Deflator for the Gross Domestic Product. FDA does not expect this proposed rule to result in any 1-year expenditure that would meet or exceed this amount. B. Summary The proposed rule would amend FDA’s regulations to implement sections 506C and 506E of the FD&C Act, as amended by FDASIA. The proposed rule would require all applicants of covered, approved drugs or biological products other than blood or blood components, all applicants of blood or blood components that manufacture a significant percentage of the U.S. blood supply, and all manufacturers of covered drugs marketed without an approved application, to notify FDA electronically of a permanent discontinuance or an interruption in manufacturing of the product that is likely to lead to a meaningful disruption in supply (or a significant disruption for blood or blood components) of the product in the United States. Notification would be required 6 months in advance of the permanent discontinuance or interruption in manufacturing, or, if that is not possible, as soon as practicable. The proposed rule also describes how to submit such a notification, the information required to be included in such a notification, the consequences for failure to submit a required notification, the disclosure of shortage-related information, and the meaning of certain terms. The proposed rule would impose annual costs of up to $39.34 million on those applicants or entities affected by E:\FR\FM\04NOP1.SGM 04NOP1 65918 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules the rule, and up to $8.29 million on FDA associated with reporting and undertaking mitigation strategies. Estimated total annual costs of the interactions between industry and FDA range between $14.99 million and $47.62 million. Discounting over 20 years, annual quantified benefits from avoiding the purchase of alternative products, managing product shortages, and life-years gained, would range from $27.56 million to $86.77 million using a 3 percent discount rate, and from $27.50 million to $86.61 million using a 7 percent discount rate. Annualized over 20 years, net benefits range from $12.57 million to $39.15 million using a 3 percent discount rate, and from $12.51 million to $38.99 million using a 7 percent discount rate. The public health benefits, mostly nonquantified, include the value of information that would assist FDA, manufacturers, health care providers, and patients in evaluating, mitigating, and preventing shortages of drugs and biological products that could otherwise result in non-fatal adverse events, errors, delayed patient treatment, or interruption in clinical trial development. The costs and benefits are summarized in table 2. Under the current environment all notifications provide meaningful information to identify a shortage or to prevent one, but there is uncertainty as to whether the scope of the proposed rule could result in notifications that do not provide information about any shortage and lead to additional costs. FDA seeks comments on this issue. The full discussion of economic impacts is available in docket FDA– 2011–N–0898 and at https:// www.fda.gov/AboutFDA/ ReportsManualsForms/Reports/ EconomicAnalyses/default.htm (Ref. 3 of this proposed rule). TABLE 2—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF PROPOSED RULE Category Primary estimate Low estimate High estimate Year dollars Discount rate Period covered Notes There is uncertainty surrounding these estimates since some underlying estimates came from non-representative studies. 20–63 preventable shortages per year. Benefits Annualized Monetized (millions $/year). $57.165 $57.055 $27.556 $27.501 $86.773 $86.609 2012 2012 3% 7% 2014–33 2014–33 Annualized Quantified ................ ................ ................ ................ 3% 7% 2014–33 2014–33 Qualitative .................. Reduction in errors and non-fatal adverse events associated with shortages. Uninterrupted patient access to drugs and biological products necessary for treatment; continued access to drugs used in clinical trial development. Costs Annualized Monetized (millions $/year). $31.306 $31.306 $14.990 $14.990 Annualized Quantified 2012 2012 3% 7% 2014–33 2014–33 There is uncertainty about potential noise from notifications that might not provide meaningful information, but which could result in additional review costs. In addition, these estimates assume that applicants will participate in mitigation or preventive strategies. None estimated. Qualitative .................. $47.621 $47.621 None estimated. Transfers Federal Annualized Monetized (millions $/year). None estimated. Other Annualized Monetized (millions $/year). None estimated. Effects None. Small Business ........... EMCDONALD on DSK67QTVN1PROD with PROPOSALS State, Local or Tribal Gov’t. FDA anticipates that when finalized, small business entities covered by the proposed rule will incur small costs, $224 per notification or up to 0.10 percent of their average annual sales. Although the proposed rule would not require it, some firms may choose to incur additional costs associated with mitigation or prevention strategies. Wages ........................ No estimated effect. Growth ........................ No estimated effect. VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 PO 00000 Frm 00029 Fmt 4702 Sfmt 4702 E:\FR\FM\04NOP1.SGM 04NOP1 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules EMCDONALD on DSK67QTVN1PROD with PROPOSALS VI. Paperwork Reduction Act of 1995 This proposed rule contains collections of information that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501–3520) (the PRA). A description of these provisions is given below with an annual reporting burden. Included in the estimate is the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. FDA invites comments on: (1) Whether the proposed collection of information is necessary for proper performance of FDA’s functions, including whether the information will have practical utility; (2) the accuracy of FDA’s estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used; (3) ways to enhance the quality, utility, and clarity of the information to be collected; and (4) ways to minimize the burden of the collection of information on respondents, including through the use of automated collection techniques, when appropriate, and other forms of information technology. Title: Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products; Proposed Rule Description: Under the proposed rule, applicants with an approved NDA or ANDA for a covered drug product, manufacturers of a covered drug product marketed without an approved application, and applicants with an approved BLA for a covered biological product (including certain applications of blood or blood components) would be required to notify FDA in writing of a permanent discontinuance of the manufacture of the drug or biological product or an interruption in manufacturing of the drug or biological product that is likely to lead to a meaningful disruption in the applicant’s supply (or a significant disruption for blood or blood components) of that product. The notification would be required if the drug or biological product is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including use in emergency medical care or during surgery, and if the drug or biological product is not a radiopharmaceutical drug product. The proposed rule would require the notification to include the following information: (1) The name of the drug or VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 biological product subject to the notification, including the NDC (or, for a biological product that does not have an NDC, an alternative standard for identification and labeling that has been recognized as acceptable by the Center Director); (2) the name of each applicant of the drug or biological product; (3) whether the notification relates to a permanent discontinuance of the drug or biological product or an interruption in manufacturing of the product; (4) a description of the reason for the permanent discontinuance or interruption in manufacturing; and (5) the estimated duration of the interruption in manufacturing. Under the proposed rule, the notification would be required to be submitted to FDA electronically at least 6 months prior to the date of the permanent discontinuance or interruption in manufacturing. If 6 months’ advance notice is not possible because the permanent discontinuance or interruption in manufacturing was unanticipated 6 months in advance, the applicant would be required to notify FDA as soon as practicable, but in no case later than 5 business days after the permanent discontinuance or interruption in manufacturing occurs. If an applicant fails to submit the required notification, the proposed rule would require FDA to issue a letter informing the applicant or manufacturer of its noncompliance. The applicant would be required to submit to FDA, not later than 30 calendar days after FDA issues the letter, a written response setting forth the basis for noncompliance and providing the required notification. Description of Respondents: Applicants of prescription drugs and biological products subject to an approved NDA, ANDA, or BLA, and manufacturers of prescription drug products marketed without an approved ANDA or NDA, if the product is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including use in emergency medical care or during surgery, and is not a radiopharmaceutical product. If the BLA applicant is a manufacturer of blood or blood components, it is only subject to this rule if it manufactures a significant percentage of the nation’s blood supply. Burden Estimates: Based on the number of drug and biological product shortage related notifications we have seen during the past 12 months, we estimate that annually a total of approximately 75 respondents (‘‘number of respondents’’ in table 3) would notify us of a permanent discontinuance of the manufacture of a drug or biological PO 00000 Frm 00030 Fmt 4702 Sfmt 4702 65919 product or an interruption in manufacturing of a drug or biological product that is likely to lead to a meaningful disruption in the respondent’s supply of that product under the proposed rule. We estimate that these respondents would submit annually a total of approximately 305 notifications as required under proposed §§ 310.306, 314.81(b)(3)(iii), and 600.82. Approximately 80 of these notifications are notifications that we currently receive under OMB control number 0910–0699 for the IFR, thus we expect to receive approximately 225 new notifications under the proposed rule (‘‘total annual responses’’ in table 3).10 We estimate three notifications per respondent, because a respondent may experience multiple discontinuances or interruptions in manufacturing in a year that require notification (‘‘no. of responses per respondent’’ in table 3). We also estimate that preparing and submitting these notifications to FDA would take approximately 2 hours per respondent (‘‘hours per response’’ in table 3). We base these estimates on our experience with the reporting of similar information to FDA since the issuance of the President’s Executive Order 13588 of October 31, 2011 (Ref. 1 of this proposed rule), and under the interim final rule entitled ‘‘Applications for Food and Drug Administration Approval To Market a New Drug; Revision of Postmarketing Reporting Requirements—Permanent’’ (76 FR 78530; December 19, 2011), and the draft guidance entitled ‘‘Draft Guidance for Industry on Notification to Food and Drug Administration of Issues That May Result in a Prescription Drug Shortage’’ (77 FR 11550; February 27, 2012). FDA estimates the burden of this collection of information as follows: 10 This estimate is based on the number of new notifications we would receive under the proposed rule as compared to notifications we currently receive under the IFR. The IFR is our baseline for comparison for purposes of estimating the burden under the PRA, because additional notifications that we may currently receive, but that are not required under the IFR (e.g., as requested in the draft guidance for industry on Notification to the Food and Drug Administration of Issues That May Result in a Prescription Drug Shortage) are not covered under any existing OMB control number, and thus must be captured in this PRA estimate. In contrast, the preliminary analysis of impacts of the proposed rule estimates the costs and benefits of the proposed rule as compared to current practice. As a result of the use of different baselines for comparison, the estimate of new notifications under the PRA does not match the estimate of new notifications included in the preliminary analysis of impacts (see Table 2B of Ref. 3, which estimates the number of new notifications we would receive under the proposed rule, as compared to the number of notifications the Agency receives currently, including all voluntary notifications not specifically required by the IFR). E:\FR\FM\04NOP1.SGM 04NOP1 65920 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules TABLE 3—ESTIMATED REPORTING BURDEN 1 Number of respondents Number of responses per respondent Total annual responses Hours per response Total hours 75 3 225 2 450 Notifications required under proposed §§ 310.306 (unapproved drugs), 314.81(b)(3)(iii) (products approved under an NDA or ANDA), and 600.82 (products approved under a BLA) ........................................................ 1 There are no capital costs or operating and maintenance costs associated with this information collection. The information collection provisions of this proposed rule have been submitted to OMB for review. Interested persons are requested to fax comments regarding the information collection by December 4, 2013, to the Office of Information and Regulatory Affairs, OMB. 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: 202–395–7245, or emailed to oira_ submission@omb.eop.gov. All comments should be identified with the title of this information collection and should include the FDA docket number found in brackets in the heading of this document. EMCDONALD on DSK67QTVN1PROD with PROPOSALS VII. Federalism FDA has analyzed this proposed rule in accordance with the principles set forth in Executive Order 13132. FDA has determined that the proposed rule, if finalized, does not contain policies that have substantial direct effects on the States, on the relationship between the National Government and the States, or on the distribution of power and responsibilities among the various levels of government. Accordingly, the Agency tentatively concludes that the proposed rule does not contain policies that have federalism implications as defined in the Executive order and, consequently, a federalism summary impact statement is not required. VIII. Environmental Impact The Agency has determined under 21 CFR 25.30(h) that this action is of a type that does not individually or cumulatively have a significant effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required. IX. Comments Interested persons may submit either electronic comments regarding this document to https://www.regulations.gov or written comments to the Division of Dockets Management (see ADDRESSES). It is only necessary to send one set of VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 comments. Identify comments with the docket number found in brackets in the heading of this document. Received comments may be seen in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday, and will be posted to the docket at https:// www.regulations.gov. devices, Reporting and recordkeeping requirements. X. References 21 CFR Part 600 The following references have been placed on display in the Division of Dockets Management (see ADDRESSES) and may be seen by interested persons between 9 a.m. and 4 p.m., Monday through Friday, and are available electronically at https:// www.regulations.gov. (FDA has verified all the Web site addresses in this reference section, but we are not responsible for any subsequent changes to the Web sites after this document publishes in the Federal Register). Biologics, Reporting and recordkeeping requirements. 21 CFR Part 314 Administrative practice and procedure, Confidential business information, Drugs, Reporting and recordkeeping requirements. Therefore, under the Federal Food, Drug, and Cosmetic Act, the Public Health Service Act, and under authority delegated to the Commissioner of Food and Drugs, it is proposed that 21 CFR parts 20, 310, 314, and 600 be amended as follows: PART 20—PUBLIC INFORMATION 1. The authority citation for 21 CFR part 20 continues to read as follows: 1. Executive Order 13588, Reducing Prescription Drug Shortages, October 31, 2011, available at https://www.gpo.gov/ fdsys/pkg/FR-2011-11-03/pdf/201128728.pdf, accessed November 2012. 2. Center for Drug Evaluation and Research, Manual of Policies and Procedures 6003.1, Drug Shortage Management, September 26, 2006, available at https:// www.fda.gov/downloads/AboutFDA/ CentersOffices/CDER/ ManualofPoliciesProcedures/ ucm079936.pdf, accessed November 2012. 3. Preliminary Regulatory Impact Analysis, Initial Regulatory Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products; Proposed Rule, available at https:// www.fda.gov/AboutFDA/ ReportsManualsForms/Reports/ EconomicAnalyses/default.htm. ■ List of Subjects PART 310—NEW DRUGS 21 CFR Part 20 ■ Confidential business information, Courts, Freedom of information, Government employees. 21 CFR Part 310 Administrative practice and procedure, Drugs, Labeling, Medical PO 00000 Frm 00031 Fmt 4702 Sfmt 4702 Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531–2582; 21 U.S.C. 321–393; 1401– 1403; 42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263, 263b–263n, 264, 265, 300u– 300u–5, 300aa–1. 2. Revise § 20.100 by adding paragraph (c)(45) to read as follows: ■ § 20.100 Applicability; cross-reference to other regulations. * * * * * (c) * * * (45) Postmarket notifications of a permanent discontinuance or an interruption in manufacturing of certain drugs or biological products, in §§ 310.306, 314.81(b)(3)(iii), and 600.82 of this chapter. 3. The authority citation for 21 CFR part 310 is revised to read as follows: Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356c, 356e, 360b–360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 263b–263n. 4. Add § 310.306 to subpart D to read as follows: ■ E:\FR\FM\04NOP1.SGM 04NOP1 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules § 310.306 Notification of a permanent discontinuance or an interruption in manufacturing of marketed prescription drugs for human use without approved new drug applications. (a) Applicability. Marketed prescription drug products that are not the subject of an approved new drug or abbreviated new drug application are subject to this section. (b) Notification of a permanent discontinuance or an interruption in manufacturing. The manufacturer of each product subject to this section must make the notifications required under § 314.81(b)(3)(iii) of this chapter and otherwise comply with § 314.81(b)(3)(iii) of this chapter. If the manufacturer of a product subject to this section fails to provide notification as required under § 314.81(b)(3)(iii), FDA will send a letter to the manufacturer and otherwise follow the procedures set forth under § 314.81(b)(3)(iii)(e). (c) Drug Shortages List. FDA will include on the drug shortages list required by § 314.81(b)(3)(iii)(d) drug products that are subject to this section that it determines to be in shortage. For such drug products, FDA will provide the names of each manufacturer rather than the names of each applicant. With respect to information collected under this paragraph FDA will observe the confidentiality and disclosure provisions set forth in § 314.81(b)(3)(iii)(d)(2). PART 314—APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG 5. The authority citation for 21 CFR part 314 is revised to read as follows: ■ Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a, 356b, 356c, 356e, 371, 374, 379e. 6. Revise § 314.81 paragraph (b)(3)(iii) to read as follows: ■ § 314.81 Other postmarketing reports. EMCDONALD on DSK67QTVN1PROD with PROPOSALS * * * * * (b) * * * (3) * * * (iii) Notification of a permanent discontinuance or an interruption in manufacturing. (a) An applicant of a prescription drug product must notify FDA in writing of a permanent discontinuance of manufacture of the drug product or an interruption in manufacturing of the drug product that is likely to lead to a meaningful disruption in supply of that drug in the United States if: (1) The drug product is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such drug used in VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 emergency medical care or during surgery; and (2) The drug product is not a radiopharmaceutical drug product. (b) Notifications required by paragraph (b)(3)(iii)(a) of this section must be submitted to FDA electronically in a format that FDA can process, review, and archive: (1) At least 6 months prior to the date of the permanent discontinuance or interruption in manufacturing; or (2) If 6 months’ advance notice is not possible because the permanent discontinuance or interruption in manufacturing was not reasonably anticipated 6 months in advance, as soon as practicable thereafter, but in no case later than 5 business days after the permanent discontinuance or interruption in manufacturing occurs. (c) Notifications required by paragraph (b)(3)(iii)(a) of this section must include the following information: (1) The name of the drug subject to the notification, including the NDC for such drug; (2) The name of the applicant; (3) Whether the notification relates to a permanent discontinuance of the drug or an interruption in manufacturing of the drug; (4) A description of the reason for the permanent discontinuance or interruption in manufacturing; and (5) The estimated duration of the interruption in manufacturing. (d)(1) FDA will maintain a publicly available list of drugs that are determined by FDA to be in shortage. This drug shortages list will include the following information: (i) The names and NDC(s) for such drugs; (ii) The name of each applicant for such drugs; (iii) The reason for the shortage, as determined by FDA from the following categories: Requirements related to complying with good manufacturing practices; regulatory delay; shortage of an active ingredient; shortage of an inactive ingredient component; discontinuation of the manufacture of the drug; delay in shipping of the drug; demand increase for the drug; or other reason; and (iv) The estimated duration of the shortage. (2) FDA may choose not to make information collected to implement this paragraph available on the drug shortages list or available under section 506C(c) of the FD&C Act if FDA determines that disclosure of such information would adversely affect the public health (such as by increasing the possibility of hoarding or other disruption of the availability of drug to PO 00000 Frm 00032 Fmt 4702 Sfmt 4702 65921 patients). FDA will also not provide information on the public drug shortages list or under section 506C(c) of the FD&C Act that is protected by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4), including trade secrets and commercial or financial information that is considered confidential or privileged under § 20.61. (e) If an applicant fails to submit a notification as required under paragraph (b)(3)(iii)(a) of this section and in accordance with paragraph (b)(3)(iii)(b) of this section, FDA will issue a letter to the applicant informing it of such failure. (1) Not later than 30 calendar days after the issuance of such a letter, the applicant must submit to FDA a written response setting forth the basis for noncompliance and providing the required notification under paragraph (b)(3)(iii)(a) of this section and including the information required under paragraph (b)(3)(iii)(c) of this section; and (2) Not later than 45 calendar days after the issuance of a letter under paragraph (b)(3)(iii)(e) of this section, FDA will make the letter and the applicant’s response to the letter public, unless, after review of the applicant’s response, FDA determines that the applicant had a reasonable basis for not notifying FDA as required under paragraph (b)(3)(iii)(a) of this section. (f) The following definitions of terms apply to paragraph (b)(3)(iii) of this section: Drug shortage or shortage means a period of time when the demand or projected demand for the drug within the United States exceeds the supply of the drug. Intended for use in the prevention or treatment of a debilitating disease or condition means a drug product intended for use in the prevention or treatment of a disease or condition associated with mortality or morbidity that has a substantial impact on day-today functioning. Life supporting or life sustaining means a drug product that is essential to, or that yields information that is essential to, the restoration or continuation of a bodily function important to the continuation of human life. Meaningful disruption means a change in production that is reasonably likely to lead to a reduction in the supply of a drug by a manufacturer that is more than negligible and affects the ability of the manufacturer to fill orders or meet expected demand for its product, and does not include interruptions in manufacturing due to matters such as routine maintenance or E:\FR\FM\04NOP1.SGM 04NOP1 65922 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time. * * * * * § 314.91 ■ [Removed] 7. Remove § 314.91. PART 600—BIOLOGICAL PRODUCTS: GENERAL 8. The authority citation for 21 CFR part 600 is revised to read as follows: ■ Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356c, 356e, 360, 360i, 371, 374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa–25. 9. Add § 600.82 to subpart D to read as follows: ■ EMCDONALD on DSK67QTVN1PROD with PROPOSALS § 600.82 Notification of a permanent discontinuance or an interruption in manufacturing. (a) Notification of a permanent discontinuance or an interruption in manufacturing. (1) An applicant of a biological product, other than blood or blood components for transfusion, which is licensed under section 351 of the Public Health Service Act, and which may be dispensed only under prescription under section 503(b)(1) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 353(b)(1)), must notify FDA in writing of a permanent discontinuance of manufacture of the biological product or an interruption in manufacturing of the biological product that is likely to lead to a meaningful disruption in supply of that biological product in the United States if: (i) The biological product is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such biological product used in emergency medical care or during surgery; and (ii) The biological product is not a radiopharmaceutical biological product. (2) An applicant of blood or blood components for transfusion, which is licensed under section 351 of the Public Health Service Act, and which may be dispensed only under prescription under section 503(b) of the Federal Food, Drug, and Cosmetic Act, must notify FDA in writing of a permanent discontinuance of manufacture of any product listed in its license or an interruption in manufacturing of any such product that is likely to lead to a significant disruption in supply of that product in the United States if: (i) The product is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 product used in emergency medical care or during surgery; and (ii) The applicant is a manufacturer of a significant percentage of the U.S. blood supply. (b) Submission and timing of notification. Notifications required by paragraph (a) of this section must be submitted to FDA electronically in a format that FDA can process, review, and archive: (1) At least 6 months prior to the date of the permanent discontinuance or interruption in manufacturing; or (2) If 6 months’ advance notice is not possible because the permanent discontinuance or interruption in manufacturing was not reasonably anticipated 6 months in advance, as soon as practicable thereafter, but in no case later than 5 business days after such a permanent discontinuance or interruption in manufacturing occurs. (c) Information included in notification. Notifications required by paragraph (a) of this section must include the following information: (1) The name of the biological product subject to the notification, including the National Drug Code for such biological product, or an alternative standard for identification and labeling that has been recognized as acceptable by the Center Director; (2) The name of the applicant of the biological product; (3) Whether the notification relates to a permanent discontinuance of the biological product or an interruption in manufacturing of the biological product; (4) A description of the reason for the permanent discontinuance or interruption in manufacturing; and (5) The estimated duration of the interruption in manufacturing. (d)(1) Public list of biological product shortages. FDA will maintain a publicly available list of biological products that are determined by FDA to be in shortage. This biological product shortages list will include the following information: (i) The names and National Drug Codes for such biological products, or the alternative standards for identification and labeling that have been recognized as acceptable by the Center Director; (ii) The name of each applicant for such biological products; (iii) The reason for the shortage, as determined by FDA, selecting from the following categories: Requirements related to complying with good manufacturing practices; regulatory delay; shortage of an active ingredient; shortage of an inactive ingredient component; discontinuation of the manufacture of the biological product; PO 00000 Frm 00033 Fmt 4702 Sfmt 4702 delay in shipping of the biological product; demand increase for the biological product; or other reason; and (iv) The estimated duration of the shortage. (2) Confidentiality. FDA may choose not to make information collected to implement this paragraph available on the biological product shortages list or available under section 506C(c) of the FD&C Act if FDA determines that disclosure of such information would adversely affect the public health (such as by increasing the possibility of hoarding or other disruption of the availability of the biological product to patients). FDA will also not provide information on the public shortages list or under section 506C(c) of the FD&C Act that is protected by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4), including trade secrets and commercial or financial information that is considered confidential or privileged under § 20.61 of this chapter. (e) Noncompliance letters. If an applicant fails to submit a notification as required under paragraph (a) of this section and in accordance with paragraph (b) of this section, FDA will issue a letter to the applicant informing it of such failure. (1) Not later than 30 calendar days after the issuance of such a letter, the applicant must submit to FDA a written response setting forth the basis for noncompliance and providing the required notification under paragraph (a) of this section and including the information required under paragraph (c) of this section; and (2) Not later than 45 calendar days after the issuance of a letter under this paragraph, FDA will make the letter and the applicant’s response to the letter public, unless, after review of the applicant’s response, FDA determines that the applicant had a reasonable basis for not notifying FDA as required under paragraph (a) of this section. (f) Definitions. The following definitions of terms apply to this section: Biological product shortage or shortage means a period of time when the demand or projected demand for the biological product within the United States exceeds the supply of the biological product. Intended for use in the prevention or treatment of a debilitating disease or condition means a biological product intended for use in the prevention or treatment of a disease or condition associated with mortality or morbidity that has a substantial impact on day-today functioning. Life supporting or life sustaining means a biological product that is E:\FR\FM\04NOP1.SGM 04NOP1 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules essential to, or that yields information that is essential to, the restoration or continuation of a bodily function important to the continuation of human life. Meaningful disruption means a change in production that is reasonably likely to lead to a reduction in the supply of a biological product by a manufacturer that is more than negligible and affects the ability of the manufacturer to fill orders or meet expected demand for its product, and does not include interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time. Significant disruption means a change in production that is reasonably likely to lead to a reduction in the supply of blood or blood components by a manufacturer that substantially affects the ability of the manufacturer to fill orders or meet expected demand for its product, and does not include interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time. Dated: October 28, 2013. Leslie Kux, Assistant Commissioner for Policy. [FR Doc. 2013–25956 Filed 10–31–13; 11:15 am] BILLING CODE 4160–01–P DEPARTMENT OF JUSTICE Drug Enforcement Administration 21 CFR Part 1308 [Docket No. DEA–351] Schedules of Controlled Substances: Placement of Tramadol Into Schedule IV Drug Enforcement Administration, Department of Justice. ACTION: Notice of proposed rulemaking. AGENCY: The Drug Enforcement Administration (DEA) proposes to place the substance 2((dimethylamino)methyl)-1-(3methoxyphenyl)cyclohexanol, its salts, isomers, salts of isomers, and all isomeric configurations of possible forms including tramadol (the term ‘‘isomers’’ includes the optical and geometric isomers) into Schedule IV of the Controlled Substances Act (CSA). This proposed action is based on a recommendation from the Assistant EMCDONALD on DSK67QTVN1PROD with PROPOSALS SUMMARY: VerDate Mar<15>2010 16:13 Nov 01, 2013 Jkt 232001 Secretary for Health of the Department of Health and Human Services (HHS) and an evaluation of all other relevant data by the DEA. If finalized, this action would impose the regulatory controls and administrative, civil, and criminal sanctions applicable to Schedule IV controlled substances on persons who handle (manufacture, distribute, dispense, import, export, engage in research, conduct instructional activities, or possess) or propose to handle tramadol. DATES: Interested persons may file written comments on this proposal pursuant to 21 CFR 1308.43(g). Electronic comments must be submitted, and written comments must be postmarked, on or before January 3, 2014. Commenters should be aware that the electronic Federal Docket Management System will not accept comments after midnight Eastern Time on the last day of the comment period. Interested persons, defined as those ‘‘adversely affected or aggrieved by any rule or proposed rule issuable pursuant to section 201 of the Act (21 U.S.C. 811),’’ 21 CFR 1300.01, may file a request for hearing pursuant to 21 CFR 1308.44 and in accordance with 21 CFR 1316.45 and 1316.47. Requests for hearing, notices of appearance, and waivers of an opportunity for a hearing or to participate in a hearing must be received on or before December 4, 2013. ADDRESSES: To ensure proper handling of comments, please reference ‘‘Docket No. DEA–351’’ on all electronic and written correspondence. The DEA encourages that all comments be submitted electronically through the Federal eRulemaking Portal, which provides the ability to type short comments directly into the comment field on the Web page or attach a file for lengthier comments. Go to https:// www.regulations.gov and follow the online instructions at that site for submitting comments. An electronic copy of this document and supplemental information to this proposed rule are also available at the https://www.regulations.gov Web site for easy reference. Paper comments that duplicate electronic submissions are not necessary. All comments submitted to https://www.regulations.gov will be posted for public review and are part of the official docket record. Should you, however, wish to submit written comments in lieu of electronic comments, they should be sent via regular or express mail to: Drug Enforcement Administration, Attention: DEA Federal Register Representative/ ODW, 8701 Morrissette Drive, Springfield, Virginia 22152. All requests PO 00000 Frm 00034 Fmt 4702 Sfmt 4702 65923 for hearing must be sent to Drug Enforcement Administration, Attention: Hearing Clerk/LJ, 8701 Morrissette Drive, Springfield, Virginia 22152. FOR FURTHER INFORMATION CONTACT: Ruth A. Carter, Chief, Policy Evaluation and Analysis Section, Office of Diversion Control, Drug Enforcement Administration, 8701 Morrissette Drive, Springfield, Virginia 22152; Telephone (202) 598–6812. Posting of Public Comments: Please note that comments received in response to this NPRM are considered part of the public record and will be made available for public inspection and posted at https:// www.regulations.gov and in the DEA’s public docket. Such information includes personal identifying information (such as your name, address, etc.) voluntarily submitted by the commenter. If you want to submit personal identifying information (such as your name, address, etc.) as part of your comment, but do not want it to be made public, you must include the phrase ‘‘PERSONAL IDENTIFYING INFORMATION’’ in the first paragraph of your comment. You must also place all of the personal identifying information you do not want to be made publicly available in the first paragraph of your comment and identify what information you want redacted. If you want to submit confidential business information as part of your comment, but do not want it to be made publicly available, you must include the phrase ‘‘CONFIDENTIAL BUSINESS INFORMATION’’ in the first paragraph of your comment. You must also prominently identify confidential business information to be redacted within the comment. If a comment has so much confidential business information that it cannot be effectively redacted, all or part of that comment may not be made publicly available. Comments containing personal identifying information and confidential business information identified and located as set forth above will be made available in redacted form. The Freedom of Information Act (FOIA) applies to all comments received. If you wish to personally inspect the comments and materials received or the supporting documentation the DEA used in preparing the proposed action, these materials will be available for public inspection by appointment. To arrange a viewing, please see the FOR FURTHER INFORMATION CONTACT paragraph, above. SUPPLEMENTARY INFORMATION: E:\FR\FM\04NOP1.SGM 04NOP1

Agencies

[Federal Register Volume 78, Number 213 (Monday, November 4, 2013)]
[Proposed Rules]
[Pages 65904-65923]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-25956]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 310, 314, and 600

[Docket No. FDA-2011-N-0898]
RIN 0910-AG88

Permanent Discontinuance or Interruption in Manufacturing of
Certain Drug or Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; request for comments.

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

SUMMARY: The Food and Drug Administration (FDA or the Agency) is
proposing to amend its regulations to implement certain drug shortages
provisions of the Federal Food, Drug, and Cosmetic Act (the FD&C Act),
as amended by the Food and Drug Administration Safety and Innovation
Act (FDASIA). The proposed rule would require all applicants of covered
approved drugs or biological products--including certain applicants of
blood or blood components for transfusion and all manufacturers of
covered drugs marketed without an approved application--to notify FDA
electronically of a permanent discontinuance or an interruption in
manufacturing of the product that is likely to lead to a meaningful
disruption in supply (or a significant disruption in supply for blood
or blood components) of the product in the United States.

DATES: Submit either electronic or written comments on the provisions
of this proposed rule by January 3, 2014. Submit comments on the
information collection requirements under the Paperwork Reduction Act
of 1995 (the PRA) by December 4, 2013 (see the ``Paperwork Reduction
Act of 1995'' section).

ADDRESSES: You may submit comments, identified by Docket No. FDA-2011-
N-0898 by any of the following methods, except that comments on
information collection issues under the PRA must be submitted to the
Office of Information and Regulatory Affairs, Office of Management and
Budget (OMB) (see the ``Paperwork Reduction Act of 1995'' section).

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions:

Submit written submissions in the following ways:
Mail/Hand delivery/Courier (for paper or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the Agency name
and Docket No. 2011-N-0898 for this rulemaking. All comments received
may be posted without change to https://www.regulations.gov, including
any personal information provided. For additional information on
submitting comments, see the ``Comments'' heading of the SUPPLEMENTARY
INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to https://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Kalah Auchincloss, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6208, Silver Spring, MD 20993, 301-796-
0659; or Stephen Ripley, Center for Biologics Evaluation and Research,
Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-
1448, 301-827-6210.

Table of Contents

I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Summary of the Costs and Benefits of the Proposed Rule
II. Introduction
III. Description of the Proposed Rule
A. Persons Subject to the Proposed Rule
B. Products Subject to the Proposed Rule
C. Notification of a Permanent Discontinuance or an Interruption
in Manufacturing
IV. Legal Authority
V. Analysis of Impacts
A. Introduction
B. Summary
VI. Paperwork Reduction Act of 1995
VII. Federalism
VIII. Environmental Impact
IX. Comments
X. References

SUPPLEMENTARY INFORMATION:

I. Executive Summary

A. Purpose of the Proposed Rule

FDASIA (Pub. L. 112-144) significantly amended provisions in the
FD&C Act related to drug shortages. Among other things, FDASIA amended
section 506C of the FD&C Act (21 U.S.C. 356c) to require all
manufacturers of certain drugs to notify FDA of a permanent
discontinuance or an interruption in manufacturing of these drugs 6
months in advance of the permanent discontinuance or interruption in
manufacturing, or as soon practicable. FDASIA also added section 506E
to the FD&C Act (21 U.S.C. 356e) requiring FDA to maintain a current
list of drugs that are determined by FDA to be in shortage in the
United States, and to include on that public list certain information
about those shortages. Finally, FDASIA permits FDA to apply section
506C to biological products by regulation, and requires FDA to issue a
final rule implementing

[[Page 65905]]

certain drug shortages provisions in FDASIA by January 9, 2014.
In accordance with FDASIA, FDA is issuing this proposed rule, which
we believe will improve FDA's ability to identify potential drug
shortages and to prevent or mitigate the impact of these shortages.

B. Summary of the Major Provisions of the Proposed Rule

The proposed rule would modify FDA's regulations to implement
sections 506C and 506E of the FD&C Act as amended by FDASIA.
Proposed Sec. Sec. 310.306, 314.81(b)(3)(iii) (21 CFR
314.81(b)(3)(iii)), and 600.82 would require all applicants of certain
approved drugs or biological products,\1\ including applicants of blood
or blood components for transfusion (``blood or blood components'')
that manufacture a significant percentage of the U.S. blood supply, and
all manufacturers of certain drugs marketed without an approved
application (``unapproved drug manufacturers''), to notify FDA
electronically of a permanent discontinuance or an interruption in
manufacturing of the product that is likely to lead to a meaningful
disruption in supply (for drugs and biological products other than
blood or blood components) or a significant disruption in supply (for
blood or blood components) of the product in the United States.
Applicants \2\ would be required to notify FDA of a permanent
discontinuance or an interruption in supply if the drug or biological
product is a prescription product that is life supporting, life
sustaining, or intended for use in the prevention or treatment of a
debilitating disease or condition, including any such drug used in
emergency medical care or during surgery, and excluding
radiopharmaceutical products (referred to in this document as
``covered'' drugs or biological products). The proposed rule would
require notification to FDA at least 6 months prior to date of the
permanent discontinuance or interruption in manufacturing, or, if 6
months' advance notice is not possible, as soon as practicable
thereafter, but in no case later than 5 business days after the
permanent discontinuance or interruption in manufacturing occurs.
---------------------------------------------------------------------------

\1\ As used throughout this preamble, the term ``biological
product'' refers to a biological product licensed under section 351
of the Public Health Service Act, other than a biological product
that also meets the definition of a device in section 201(h) of the
FD&C Act (21 U.S.C. 321(h)).
\2\ In this document, for the sake of convenience, we
collectively refer to applicants holding an abbreviated new drug
application (ANDA), new drug application (NDA), or biologics license
application (BLA) and unapproved drug manufacturers subject to this
proposed rule as the ``applicant'' (although we recognize that an
unapproved drug manufacturer is not an applicant). We may also
individually refer to the ANDA, NDA, and BLA applicant or unapproved
drug manufacturer as needed, if the context requires distinguishing
between these entities.
---------------------------------------------------------------------------

The proposed rule would also require FDA to issue a public
noncompliance letter to an applicant for failure to notify FDA under
the proposed rule; specify minimum information that must be included in
the notification; codify FDA's current practice of publicly
disseminating information on shortages and maintaining public lists of
drugs and biological products in shortage (subject to certain
confidentiality protections); and define the terms, ``drug shortage,''
``biological product shortage,'' ``meaningful disruption,''
``significant disruption,'' ``life supporting or life sustaining,'' and
``intended for use in the prevention or treatment of a debilitating
disease or condition.''
Finally, the proposed rule would include a technical revision to
Sec. 20.100 (21 CFR 20.100) (public disclosure regulations) to include
a cross-reference to the disclosure provisions in in Sec. Sec.
310.306, 314.81, and 600.82; and would remove Sec. 314.91 (21 CFR
314.91) related to reducing the 6-month notification period for ``good
cause,'' since it is no longer applicable under the FDASIA-revised
section 506C.

C. Summary of the Costs and Benefits of the Proposed Rule

The proposed rule would impose annual reporting costs of up to
$16,576 on those applicants affected by the rule, and up to $441,000 on
FDA in review costs. Undertaking mitigation strategies, as measured by
labor resources, is estimated to cost FDA between $2.44 and $7.84
million, and industry between $3.86 and $12.43 million. We also
estimate annual costs for industry between $8.54 and $26.89 million
associated with increasing production. Estimated total annual costs of
the interactions between industry and FDA range between $14.99 and
$47.62 million. Discounting over 20 years, annual quantified benefits
from avoiding the purchase of alternative products, managing product
shortages, and life-years gained, would range from $27.56 million to
$86.77 million using a 3 percent discount rate, and from $27.50 million
to $86.61 million using a 7 percent discount rate. The public health
benefits, mostly nonquantified, include the value of information that
would assist FDA, manufacturers, health care providers, and patients in
evaluating, mitigating, and preventing shortages of drugs and
biological products that could otherwise result in delayed patient
treatment or interruption in clinical trial development.

II. Introduction

Recent experience with shortages of drugs and biological products
in the United States has shown the serious and immediate effects they
can have on patients and health care providers. According to
information from FDA's drug and biological product shortages databases,
the number of drug and biological product shortages quadrupled from
approximately 61 in 2005 to more than 250 shortages in 2011. Although
the number of drug shortages significantly decreased in 2012 to 117
shortages, drug and biological product shortages still represent an
ongoing challenge to public health.\3\ Shortages can involve critical
drugs used to treat cancer, to provide required parenteral nutrition,
or to address other serious medical conditions and can delay or deny
needed care for patients. Shortages can also result in providers
prescribing second-line alternatives, which may be less effective or
higher risk than first-line therapies.
---------------------------------------------------------------------------

\3\ Information on drug shortages can be found at https://www.fda.gov/drugs/drugsafety/drugshortages/default.htm (drug
shortages) and https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm (biological product
shortages).
---------------------------------------------------------------------------

Preventing drug and biological product shortages is a top priority
for FDA. Working closely with manufacturers and other stakeholders, FDA
was able to help prevent just under 200 drug and biological product
shortages in 2011 and more than 280 such shortages in 2012, using tools
such as:
Working with manufacturers to resolve manufacturing and
quality issues contributing to short supply.
Expediting FDA inspections and reviews of submissions from
manufacturers to prevent and/or alleviate shortages.
Identifying and working with manufacturers willing to
initiate or increase production to cover expected gaps in supply.
Exercising enforcement discretion in appropriate
circumstances, if this would not cause undue risk to patients.
In response to the increasing concerns about the impact of
shortages on health care in the United States, on October 31, 2011,
President Obama issued Executive Order 13588 directing FDA to ``take
steps that will help to prevent and reduce current and future
disruptions in the supply of lifesaving medicines'' and noting that
``one important step is

[[Page 65906]]

ensuring that FDA and the public receive adequate advance notice of
shortages whenever possible'' (Ref. 1 of this proposed rule). In
response to the Executive Order's directive to address the growing
problem of drug shortages, FDA published an interim final rule (IFR) on
December 19, 2011 (effective January 18, 2012), modifying the
regulation at Sec. 314.81 related to drug shortages (76 FR 78530). As
a result of the Executive Order and IFR, early notifications to FDA of
potential shortages increased from an average of 10 a month before the
Executive Order to approximately 60 a month in the months after the
IFR. This dramatic increase in early notifications enabled FDA to work
with manufacturers to successfully prevent numerous shortages. As we
stated above, FDA was able to prevent just under 200 drug and
biological product shortages in 2011 and more than 280 such shortages
in 2012. Moreover, the number of new drug shortages decreased from more
than 250 in 2011 to 117 in 2012--a 50 percent reduction.
In July 2012, FDASIA amended the FD&C Act to modify existing drug
shortages requirements and to add new drug shortages provisions. This
rule proposes to implement the drug shortages provisions of FDASIA,
and, when final, will supersede the IFR. Although many of the issues
raised by the 11 comments we received on the IFR are no longer directly
applicable to this rulemaking given the changes to the underlying
statute made by FDASIA, when drafting this proposed rule we considered
these comments to the extent that they were applicable.\4\ Where
appropriate, we have summarized and responded to the IFR comments in
this preamble.
---------------------------------------------------------------------------

\4\ The IFR comments are available electronically at https://www.regulations.gov, Docket No. FDA-2011-N-0898, or can be obtained
in person at the Division of Dockets Management, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
---------------------------------------------------------------------------

III. Description of the Proposed Rule

Section 1001 of FDASIA made substantial changes to section 506C of
the FD&C Act related to reporting and addressing ``permanent
discontinuances'' or ``interruptions in manufacturing'' of certain drug
products. Most significantly for purposes of this proposed rule,
section 506C of the FD&C Act as amended:
Requires all manufacturers of a prescription drug that is
life supporting, life sustaining, or intended for use in the prevention
or treatment of a debilitating disease or condition, including any such
drug used in emergency medical care or during surgery, and excluding
radiopharmaceutical products, to notify FDA of a permanent
discontinuance in the manufacture of the drug or an interruption in the
manufacturing of the drug that is likely to lead to a meaningful
disruption in the supply of that drug in the United States at least 6
months prior to the date of the permanent discontinuance or
interruption in manufacturing, or, if that is not possible, as soon as
practicable.
Requires the manufacturer to include in the notification
the reason for the permanent discontinuance or interruption in
manufacturing.
Requires FDA to issue a letter to a ``person'' who fails
to comply with the notification requirements in section 506C.
Defines the terms ``drug,'' ``drug shortage,'' and
``meaningful disruption,'' and requires FDA to define the terms ``life
supporting,'' ``life sustaining,'' and ``intended for use in the
prevention or treatment of a debilitating disease or condition.''
Permits FDA to apply section 506C to biological products,
including vaccines and plasma-derived products and their recombinant
analogs, if FDA determines the inclusion would benefit public health,
taking into account existing supply reporting programs and aiming to
reduce duplicative notifications.
Requires FDA to distribute information on drug shortages
to the public, to the maximum extent possible, subject to certain
confidentiality protections.
In addition to modifying section 506C, FDASIA added several new
drug shortage-related sections to the FD&C Act, including section 506E.
Section 506E of the FD&C Act requires FDA to maintain an up-to-date
list of drugs that are determined by FDA to be in shortage, including
the names and the National Drug Codes (NDCs) of such drugs in shortage,
the name of each manufacturer of the drug, the reason for each shortage
as determined by FDA (choosing from a list of reasons enumerated in the
statute), and the estimated duration of each shortage. Section 506E of
the FD&C Act also includes confidentiality provisions.
This rule proposes to implement sections 506C and 506E of the FD&C
Act by amending Sec. 314.81(b)(3)(iii) (permanent discontinuance or
interruption in manufacturing of approved prescription drugs) and Sec.
20.100 (cross-reference to disclosure provisions); adding new Sec.
310.306 (permanent discontinuance or interruption in manufacturing of
marketed prescription unapproved new drugs) and Sec. 600.82 (permanent
discontinuance or interruption in manufacturing of prescription
biological products); and removing Sec. 314.91 (reduction in the
discontinuance notification period). Table 1 compares the proposed rule
to the current regulation (IFR).
---------------------------------------------------------------------------

\5\ With respect to blood and blood components for transfusion,
the reporting requirement applies only to an applicant that
manufactures a significant percentage of the U.S. blood supply.

Table 1--Current Regulation (IFR) Compared With Proposed Rule
------------------------------------------------------------------------
Current
Requirement regulation (IFR) Proposed rule
------------------------------------------------------------------------
Scope of products subject to Sec. Sec. 310.306.
notification requirements. 314.81(b)(3)(iii Sec.
)(a). 314.81(b)(3)(ii
i)(a) and (f).
Sec. 600.82(a)
and (f).
A drug product All prescription
approved under drugs and
an NDA or ANDA biological
that is: products,
Life including
supporting, life marketed
sustaining or unapproved
intended for use prescription
in the drugs, that
prevention of a are:
serious disease Life
or condition; supporting,
and. life sustaining
Not or intended for
originally use in the
derived from prevention or
human tissue and treatment of a
replaced by a debilitating
recombinant disease or
product.. condition,
including any
such drug used
in emergency
medical care or
during surgery;
and
That
are not
radiopharmaceut
ical
products.\5\

[[Page 65907]]

The terms ``life
supporting or
life
sustaining''
and ``intended
for use in the
prevention or
treatment of a
debilitating
disease or
condition'' are
defined in the
proposed rule.
What triggers notification......... Sec. Sec.
314.81(b)(3)(iii 314.81(b)(3)(ii
)(a) and (d). i)(a) and (f).
Sec.
600.82(a)(1)
and (f).
A For products
``discontinuance other than
,'' defined as blood or blood
``any components, a
interruption in ``permanent
manufacturing . discontinuance'
. . that could ' or an
lead to a ``interruption
potential in
disruption in manufacturing
supply of the that is likely
drug product [in to lead to a
the United meaningful
States], whether disruption in
the interruption supply of the
is intended to product in the
be temporary or United
permanent''. States'';
``meaningful
disruption'' is
defined in the
statute and the
proposed rule.
Sec.
600.82(a)(2)
and (f).
For blood or
blood
components, a
``permanent
discontinuance'
' or an
``interruption
in
manufacturing
that is likely
to lead to a
significant
disruption in
supply of the
product in the
United
States'';
``significant
disruption'' is
defined in the
proposed rule.
Who must notify FDA................ Sec. Sec.
314.81(b)(3)(iii 314.81(b)(3)(ii
)(a) and (d). i)(a).
Sec.
600.82(a).
Applicants who All applicants
are sole for covered,
manufacturers of approved drugs
covered drugs; and biological
sole products (other
manufacturer is than blood or
defined in the blood
regulation. components),
all applicants
for blood or
blood
components that
manufacture a
significant
percentage of
the U.S. blood
supply, and all
manufacturers
of covered
drugs marketed
without an
approved
application.
When to notify FDA................. Sec. Sec.
314.81(b)(3)(iii 314.81(b)(3)(ii
)(a). i)(b).
Sec.
600.82(b).
At least 6 months
prior to the
discontinuance.
Sec. 314.91.... At
Applicants may least 6 months
seek, and FDA prior to the
may grant, a permanent
reduction in the discontinuance
6-month or interruption
notification in
period for manufacturing;
``good cause.''. or
If
notification at
least 6 months
prior is
impossible,
``as soon as
practicable,''
which is
further
described in
the proposed
rule.
Deletes
Sec. 314.91
in its
entirety,
because it is
no longer
applicable
under section
506C of the
FD&C Act as
amended by
FDASIA.
How to notify FDA.................. Sec. Sec.
314.81(b)(3)(iii 314.81(b)(3)(ii
)(b). i)(b).
Sec.
600.82(b).
Electronically or Electronically
by phone, in a format FDA
according to can process,
instructions on review, and
FDA's drug archive.
shortages Web
page.
What to include in the notification Not specified.... Sec.
314.81(b)(3)(ii
i)(c).
Sec.
600.82(c).
Name,
NDC (or, for
certain
biological
products, an
alternative, as
applicable),
and applicant
of the product;
Whether
the
notification is
a permanent
discontinuance
or an
interruption in
manufacturing;
A
description of
the reason for
the permanent
discontinuance
or interruption
in
manufacturing;
and Estimated
duration of the
interruption in
manufacturing.
Dissemination of information....... Sec. Sec.
314.81(b)(3)(iii 310.306(c).
)(c). Sec.
314.81(b)(3)(ii
i)(c).
Sec.
600.82(c).
FDA will publicly FDA will
disclose a list maintain public
of all drug lists of drugs
products and biological
discontinued products
under Sec. determined by
314.81(b)(3)(iii FDA to be in
)(a). shortage,
including the
names, NDCs
(or, for
certain
biological
products, an
alternative, as
applicable),
and each
applicant of
the product
(or, for
marketed
unapproved
prescription
drugs, each
manufacturer of
the product);
the reason for
the shortage;
and the
estimated
duration of the
shortage.
Confidentiality.................... Not specified in Sec.
regulation, but 314.81(b)(3)(ii
information i)(d)
submitted to FDA Sec. 600.82(d)
under the ................
regulation is Includes
subject to specific
protections for reference to
trade secrets protection of
and confidential trade secrets
commercial and and
financial confidential
information commercial
where applicable. information
submitted to
FDA under the
proposed rule
and allows FDA
to choose not
to make certain
other
information
public if it
determines that
would adversely
affect the
public health.
No equivalent Sec.
provision. 20.100(c)(45).

[[Page 65908]]

Cross-reference
to disclosure
provisions in
Sec. Sec.
310.306,
314.81, and
600.82.
Noncompliance...................... No equivalent Sec.
provision. 310.306(b).
Sec.
314.81(b)(3)(ii
i)(e).
Sec.
600.82(e).
If an applicant
of a covered
drug or
biological
product, or
manufacturer of
a covered,
marketed
unapproved
prescription
drug, fails to
submit a
notification
required under
the proposed
rule within the
required
timeframe, FDA
will issue a
publicly
available
noncompliance
letter to the
applicant or
unapproved drug
manufacturer.
------------------------------------------------------------------------

A. Persons Subject to the Proposed Rule

Proposed Sec. Sec. 310.306, 314.81(b)(3)(iii), and 600.82 would
require notification to FDA of a permanent discontinuance or an
interruption in manufacturing of a covered drug or biological product.
Under the proposed rule, the following persons would be subject to
these notification requirements:
All applicants with an approved NDA or ANDA for a covered
drug product (proposed Sec. 314.81(b)(3)(iii)).
All applicants with an approved BLA for a covered
biological product, other than blood or blood components (proposed
Sec. 600.82(a)(1)).
Applicants with an approved BLA for blood or blood
components, if the applicant is a manufacturer of a significant
percentage of the U.S. blood supply (proposed Sec. 600.82(a)(2)).
All manufacturers of a covered drug product marketed
without an approved NDA or ANDA (proposed Sec. 310.306, which applies
Sec. 314.81(b)(3)(iii) in its entirety to covered drug products
marketed without an approved NDA or ANDA).
Section 506C of the FD&C Act as amended by FDASIA requires a
``manufacturer'' to notify FDA of a permanent discontinuance or an
interruption in manufacturing. The proposed rule would require the
ANDA, NDA, or BLA applicant (for approved drugs or biological products)
or the unapproved drug manufacturer (for marketed, unapproved drugs) to
notify FDA of a permanent discontinuance or an interruption in
manufacturing.
For purposes of section 506C of the FD&C Act, under the proposed
rule an ANDA, NDA, or BLA applicant would be considered the
manufacturer of an approved, covered product, even if the ANDA, NDA, or
BLA applicant contracts that function out to another entity. In other
words, the proposed rule makes clear that for approved, covered drugs
and biological products, the ANDA, NDA, or BLA applicant bears the
responsibility for reporting to FDA a permanent discontinuance or an
interruption in manufacturing, whether the product is manufactured by
the applicant itself or for the applicant under contract with one or
more different entities.
As such, the ANDA, NDA, or BLA applicant should establish a process
with any relevant contract manufacturer, active pharmaceutical
ingredient (API) supplier, or other nonapplicant that ensures the
applicant's compliance with this proposed rule. For example, assume
that Applicant X holds an ANDA, NDA, or BLA for a covered drug or
biological product and contracts with a third party to manufacture the
drug or biological product for the purposes of marketing and selling
the drug or biological product in the United States. If the third party
contract manufacturer experiences a manufacturing issue that results in
a permanent discontinuance or an interruption in manufacturing of
Applicant X's product that would be reportable under proposed Sec.
314.81(b)(3)(iii) or Sec. 600.82, Applicant X, not the contract
manufacturer, must notify FDA of this permanent discontinuance or
interruption in manufacturing. Therefore, Applicant X should establish
a process with the contract manufacturer that ensures Applicant X's
ability to timely report to FDA the permanent discontinuance or
interruption in manufacturing.
Section 506C(i)(3) of the FD&C Act, as amended by FDASIA, directs
FDA to ``take into account any supply reporting programs [for
biological products] and . . . aim to reduce duplicative notification''
in applying section 506C to biological products by regulation.
Accordingly, with respect to blood or blood components, we are
proposing to limit this rule only to applicants that are manufacturers
of a ``significant percentage of the United States blood supply.'' As
described more fully in sections II.B.2.c and II.C.1.b.ii, FDA believes
that this approach with respect to blood or blood components will
ensure that the Agency receives information that is essential to
preventing shortages of these products, without being unnecessarily
duplicative of existing systems or unduly burdensome to industry. For
purposes of this proposed rule, FDA intends to consider an applicant
that holds a BLA for blood or blood components to be a manufacturer of
a ``significant percentage'' of the U.S. blood supply if the applicant
manufactures 10 percent or more of the U.S. blood supply (e.g., greater
than 1.5 million units of whole blood annually or approximately 125,000
units per month).

B. Products Subject to the Proposed Rule

1. Prescription Drug and Biological Products That Are Life Supporting,
Life Sustaining, or Intended for Use in the Prevention or Treatment of
a Debilitating Disease or Condition
The proposed rule would apply to all prescription drug products
approved under an NDA or ANDA (proposed Sec. 314.81(b)(3)(iii)), all
marketed unapproved prescription drug products (proposed Sec.
310.306), and all prescription biological products approved under a BLA
(proposed Sec. 600.82) that are:
Life supporting; life sustaining; or intended for use in
the prevention or treatment of a debilitating disease or condition,
including any such product used in emergency medical care or during
surgery; and
not radiopharmaceutical products.\6\
---------------------------------------------------------------------------

\6\ With respect to blood and blood components for transfusion,
the reporting requirement applies only to an applicant that
manufactures a significant percentage of the U.S. blood supply.
---------------------------------------------------------------------------

FDASIA does not define the terms ``life supporting,'' ``life
sustaining,'' or ``intended for use in the prevention or treatment of a
debilitating disease or

[[Page 65909]]

condition,'' but instead requires FDA to define them. Proposed
Sec. Sec. 314.81(b)(3)(iii)(f) and 600.82(f) would define a ``life
supporting or life sustaining'' drug product as one that is ``essential
to, or that yields information that is essential to, the restoration or
continuation of a bodily function important to the continuation of
human life.'' This definition of ``life supporting'' or ``life
sustaining'' is consistent with language used to describe this term in
the preamble to the final rule implementing the pre-FDASIA section 506C
(72 FR 58993 at 58994 (October 18, 2007)), and in medical device
regulations (see 21 CFR 821.3(g)).
Under the proposed rule, ``intended for use in the prevention or
treatment of a debilitating disease or condition'' would refer to ``a
drug product intended for use in the prevention or treatment of a
disease or condition associated with mortality or morbidity that has a
substantial impact on day-to-day functioning'' (proposed Sec. Sec.
314.81(b)(3)(iii)(f) and 600.82(f)). We have equated ``debilitating
disease or condition'' with ``serious disease or condition'' under this
proposed definition and defined it according to the definition of
``serious'' found in 21 CFR 312.300. This definition of ``intended for
use in the prevention or treatment of a debilitating disease or
condition'' is also consistent with our discussion of the term in the
preamble to the proposed rule implementing the pre-FDASIA section 506C
(65 FR 66665 at 66666 (November 7, 2000)).
When defining these terms, we also took into account comments we
received on the IFR, including: A request for additional clarity on how
these terms relate to FDA's use of the term ``medically necessary''
with respect to drug and biological product shortages; comments
recommending that FDA interpret this terminology to require
notification for ``medicines at risk of being in shortage''; and a
related comment suggesting that once FDA identifies ``medicines at risk
of being in shortage,'' the Agency should establish a mechanism for the
purchase and storage of advance supplies of drugs on the list.
According to this comment, this ``government stockpile'' could prevent
shortages from occurring or mitigate the impact of an unavoidable
shortage.
In response to the first comment, the proposed definitions of
``life supporting or life sustaining'' and ``intended for use in the
prevention or treatment of a debilitating disease or condition'' are,
in important respects, different than FDA's definition of ``medically
necessary'' as used in the context of the existing Center for Drug
Evaluation and Research (CDER) Manual of Policies and Procedures (MAPP)
on drug shortages (CDER MAPP 6003.1) (Ref. 2 of this proposed rule).
FDA considers a product to be medically necessary under this internal
MAPP if ``there is no other adequately available drug product that is
judged by medical staff to be an appropriate substitute'' (Ref. 2 of
this proposed rule). Under this proposed rule, the applicant would be
required to notify FDA of a permanent discontinuance or an interruption
in manufacturing of a drug or biological product that is life
supporting, life sustaining, or intended for use in the prevention or
treatment of debilitating disease or condition, whether or not the
product is considered medically necessary under the MAPP. Under the
MAPP, FDA uses the definition of medically necessary to prioritize the
Agency's response to specific shortages or potential shortages and to
allocate resources appropriately.
In response to the second group of comments, the proposed rule does
not define either ``life supporting or life sustaining'' or ``intended
for use in the prevention or treatment of debilitating disease or
condition'' to mean ``medicines at risk of being in shortage,'' because
shortages are often triggered by factors related to manufacturing and
product quality that cannot be anticipated in advance, making it
difficult, if not impossible, to accurately predict drugs or biological
products that are vulnerable to shortage. This suggested interpretation
of these terms would also be inconsistent with the statutory text,
which defines drugs subject to the notification provisions by their
uses, and contains separate language to explain when risks to supply
require a notification.
Finally, in response to the suggestion to create a national
stockpile of drugs and biological products vulnerable to shortage, FDA
concludes that this is beyond the scope of the current proposal, which
is to implement amended sections 506C and 506E of the FD&C Act.
We are interested in comments on the definitions of ``life
supporting or life-sustaining'' and ``intended for use in the
prevention or treatment of a debilitating disease or condition.'' FDA
believes these definitions are consistent with the industry's (and
Agency's) current understanding of the terms, and that more information
rather than less is essential for resolving drug shortages. However, we
are specifically interested in comments on whether these definitions
might unintentionally broaden the scope of reporting to such an extent
that the Agency is ``over-notified,'' particularly in the context of
the requirement for applicants to notify FDA of a meaningful disruption
in the manufacturer's supply, without regard to the market as a whole
(see section III.C.1. for further discussion on meaningful disruption
in supply).
2. Biological Products
Section 506C of the FD&C Act, as amended, states that for purposes
of this section the term ``drug'' does not include biological products
as defined in section 351(i) of the Public Health Service Act, unless
the Secretary of Health and Human Services (the Secretary) applies
section 506C to such products by regulation. Section 506C(i)(3) of the
FD&C Act provides that FDA may, by regulation, apply section 506C to
biological products, ``including plasma products derived from human
plasma protein and their recombinant analogs'' if ``the Secretary
determines that such inclusion would benefit the public health,''
taking into account ``any [existing] supply reporting programs'' and
aiming to reduce ``duplicative notification.'' Additionally, FDA may
apply section 506C of the FD&C Act to vaccines, but the Secretary must
determine whether notification of a vaccine shortage to the Centers for
Disease Control and Prevention (CDC) under its ``vaccine shortage
notification program'' could satisfy a vaccine manufacturer's
obligation to notify FDA of a permanent discontinuance or an
interruption in manufacturing under section 506C.
We are proposing to apply section 506C of the FD&C Act to all
biological products, including recombinant therapeutic proteins,
monoclonal antibody products, vaccines, allergenic products, plasma-
derived products and their recombinant analogs, blood or blood
components, and cellular and gene therapy products. Like drug
shortages, shortages of biological products can have serious negative
consequences for patients who rely on these products for their
treatment. For example, recent shortages of biological products such as
agalsidase beta (Fabrazyme), peginterferon alfa-2a (Pegasys), and BCG
\7\ Live (Intravesical) (TheraCys) have adversely affected patient
care. Fabrazyme is indicated for the treatment of Fabry's disease, a
life shortening, inherited disease caused by a deficiency of alpha-
galactosidase A, an enzyme needed to metabolize lipids. The Fabrazyme
shortage resulted from contamination at the manufacturing

[[Page 65910]]

plant and led to rationing of the product at one-third the recommended
dose for current patients using the drug. As a result of the reduced
doses, some patients reported a progression of Fabry's disease,
including serious adverse events affecting the heart, central nervous
system, and kidneys. Similarly, shortages of the antiviral drug Pegasys
and the bladder cancer biological drug TheraCys threatened the timely
treatment of patients with debilitating diseases, interrupting the
continuity (and potentially undercutting the effectiveness) of
treatment for patients prescribed these medications as well as
preventing new patients from obtaining these medications.
---------------------------------------------------------------------------

\7\ BCG is an attenuated live culture preparation of the
Bacillus of Calmette and Guerin (BCG) strain of Mycobaterium bovis.
---------------------------------------------------------------------------

Early notification of a permanent discontinuance or an interruption
in the manufacturing of biological products would allow FDA to address,
prevent, or mitigate a shortage of these products, greatly benefiting
the public health. In addition, for the reasons described in this
document, we have determined that requiring manufacturers of biological
products to notify FDA under this proposed rule would not duplicate the
existing reporting programs of which we are aware.
a. Plasma-derived products and their recombinant analogs. As stated
previously, we are proposing to apply section 506C of the FD&C Act to
all biological products, including plasma products derived from human
plasma protein and their recombinant analogs (referred to in this
document as plasma-derived products and their recombinant analogs).
With respect to plasma-derived products and their recombinant analogs,
FDA recognizes that the Plasma Protein Therapeutics Association (PPTA)
has developed a voluntary data system that captures the distribution
and supply of five plasma product groups in the United States: Plasma-
Derived Factor VIII, Recombinant Factor VIII, Immune Globulin (Ig),
Albumin 5%, and Albumin 25%. The PPTA, in consultation with a third
party, voluntarily submits a monthly report to FDA of aggregate
distribution data for these five product groups. This information
provides a picture of the total supply and distribution of these five
products in any given month as compared to the last 12 months (see,
e.g., https://www.pptaglobal.org/UserFiles/file/Sept2012PDfviii.pdf).
(FDA has verified the Web sites in this document but is not responsible
for any subsequent changes to the Web sites after this document
publishes in the Federal Register.)
FDA recognizes and greatly appreciates the efforts by PPTA to
provide plasma product supply information to FDA and the public.
However, in addition to the PPTA system, for several reasons we believe
that it would benefit the public health for the Agency to receive
direct notification under this proposed rule from all manufacturers of
these products. First, the PPTA system does not include all plasma-
derived products and their recombinant analogs. FDA has approved many
plasma-derived products (and their recombinant analogs) that are not
included in the PPTA monthly report, but that would be subject to this
proposed rule, such as Rho(D) Immune Globulin and Hepatitis B Immune
Globulin; Coagulation Factor VIIa (Recombinant); and Coagulation Factor
IX.
Second, the product distribution data is submitted to PPTA (and
subsequently to FDA) on a voluntary basis; reporting under this
proposed rule would be mandatory. Finally, the PPTA data is aggregate
distribution data derived from historical supply and demand. Unlike the
notifications proposed under this rule, it is not real-time data, nor
does it capture the types of circumstances that would be considered a
``permanent discontinuance'' or an ``interruption in manufacturing''
under this proposed rule. Rather, as described previously, the PPTA
data provides a snapshot of current aggregate supply as compared to
historical supply. It is not intended to identify circumstances that
could lead to a future permanent discontinuance or an interruption in
manufacturing of all plasma-derived products and their recombinant
analogs.
Because the PPTA program, although helpful, does not serve the same
purpose as notification under this proposed rule, including plasma-
derived products and their recombinant analogs in this rulemaking will
not duplicate the PPTA system. FDA believes that including these
products within the scope of the proposed rule is essential to FDA's
efforts to identify permanent discontinuances and interruptions in
manufacturing of these products, and consequently, essential to our
efforts to address, prevent, or mitigate shortages of these products.
b. Vaccines. We are proposing to apply section 506C of the FD&C Act
to all biological products, including vaccines. Under section
506C(i)(3)(B) of the FD&C Act, if FDA applies section 506C to vaccines,
the Secretary must specifically consider whether the notification
requirement may be satisfied by submitting a notification to CDC under
CDC's ``vaccine shortage notification program.''
CDC contracts with vaccine manufacturers as part of the Vaccines
for Children (VFC) program.\8\ FDA recognizes that CDC includes
language in its contracts with vaccine manufacturers requiring the
manufacturer to notify CDC of vaccine supply issues that could affect
the manufacturer's ability to fulfill its contract with CDC.\9\
---------------------------------------------------------------------------

\8\ The VFC program is a federally funded program that provides
vaccines at no cost to children and adults who might not otherwise
be vaccinated because of inability to pay. VFC was created by the
Omnibus Budget Reconciliation Act of 1993 as a new entitlement
program to be a required part of each state's Medicaid plan. CDC
buys vaccines at a discount from the manufacturers and distributes
them to awardees--i.e., State health departments and certain local
and territorial public health Agencies--who in turn distribute them
at no charge to those private physicians' offices and public health
clinics registered as VFC providers. (See https://www.cdc.gov/vaccines/programs/vfc/.)
\9\ The Biomedical Advanced Research and Development Authority
(BARDA), which is responsible for the procurement of certain
vaccines related to medical countermeasures, also includes similar
language in its procurement contracts. Contracts for the procurement
of medical countermeasures against chemical, biological, nuclear,
and radiological threat agents (e.g. smallpox and anthrax vaccines)
are administered by BARDA, part of the Office of the Assistant
Secretary for Preparedness and Response in the U.S. Department of
Health and Human Services (HHS). (See https://www.hhs.gov/aspr.)
---------------------------------------------------------------------------

Only certain vaccines are included under the existing CDC program,
and thus, only manufacturers of certain vaccines are obligated to
provide notification of supply issues to CDC. Based on information from
CDC, FDA estimates that approximately 30 percent of vaccines licensed
in the United States are not subject to CDC notification, including
vaccines for rabies, yellow fever, and typhoid.
Moreover, even for the vaccines that are subject to CDC
notification, the information collected is not adequate for purposes of
this rule, because the existing CDC program does not require vaccine
manufacturers to provide notice 6 months in advance of a permanent
discontinuance or interruption in manufacturing. Early notice of
permanent discontinuances and interruptions is critically important to
the prevention of drug shortages. Although FDA and its HHS partners
work together closely on vaccine supply issues, and the current
framework for CDC notification is useful for contractual purposes, FDA
believes including vaccines within the scope of this rulemaking is
necessary to fully support FDA's efforts to identify, address, prevent,
or mitigate a vaccine shortage and would not be duplicative of existing
notification systems.
c. Blood or blood components for transfusion. We are proposing to
apply section 506C of the FD&C Act to blood

[[Page 65911]]

or blood components, but in a more limited manner than for other
biological products. The proposed rule would require blood or blood
component applicants (i.e., blood collection establishments subject to
licensure) that manufacture a significant percentage of the U.S. blood
supply to notify FDA of a permanent discontinuance or an interruption
in manufacturing that is likely to lead to a ``significant disruption''
in the applicant's supply of blood or blood components. As described
more fully in sections II.A and II.C.1.b.ii, the proposed rule is
intended to require reporting of large-scale, permanent
discontinuances, or interruptions in manufacturing of blood or blood
components.
The proposed rule would ensure that FDA receives information
essential to the Agency in preventing, mitigating, or addressing
shortages of blood or blood components, while avoiding duplication with
existing programs that monitor local and regional supplies of blood or
blood components by ABO blood group. We are aware of two significant
efforts to monitor local and regional supplies of blood or blood
components.
i. America's Blood Centers and the Blood Availability and Safety
Information System. America's Blood Centers (ABC) is a network of
nonprofit community blood centers in North America. ABC members operate
more than 600 blood collection sites in 45 states and provide blood or
blood components to more than 3,500 hospitals and health care
facilities. ABC also maintains a voluntary supply monitoring program
for blood and blood components. Information on local and regional blood
supply is provided weekly to ABC members nationwide through a
newsletter, and online (see https://www.americasblood.org/stoplight.aspx). In addition, ABC and certain other large licensed
blood establishments provide voluntary, daily blood supply reports to
HHS, which maintains a system called the Blood Availability and Safety
Information System (BASIS) (see https://www.usbloodreport.net/About.aspx). Certain sentinel hospitals also voluntarily provide
inventory reports to the BASIS system, and these data are compiled into
a weekly status report on blood supplies, stratified by ABO blood
group. Upon request, FDA receives BASIS reports from HHS.
The ABC and BASIS systems monitor the supply and demand of blood or
blood components on a daily and weekly basis, and in the event of a
national disaster. In other words, ABC and BASIS are tools for local
blood centers and hospitals to track their day-to-day inventory of
blood or blood components. Unlike the notifications required under this
proposed rule, ABC and BASIS are not designed to predict large-scale or
nationwide disruptions in the supply of blood or blood components.
Moreover, ABC and BASIS are voluntary systems; the proposed rule would
require mandatory reporting.
ii. Task Force. Also critical to the management of the national
blood supply is the coordinating function of the Interorganizational
Task Force on Domestic Disasters and Acts of Terrorism (Task Force),
which is managed by the AABB (formerly the American Association of
Blood Banks). The Task Force was formed in January 2002 to help make
certain that blood collection efforts resulting from domestic disasters
and acts of terrorism are managed properly, and to deliver clear and
consistent messages to the public regarding the status of the U.S.
blood supply. The Task Force is comprised of representatives from blood
establishments, trade associations, commercial entities, and liaisons
from governmental Agencies (including FDA), who work together to ensure
that adequate blood inventories are in place at all times. In addition,
the Task Force operates a system for assessing the need for collections
and transportation of blood components, should a disaster or act of
terrorism occur.
Again, the Task Force efforts, although critical to public health,
are focused on inventory management and are not intended to predict
large-scale disruptions in the supply of blood or blood components. The
Task Force coordinates the movement of blood throughout the United
States and appeals to the public for blood donations, but it is not
sufficient for FDA in the context of predicting a permanent
discontinuance or an interruption in manufacturing of these products
that would have a large-scale impact.
In short, although the information already available to FDA from
the ABC, BASIS, and Task Force programs is useful, the existing
frameworks are voluntary, do not result in a direct notification from
an applicant to FDA, and, as explained previously, only capture short-
term, day-to-day supply and distribution information. In addition, in
contrast to this proposed rule, the existing systems are not equipped
to predict large-scale, significant disruptions of blood or blood
components. Accordingly, FDA has determined that including blood or
blood components within the scope of this rule would benefit the public
health, providing information that is essential to FDA's efforts to
address shortages of these products.
However, recognizing that the existing ABC, BASIS, and Task Force
programs do provide certain information concerning the supply of blood
or blood components, we have limited the proposed reporting
requirements to apply only to applicants of blood or blood components
that manufacture a significant percentage of the U.S. blood supply, and
only to a permanent discontinuance of manufacture or an interruption in
manufacturing that is likely to lead to a ``significant disruption'' in
supply of that blood or blood component, as further described in
sections II.A and II.C.1.
d. Distribution reports (for all biological products). Under Sec.
600.81 (21 CFR 600.81), applicants are required to submit to the Center
for Biologics Evaluation and Research (CBER) or CDER, information about
the quantity of product distributed under the biologics license,
including the quantity distributed to distributors. As part of this
safety reporting requirement, manufacturers provide distribution data
to FDA every 6 months or at other intervals as may be required by FDA.
Although distribution reports submitted by applicants are helpful in
the analysis of safety reporting data, particularly for newly approved
products, these reports do not include information about a permanent
discontinuance or an interruption of the manufacture of a biological
product that is likely to lead to a meaningful disruption in the supply
of that product. Furthermore, the production cycles of biological
products vary widely (e.g., some are manufactured once a year, some are
manufactured every other year, and some are manufactured more or less
frequently), such that any distribution data received from the
manufacturer at 6-month intervals for such products will not be
current. Therefore, FDA has determined that the reporting requirements
under Sec. 600.81 do not constitute a duplicate supply reporting
program.
In summary, we are proposing to apply section 506C of the FD&C Act
to all biological products. For the reasons discussed in this document,
FDA finds that this inclusion would benefit the public health by
facilitating prompt FDA action to address, prevent, or mitigate drug
shortages, without duplicating existing reporting programs or creating
redundant reporting. With respect to vaccines, for the reasons already
described, we have determined that notification to CDC is not
sufficient for purposes of reporting to FDA under

[[Page 65912]]

section 506C of the FD&C Act and may not replace section 506C
notifications.
3. Scope of the Term ``Product''
For purposes of this proposed rule, ``product'' refers to a
specific strength, dosage form, or route of administration of a drug or
biological product. For example, if Applicant X experiences an
interruption in manufacturing of the 50-milligram (mg) strength of a
drug product that would be subject to proposed Sec. 314.81(b)(3)(iii),
but the 100 mg strength continues to be manufactured without delay,
under the proposed rule, Applicant X must notify FDA of the
interruption in manufacturing of the 50 mg strength if the interruption
is likely to lead to a meaningful disruption in the applicant's supply
of the 50 mg strength. Recent experience has shown that the permanent
discontinuance or interruption in manufacturing of a specific strength,
dosage form, or route of administration of a drug or biological product
can have a significant impact on the targeted needs of particular
patients (e.g., although the 100 mg tablet from Applicant X is
available, it may not be split in half easily for a patient that is
prescribed the 50 mg strength).
Moreover, shortages of a specific strength, dosage form, or route
of administration may lead to a shortage of another strength, dosage
form, or route of administration of the product, exacerbating patient
difficulties in acquiring the product. Obtaining this information is
consistent with the emphasis in the IFR on the importance of notifying
FDA of permanent or temporary interruptions in supply of a specific
strength, dosage form, or route of administration of covered products
(76 FR 78530 at 78533), and with the general support for this approach
we received in comments on the IFR.

C. Notification of a Permanent Discontinuance or an Interruption in
Manufacturing

1. Notification
a. Permanent discontinuance. Section 506C of the FD&C Act requires
manufacturers to notify FDA of a permanent discontinuance of
manufacture of a covered drug. Proposed Sec. Sec. 314.81(b)(3)(iii)
and 600.82 would require the applicant to report all permanent
discontinuances of covered drugs and biological products to FDA. For
purposes of this rule, we are interpreting a permanent discontinuance
to be a decision by the applicant for business or other reasons to
cease manufacturing and distributing the product indefinitely.
b. Interruption in manufacturing. In addition to permanent
discontinuances, section 506C of the FD&C Act requires manufacturers to
notify FDA of an interruption in manufacturing of a covered drug that
is likely to lead to a meaningful disruption in supply of that drug in
the United States. The statute defines ``meaningful disruption'' to
mean ``a change in production that is reasonably likely to lead to a
reduction in the supply of a drug by a manufacturer that is more than
negligible and affects the ability of the manufacturer to fill orders
or meet expected demand for its product; and does not include
interruptions in manufacturing due to matters such as routine
maintenance or insignificant changes in manufacturing so long as the
manufacturer expects to resume operations in a short period of time''
(emphasis added).
i. Drugs and biological products other than blood or blood
components. Proposed Sec. Sec. 314.81(b)(3)(iii)(a) and 600.82(a)(1)
would require the applicant for a product other than blood or blood
components to report to FDA an interruption in manufacturing of the
drug or biological product that is likely to lead to a meaningful
disruption in supply of that drug or biological product in the United
States. Proposed Sec. Sec. 314.81(b)(3)(iii)(f) and 600.82(f) would
adopt the statutory definition of meaningful disruption in supply.
Consistent with the statutory definition of meaningful disruption,
the proposed rule would require an applicant to report an interruption
in manufacturing likely to lead to a meaningful disruption in its own
supply of a covered drug or biological product. In other words, when
evaluating whether an interruption in manufacturing is reportable to
FDA under this proposed rule, rather than considering the potential
impact of the interruption on the market as a whole, the relevant
question (regardless of how large or small the applicant's market share
may be) is whether the interruption is likely to lead to a reduction in
the applicant's supply of a covered drug or biological product that is
more than negligible, and affects the ability of the applicant to fill
its own orders or meet the expected demand of its clients for the
covered product. Consistent with the statute, the proposed rule would
not require an applicant to predict the market-wide impact of its own
interruption in manufacturing, which can be difficult to accurately
assess and could lead to inconsistent interpretation of the regulation,
less accurate predictions, and under- or reporting, as suggested by
multiple comments on the IFR.
Under the proposed rule, reportable discontinuances or
interruptions in manufacturing of a covered drug or biological product
would include:
A business decision to permanently discontinue manufacture
of a covered drug or biological product.
A delay in acquiring APIs or inactive ingredients that is
likely to lead to a meaningful disruption in the applicant's supply of
a covered drug or biological product while alternative API suppliers
are located.
Equipment failure or contamination affecting the quality
of a covered drug or biological product that necessitates an
interruption in manufacturing while the equipment is repaired or the
contamination issue is addressed and that is likely to lead to a
meaningful disruption in the applicant's supply of the product.
Manufacturing shutdowns for maintenance or other routine
matters, if the shutdown extends for longer than anticipated or
otherwise is likely to lead to a meaningful disruption in the
applicant's supply of a covered drug or biological product.
A merger of firms or transfer of an application for a
covered drug or biological product to a new firm, if the merger or
transfer is likely to lead to a meaningful disruption in the
applicant's supply of the product.
An interruption in manufacturing (e.g., contamination of a
manufacturing line) that in the applicant's view may not meaningfully
disrupt the market-wide supply of the covered drug or biological
product (for example, because the applicant holds only a small share of
the market for the product), but that the applicant determines is
likely to lead to a meaningful disruption in its own supply of the
covered product.
Conversely, an applicant would not be required under the proposed
rule to notify FDA if an interruption in manufacturing is not likely to
lead to a meaningful disruption in the applicant's supply of the drug
or biological product. For example, FDA would not need to be notified
in the following circumstances:
A scheduled shutdown of an applicant's manufacturing
facility for routine maintenance, if the shutdown is anticipated and
planned for in advance; and therefore, is not expected to lead to a
meaningful disruption in the applicant's supply of a covered drug or
biological product.
An unexpected power outage that results in an unscheduled
interruption in manufacturing of a covered drug or biological product,
if the applicant expects to resume normal operations

[[Page 65913]]

within a relatively short timeframe and does not expect to experience a
meaningful disruption in its supply of the covered drug or biological
product.
In either of these circumstances, if the interruption in
manufacturing subsequently appears likely to lead to a meaningful
disruption in the applicant's supply of the covered drug or biological
product, then it would become a reportable interruption in
manufacturing under this proposed rule and the applicant would be
required to notify FDA.
The list of examples described in this document is intended to
assist industry in understanding what would (or would not) be required
to be reported under amended section 506C of the FD&C Act, but it is
not exhaustive. The proposed rule would require any permanent
discontinuance or any interruption in manufacturing that is likely to
lead to a meaningful disruption in the applicant's supply of a covered
drug or biological product to be reported to FDA, even if not
specifically described in this preamble.
ii. Blood or blood components for transfusion. Proposed Sec.
600.82(a)(2) would require an applicant that manufactures a significant
percentage of the U.S. blood supply to report to FDA an interruption in
manufacturing of a blood or blood component that is likely to lead to a
``significant disruption'' in supply of that product in the United
States. As we discussed in section II.A, an applicant that manufactures
10 percent or more of the U.S. blood supply (e.g., greater than 1.5
million units of whole blood annually or approximately 125,000 units
per month), would be considered to manufacture a significant percentage
of the U.S. blood supply for purposes of this proposed rule. Proposed
Sec. 600.82(f) defines ``significant disruption'' to mean ``a change
in production that is reasonably likely to lead to a reduction in the
supply of blood or blood components by a manufacturer that
substantially affects the ability of the manufacturer to fill orders or
meet expected demand for its product; and does not include
interruptions in manufacturing due to matters such as routine
maintenance or insignificant changes in manufacturing so long as the
manufacturer expects to resume operations in a short period of time.''
This definition of significant disruption closely follows, but is not
identical to, the statutory and regulatory definition of meaningful
disruption.
For purposes of the proposed rule, FDA intends to consider an
interruption in manufacturing that leads to a reduction of 20 percent
or more of an applicant's own supply of blood or blood components over
a one-month period to ``substantially affect'' the ability of the
applicant to fill orders or meet expected demand; accordingly, such an
interruption would be considered a ``significant disruption'' in
supply. Again, when determining when an interruption in manufacturing
is likely to lead to a significant disruption in supply, the blood or
blood component applicant should not consider the market as a whole,
but rather, should consider only its own supply of product.
The proposed definition of ``significant disruption'' (interpreted
to mean affecting 20 percent or more of an individual applicant's
supply over a one-month period) as applied to blood or blood
components, in combination with the limitation of the proposed rule
only to applicants of blood or blood components that manufacture a
significant percentage (10 percent or more) of the nation's blood
supply, is intended to avoid duplication with existing programs to
monitor the daily and weekly distribution of blood or blood components
described in section II.B.2.c. As described in that section, in
general, existing programs maintained by ABC, BASIS, and the Task Force
monitor and resolve temporary, local shortfalls of a particular ABO
blood group or a particular blood component. Accordingly, the
definition of ``significant disruption'' is intended to capture events
that are likely to precipitate large-scale disruptions in an
applicant's blood supply, and that are unlikely to be identified and
corrected by the existing ABC, BASIS, and Task Force programs. The
additional limitation of the proposed rule to applicants that
manufacture a significant percentage of the nation's blood supply
further ensures that reporting to FDA will not unnecessarily duplicate
reporting to the ABC, BASIS, and Task Force systems, but still allows
FDA to receive information that is essential to the Agency in
preventing large-scale shortages of these products.
Under the proposed rule, circumstances that would trigger
notification to FDA of a permanent discontinuance or an interruption in
manufacturing of blood or blood components would include the following
examples. We recognize that, with the exception of the first example of
a permanent discontinuance, the following interruptions are unlikely to
be reasonably anticipated 6 months in advance. In that case they would
be reportable as soon as practicable, but in no case later than 5
business days after the interruption in manufacturing occurs:
A business decision by an applicant that manufactures 10
percent or more of the nation's blood supply to permanently discontinue
manufacture of blood or blood components;
A computer system failure that causes an applicant of a
blood establishment that collects 10 percent or more of the nation's
blood supply to be unable to label blood for 2 weeks, resulting in a 20
percent monthly shortfall of blood for that applicant;
An issue with blood collection bags, such that they are
unavailable, causing an applicant that manufactures 10 percent or more
of the nation's blood supply to experience a 20 percent monthly
shortfall in normal production for that applicant;
An issue with apheresis collection devices that causes an
applicant of a blood establishment that collects 10 percent or more of
the nation's blood supply to be unable to collect platelets by
apheresis, resulting in a 20 percent monthly shortfall in platelet
supply for that applicant;
An explosion or fire that damages a large testing
laboratory that performs blood testing for an applicant that
manufactures 10 percent or more of the nation's blood supply, resulting
in a 20 percent monthly shortfall of blood or blood components for that
applicant.
Conversely, a covered blood or blood component applicant would not
be required under the proposed rule to notify FDA if an interruption in
manufacturing is not likely to lead to a significant disruption in the
applicant's supply of blood or blood components. For example, FDA would
not need to be notified if a covered blood or blood component applicant
experiences a temporary drop in blood donations at one of its local
blood donation centers, such that it is unable to fully supply its
hospital customers with blood for several days, provided the donation
center quickly returns to its normal donation and supply levels and the
dip in blood donations is not likely to lead to a 20 percent decrease
in the applicant's overall supply of blood over a one-month period. We
expect that this type of situation would be identified and resolved
through the ABC, BASIS, and Task Force systems (e.g., these systems
would identify the issue and locate temporary, alternative blood
supplies for the applicant's customers). If such an event does lead to
a significant disruption in a covered applicant's supply of blood or
blood components, it would need to be reported to FDA under the
proposed rule.

[[Page 65914]]

Again, the list of examples described in this document is intended
to assist industry in understanding what must be reported under amended
section 506C of the FD&C Act, but the list is not exhaustive. The
proposed rule would require any permanent discontinuance or any
interruption in manufacturing that is likely to lead to a significant
disruption (as defined by the proposed rule) in a covered applicant's
supply of blood or blood components to be reported to FDA, even if not
specifically discussed in this preamble.
c. Consideration of comments to the IFR. Several comments on the
IFR suggested alternative ways of defining circumstances that must be
reported to FDA under pre-FDASIA section 506C of the FD&C Act. We have
considered whether these may be relevant to amended section 506C of the
FD&C Act. For example, one comment suggested that historical supply and
demand should be considered when determining whether to notify FDA
under section 506C of the FD&C Act. Specifically, the comment suggested
that notification should only be required if an interruption in
manufacturing is expected to affect the supply of the product based on
``historical inventory levels and other factors.'' Another comment
suggested that an applicant should be required to report to FDA only
after the disruption in supply occurs, for example when it is ``unable
to ship 90 percent or more of its full quantity of [covered] product as
reasonably ordered by its customers for more than 4 weeks.'' In other
words, the applicant should report to FDA if it experiences a 10
percent reduction in supply for a 4-week period. A third comment
suggested that notification should be required when an event causes an
applicant to predict that patients will be unable to obtain a covered
product for a certain, extended period of time (e.g., at the point when
an applicant projects that it will be unable to ship the drug or
biological product to customers for 8 weeks).
Although we agree that it could be appropriate to consider
historical supply and demand or shipping schedules in deciding whether
a notification would be required under this proposed rule, we decline
to limit the term ``interruption in manufacturing that is likely to
lead to a meaningful disruption in supply'' to consideration only of
such factors, and we decline to define the requirement by codifying a
preset, numerical threshold. The purpose of FDASIA, and this proposed
rule, is to improve FDA's ability to prevent or mitigate the impact of
drug and biological product shortages by broadening the scope of
information that the Agency receives regarding permanent
discontinuances and interruptions in manufacturing. If reportable
circumstances are limited to situations in which a manufacturer is
unable to ship a certain percentage of historic demand for a certain
period time, or unable to ship at all for a certain period of time,
some circumstances that could lead to a shortage may not be reported to
FDA, putting the Agency at a disadvantage in addressing those
situations.
For example, if notification under this proposed rule is triggered
only by the inability of an applicant to ship at least 90 percent of
its full quantity of a particular drug product as reasonably ordered by
its customers for more than 4 weeks (10 percent reduction in supply),
if an applicant were able to ship 92 percent of its supply (i.e., it
experiences an 8 percent reduction in supply), the interruption would
not be reportable to FDA. Yet this interruption in manufacturing may
still have an impact on a patient's ability to obtain the product and
could still lead to a product shortage that is ``more than
negligible.''
Instead, this proposed rule defines ``meaningful disruption in
supply'' consistent with the statutory text, and this preamble provides
examples of reportable interruptions in manufacturing as illustrations
for industry. An applicant may, at its discretion, analyze historical
supply and demand and estimate shipping schedules to help determine
whether an interruption in manufacturing is likely to lead to a
meaningful disruption in supply, but the applicant should not
substitute a rigid calculation for a full consideration of all
circumstances applicable to determining whether the change in
production is reasonably likely to lead to a reduction in supply that
is more than negligible and that affects the manufacturer's ability to
fill orders or meet expected demand for its product.
2. Timing and Submission of Notification
a. Timing of notification. Section 506C of the FD&C Act requires
notification to FDA ``(1) at least 6 months prior to the date of the
permanent discontinuance or interruption [in manufacturing]; or (2) if
compliance with paragraph (1) is not possible, as soon as
practicable.'' Consistent with the statute, proposed Sec. Sec.
314.81(b)(3)(iii)(b) and 600.82(b) would require an applicant to notify
FDA of a permanent discontinuance or an interruption in manufacturing
at least 6 months in advance of the date of the permanent
discontinuance or interruption in manufacturing; or, if 6 months'
advance notice is not possible, as soon as practicable thereafter, but
in no case later than 5 business days after the permanent
discontinuance or interruption in manufacturing occurs.
The Agency's most powerful tool for addressing drug and biological
product shortages is early notification, which provides lead time for
FDA to work with manufacturers and other stakeholders to prevent a
shortage or to mitigate the impact of an unavoidable shortage. As such,
we expect that applicants would provide 6 months' advance notice
whenever possible. In particular, FDA believes that an applicant will
generally know of a permanent discontinuance at least 6 months in
advance, and in that case the applicant would be required to provide
notification of a permanent discontinuance to FDA at least 6 months in
advance. We understand that an applicant may not reasonably be able to
anticipate certain interruptions in manufacturing that are likely to
lead to a meaningful disruption in supply 6 months in advance. For
example, if an applicant discovers fungal contamination that requires
an immediate, temporary shutdown of its manufacturing plant for a
covered product, the applicant will not be able to provide FDA with 6
months' advance notice of the interruption in manufacturing. Instead,
the proposed rule would require the applicant to notify FDA ``as soon
as practicable,'' but in no case more than 5 business days after the
interruption in manufacturing occurs. In this example, the applicant
would need to notify FDA as soon as it reasonably anticipates that an
interruption in manufacturing caused by fungal contamination is likely
to result in a meaningful disruption in supply of the applicant's
product. The applicant should not wait until it or its manufacturer
begins rejecting or delaying fulfillment of orders for the product from
available inventory (i.e., the applicant should not wait until the
interruption in manufacturing actually begins to disrupt supply and
affect patient access to the product).
In our experience, even if it is not possible for an applicant to
notify the Agency before a permanent discontinuance or an interruption
in manufacturing occurs, it should generally be possible for the
applicant to provide notice within a day or two, and it should always
be possible for the applicant to notify the Agency no later than 5 days
after the permanent discontinuance or interruption occurs, even in the
event of a natural disaster

[[Page 65915]]

or some other catastrophic incident. Accordingly, the 5-day provision
in our proposal represents a date certain after which FDA would be able
to take action under section 506C(f) of the FD&C Act against an
applicant for failure to comply with the notification requirements (see
section II.C.5 of this document for further discussion of the
consequences of failure to notify FDA). Additionally, an applicant that
could have notified the Agency before five days had passed, but waited
until the end of the 5-day period would be in violation of the proposed
regulation. Consistent with the statutory intent, whenever possible,
applicants would be required to provide us with advance notice, whether
6 months' advance notice, or ``as soon as practicable'' thereafter
(e.g., 3 months' advance notice).
b. Submission of notification. Proposed Sec. Sec.
314.81(b)(3)(iii)(b) and 600.82(b) would require an applicant to notify
FDA of a permanent discontinuance or an interruption in manufacturing
electronically in a format FDA can process, review, and archive.
Applicants must email notifications to drugshortages@fda.hhs.gov (for
products regulated by CDER) or cbershortage@fda.hhs.gov (for products
regulated by CBER). In the future, the Agency may consider creating an
electronic notification portal linked to the Agency's internal drug
shortages database to facilitate submission of these notifications.
Unless and until this portal is created, however, email notifications
will be used.
c. Reduction in notification period for ``good cause''. Under the
pre-FDASIA section 506C(b), a manufacturer could seek, and FDA could
grant, a reduction in the required 6-month advance notification period
for ``good cause.'' The statute listed several reasons that would
constitute ``good cause,'' including when continuing to manufacture the
product for the full 6-month notification period could cause a public
health problem or result in substantial economic or legal hardship for
the manufacturer. The regulation at Sec. 314.91 implemented the pre-
FDASIA section 506C(b). Because section 506C of the FD&C Act as amended
by FDASIA does not include an option for formally seeking a reduction
in the 6-month advance notification period based on ``good cause,''
this rule proposes to eliminate Sec. 314.91 in its entirety.
3. Contents of the Notification
Proposed Sec. Sec. 314.81(b)(3)(iii)(c) and 600.82(c) would
require an applicant to include the following items in notifications
submitted under section 506C(a) of the FD&C Act:
The name of the drug or biological product subject to the
notification, including the NDC for the drug or biological product (or,
for a biological product that does not have an NDC, an alternative
standard for identification and labeling that has been recognized as
acceptable by the Center Director);
The name of the applicant of the drug or biological
product;
Whether the notification relates to a permanent
discontinuance of the drug or biological product or an interruption in
manufacturing of the drug or biological product;
A description of the reason for the permanent
discontinuance or interruption in manufacturing; and
The estimated duration of the interruption in
manufacturing.
FDA is proposing to require applicants to include the minimum
information listed in this document in the initial notification to
assist the Agency in complying with section 506E of the FD&C Act, which
requires FDA to maintain a publicly available list of drugs in
shortage, as described in section II.C.4 of this document. We recognize
that the duration of an interruption in manufacturing can be difficult
to accurately predict. The applicant should provide FDA with its best
estimate of the expected duration of the interruption in manufacturing.
If, after the initial notification is submitted, the estimated duration
changes, the applicant should notify FDA of the new expected duration
of the interruption in manufacturing so that FDA can respond
appropriately. In addition, the applicant should include a detailed,
factual description of the reason for the shortage in the notification
to assist FDA in responding to the notification.
In addition to the proposed required elements of the notification,
applicants are encouraged to include any other information in the
notification that may be helpful to the Agency in working with the
applicant to resolve the permanent discontinuance or interruption in
manufacturing. Such information could include the applicant's market
share, inventory on hand or in distribution channels, allocation
procedures and/or plans for releasing available product, copies of
communications to patients and providers regarding the shortage (e.g.,
Dear Healthcare Professional letters), or initial proposals to prevent
or mitigate the shortage. As appropriate, the Agency will also follow
up with the applicant after the notification is submitted to obtain
additional information and to work with the applicant to facilitate
resolution of any shortage or potential shortage.
4. Public Lists of Products in Shortage
Section 506E of the FD&C Act requires FDA to maintain a publicly
available list of drugs (and biological products, if FDA applies
section 506C to biological products by regulation) that are determined
by FDA to be in shortage, including providing the names and NDCs of the
drugs, the name of each manufacturer of the drug, the reason(s) for the
shortage, and the estimated duration of the shortage. Section
506C(h)(2) of the FD&C Act defines ``drug shortage'' to mean ``a period
of time when the demand or projected demand for the drug within the
United States exceeds the supply of the drug.'' For purposes of section
506E of the FD&C Act, under the proposed rule, the ANDA, NDA, or BLA
applicant would be considered the manufacturer of an approved drug or
biological product, even if the ANDA, NDA, or BLA applicant contracts
that function out to another entity.
Section 506E of the FD&C Act further requires FDA to include on the
drug shortages list the reason for the shortage, choosing from the
following statutory list of categories:
Requirements relating to complying with current good
manufacturing practices (CGMPs);
Regulatory delay;
Shortage of an active ingredient;
Shortage of an inactive ingredient component;
Discontinuation of the manufacture of the drug;
Delay in shipping of the drug; and
Demand increase in the drug.
Consistent with the statute, and with FDA's current practice, under
proposed Sec. Sec. 310.306(b), 314.81(b)(3)(iii)(d), and 600.82(d),
FDA would maintain publicly available lists of drugs and biological
products that are determined by FDA to be in shortage, whether or not
FDA has received a notification under this proposed rule concerning the
product in shortage. Proposed Sec. Sec. 314.81(b)(3)(iii)(f) and
600.82(f) adopt the statutory definition of drug shortage (substituting
``biological product shortage'' for ``drug shortage'' in Sec.
600.82(f)). Under the proposed rule, the shortages lists would include
the following required statutory elements for drugs or biological
products in shortage: Names and NDCs (or the alternative standard for
certain biological products) of the drugs or biological products, names
of each applicant, reason for each shortage, and estimated duration of
each shortage.

[[Page 65916]]

If FDA has received a notification under the proposed rule for the
drug or biological product, FDA would consider the reason for the
shortage supplied by the applicant in its notification, and, where
applicable, other relevant information before the Agency, in
determining how to categorize the reason for the shortage under the
proposed rule. Consistent with the statute, the Agency, not the
applicant, would be responsible for determining which categorical
reason best fits a particular situation. FDA would generally choose the
categorical reason that best fits the applicant's supplied description.
To facilitate FDA's determination of the categorical reason for the
shortage, under the proposed rule we would expect applicants to supply
as many details and facts as possible concerning the reason for the
permanent discontinuance or interruption in manufacturing when
submitting a 506C notification. This information would also assist FDA
in responding quickly to the notification. FDA works proactively with
applicants and others experiencing issues that could lead to a product
shortage. We are committed to working with industry to address any
underlying quality or manufacturing issues, and we seek to avoid
shutdowns and long-term interruptions in supply whenever possible to
ensure continued patient access to vital safe and effective drugs and
biological products.
If FDA has not received a notification under the proposed rule, but
becomes aware of a shortage through other means, FDA would consider
information before the Agency when determining and choosing the reason
for the shortage to be included on the public list.
In addition to the list of statutory reasons for the shortage that
FDA may choose from, we are also proposing to add an eighth category,
entitled ``Other reason.'' We are proposing to add this category
because the Agency believes that some quality or manufacturing problems
that result in a shortage may not fit into any of the listed categories
in the statute (e.g., not all quality concerns are the result of
noncompliance with CGMPs). The Agency would only choose ``Other
reason'' if none of the other listed reasons is applicable. For
example, an interruption in manufacturing as a result of a natural
disaster or other catastrophic loss would fall into the ``Other
reason'' category. Moreover, as described in this document, although
FDA may choose the ``Other reason'' category, the public shortages list
would also include a brief summary of the reason for the shortage
submitted by the applicant, thus providing additional information to
the public on the cause of the shortage.
As noted previously, the proposed rule would codify, consistent
with FDASIA, FDA's current practice of maintaining public lists of
drugs and biological products in shortage, available on FDA's Web site
at https://www.fda.gov/drugs/drugsafety/drugshortages/default.htm (drug
shortages) and https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm (biological product
shortages).
FDA's current drug shortages list was reorganized after the
enactment of FDASIA to begin implementing revised section 506E of the
FD&C Act. The drug shortages list now includes six categories of
information about each drug product on the list: Company (manufacturer
of product and contact information); Product (name, strength,
formulation, dosage, and NDC); Availability and Estimated Shortage
Duration; Related Information (includes applicant's submitted
description of reason for shortage); Shortage Reason (FDA-determined
reason for the shortage, chosen from the list in proposed Sec. Sec.
314.81(b)(3)(iii)(d)); and Date Updated (last date FDA updated the
information for that particular product). The biological product
shortage list includes similar information in fields for Product Name,
Reason for Shortage, and Status.
In reformatting and revising the drug shortages list and drafting
this proposed rule, we considered several comments on the IFR and other
suggestions from stakeholders to improve the Agency's public
communication about shortages. We agree that communication between FDA
and interested stakeholders, including industry, providers (such as
physicians, pharmacists, and nurses), and patients, is an essential
component of preventing and mitigating both drug and biological product
shortages. FDA updates the drug and biological product shortages lists
regularly, and strives to communicate in ``real-time'' so that patients
and providers have the most current data available for planning
purposes.
Moreover, consistent with section 506D(d) of the FD&C Act, FDA is
encouraging patients, providers, pharmacists, and other nonapplicants
to communicate with the Agency about potential shortages or disruptions
in supply via one of the following email addresses:
drugshortages@fda.hhs.gov or cbershortage@fda.hhs.gov. FDA is already
in frequent contact with third parties to collect and disseminate
shortage-related information, and we hope the availability of these
dedicated email addresses will further facilitate communication. We are
continuing to work diligently to improve our drug and biological
product shortages Web sites and to consider new methods for
communicating with all stakeholders about shortages. We appreciate
suggestions on how to do this more effectively.
5. Confidentiality and Disclosure
In general, as required by section 506C(c) and 506E of the FD&C
Act, and as described in this document, FDA will publicly disclose, to
the maximum extent possible, information on drug shortages, including
information provided by applicants in a notification of a permanent
discontinuance or an interruption in manufacturing.
Proposed Sec. Sec. 314.81(b)(3)(iii)(d) and 600.82(d) contain an
exception to these provisions, stating that FDA may choose not to make
information collected under the authority of this proposed rule
available to the public on the drug or biological product shortages
lists or under its general obligation to disseminate drug shortage
information under section 506C(c) of the FD&C Act if the Agency
determines that disclosure of such information would adversely affect
the public health (such as by increasing the possibility of hoarding or
other disruption of the availability of the drug or biological product
to patients). These proposed provisions closely track the statutory
language in sections 506C(c)(3) and 506E(c)(3) of the FD&C Act.
In addition, proposed Sec. Sec. 310.306(c), 314.81(b)(3)(iii)(d),
and 600.82(d) state that FDA will not provide on the public drug or
biological product shortages lists or under section 506C(c) of the FD&C
Act, information that is protected by 18 U.S.C. 1905 or 5 U.S.C.
552(b)(4), including trade secrets and commercial or financial
information that is considered confidential or privileged under 21 CFR
20.61. These proposed provisions would ensure appropriate protection
for commercial and trade secret information protected by other Federal
law and are consistent with the statutory language in sections 506C(d)
and 506E(c)(2) of the FD&C Act, which clarify that the information
provisions in sections 506C and 506E do not alter or amend 18 U.S.C.
1905 or 5 U.S.C. 552(b)(4). Additionally, by reference to section 506E
of the FD&C Act, the Agency's obligation to disseminate to the public,
to the maximum extent possible, drug shortage information under section
506C(c) does not alter or

[[Page 65917]]

amend the protections afforded by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4).
FDA is also proposing a technical amendment to Sec. 20.100 to include
a cross-reference to Sec. Sec. 310.306, 314.81, and 600.82. Proposed
Sec. 20.100 describes, by cross-reference to other regulations, the
rules on public availability of certain specific categories of
information.
One comment on the IFR expressed concern that FDA had not discussed
how the Agency would preserve the confidentiality of proprietary
information reported to FDA in the context of (pre-FDASIA) section 506C
notifications. The comment was specifically concerned that as FDA
attempts to mitigate a potential drug shortage by contacting
manufacturers to increase production, it might reveal confidential
information, even if the interruption in manufacturing by the original
manufacturer is only temporary. Proposed Sec. Sec.
314.81(b)(3)(iii)(d) and 600.82(d) are intended to make clear that FDA
will adhere to applicable laws to protect trade secrets and
confidential commercial information as it works to mitigate or prevent
a shortage.
6. Failure To Notify
Proposed Sec. Sec. 310.306(b), 314.81(b)(iii)(3)(e), and 600.82(e)
would require FDA to issue a noncompliance letter to an applicant (or,
for a covered, unapproved drug, to a manufacturer) who fails to submit
a section 506C notification as required under proposed Sec. Sec.
314.81(b)(iii)(3)(a) and 600.82(a) within the timeframe stated in
proposed Sec. Sec. 314.81(b)(iii)(3)(b) and 600.82(b). Consistent with
the statute, as proposed in this rule, failure to notify FDA would
include failure to timely notify FDA. For example, if FDA discovers
that an applicant did not notify FDA of the permanent discontinuance of
a covered drug or biological product 6 months in advance, even though
the applicant anticipated the permanent discontinuance 6 months in
advance, FDA would issue a noncompliance letter under this proposed
rule. Similarly, if FDA determines that an applicant experienced a
reportable interruption in manufacturing that it could not reasonably
anticipate 6 months in advance, but the applicant failed to notify FDA
``as soon as practicable,'' the proposed rule would require FDA to
issue a noncompliance letter. Refer to section II.C.2.a of this
document for a discussion of the required timing for section 506C
notifications.
As required by statute, the proposed rule would provide the
applicant with 30 days from the date of issuance of the noncompliance
letter to respond to the letter. The applicant's response must set
forth the basis for noncompliance and provide the required notification
with the required information. Under the proposed rule, not later than
45 days after the date of issuance of the letter, FDA would make the
letter and the applicant's response public, after appropriate redaction
to protect any trade secret or confidential commercial information. FDA
would not make the letter and the applicant's response public if FDA
determines, based on the applicant's response, that the applicant had a
reasonable basis for not notifying FDA as required.

IV. Legal Authority

FDA is amending its regulations to implement sections 506C and 506E
of the FD&C Act (21 U.S.C. 356c and 356e) as amended by FDASIA. FDA's
authority for this rule also derives from section 701(a) of the FD&C
Act (21 U.S.C. 371(a)).

V. Analysis of Impacts

A. Introduction

FDA has examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity). OMB has determined that this proposed rule may be an
economically significant regulatory action as defined by Executive
Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The estimated per notification cost for small
business entities, $224, represents a small percentage of average
annual sales (up to 0.10 percent), for all entities covered by the
proposed rule. Although the final rule does not require specific
mitigation strategies, for firms that choose to implement mitigation or
prevention strategies, there could be additional costs of $112,000
associated with labor resources. For pharmaceutical companies with
fewer than 20 workers, these could be 2 to 7.8 percent of average
annual sales. In FDA's experience, 4-5 small business entities per year
have been affected by a shortage. For these companies, the average
annual sales was $17.54 million, and the estimated costs of
implementing mitigation or prevention strategies would represent less
than 0.64 percent of their average annual sales. The Agency anticipates
that the proposed rule will not have a significant economic impact on a
substantial number of small entities, and seeks comments on its Initial
Regulatory Flexibility Analysis.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $141 million, using the most current (2012) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.

B. Summary

The proposed rule would amend FDA's regulations to implement
sections 506C and 506E of the FD&C Act, as amended by FDASIA. The
proposed rule would require all applicants of covered, approved drugs
or biological products other than blood or blood components, all
applicants of blood or blood components that manufacture a significant
percentage of the U.S. blood supply, and all manufacturers of covered
drugs marketed without an approved application, to notify FDA
electronically of a permanent discontinuance or an interruption in
manufacturing of the product that is likely to lead to a meaningful
disruption in supply (or a significant disruption for blood or blood
components) of the product in the United States. Notification would be
required 6 months in advance of the permanent discontinuance or
interruption in manufacturing, or, if that is not possible, as soon as
practicable. The proposed rule also describes how to submit such a
notification, the information required to be included in such a
notification, the consequences for failure to submit a required
notification, the disclosure of shortage-related information, and the
meaning of certain terms.
The proposed rule would impose annual costs of up to $39.34 million
on those applicants or entities affected by

[[Page 65918]]

the rule, and up to $8.29 million on FDA associated with reporting and
undertaking mitigation strategies. Estimated total annual costs of the
interactions between industry and FDA range between $14.99 million and
$47.62 million. Discounting over 20 years, annual quantified benefits
from avoiding the purchase of alternative products, managing product
shortages, and life-years gained, would range from $27.56 million to
$86.77 million using a 3 percent discount rate, and from $27.50 million
to $86.61 million using a 7 percent discount rate. Annualized over 20
years, net benefits range from $12.57 million to $39.15 million using a
3 percent discount rate, and from $12.51 million to $38.99 million
using a 7 percent discount rate. The public health benefits, mostly
nonquantified, include the value of information that would assist FDA,
manufacturers, health care providers, and patients in evaluating,
mitigating, and preventing shortages of drugs and biological products
that could otherwise result in non-fatal adverse events, errors,
delayed patient treatment, or interruption in clinical trial
development. The costs and benefits are summarized in table 2. Under
the current environment all notifications provide meaningful
information to identify a shortage or to prevent one, but there is
uncertainty as to whether the scope of the proposed rule could result
in notifications that do not provide information about any shortage and
lead to additional costs. FDA seeks comments on this issue.
The full discussion of economic impacts is available in docket FDA-
2011-N-0898 and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 3 of this proposed rule).

Table 2--Summary of Benefits, Costs and Distributional Effects of Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
Primary Low High Year Discount Period
Category estimate estimate estimate dollars rate covered Notes
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized (millions $/year)........ $57.165 $27.556 $86.773 2012 3% 2014-33 There is uncertainty surrounding these
$57.055 $27.501 $86.609 2012 7% 2014-33 estimates since some underlying
estimates came from non-
representative studies.
Annualized Quantified......................... ......... ......... ......... ......... 3% 2014-33 20-63 preventable shortages per year.
7% 2014-33
---------------------------------------------------------------------------------------------------------
Qualitative................................... Reduction in errors and non-fatal adverse events associated with shortages. Uninterrupted patient access
to drugs and biological products necessary for treatment; continued access to drugs used in clinical
trial development.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized (millions $/year)........ $31.306 $14.990 $47.621 2012 3% 2014-33 There is uncertainty about potential
$31.306 $14.990 $47.621 2012 7% 2014-33 noise from notifications that might
not provide meaningful information,
but which could result in additional
review costs. In addition, these
estimates assume that applicants will
participate in mitigation or
preventive strategies.
---------------------------------------------------------------------------------------------------------
Annualized Quantified......................... None estimated.
---------------------------------------------------------------------------------------------------------
Qualitative................................... None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers
--------------------------------------------------------------------------------------------------------------------------------------------------------
Federal Annualized Monetized (millions $/year) None estimated.
---------------------------------------------------------------------------------------------------------
Other Annualized Monetized (millions $/year).. None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
State, Local or Tribal Gov't.................. None.
---------------------------------------------------------------------------------------------------------
Small Business................................ FDA anticipates that when finalized, small business entities covered by the proposed rule will incur
small costs, $224 per notification or up to 0.10 percent of their average annual sales. Although the
proposed rule would not require it, some firms may choose to incur additional costs associated with
mitigation or prevention strategies.
---------------------------------------------------------------------------------------------------------
Wages......................................... No estimated effect.
---------------------------------------------------------------------------------------------------------
Growth........................................ No estimated effect.
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 65919]]

VI. Paperwork Reduction Act of 1995

This proposed rule contains collections of information that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520) (the PRA). A
description of these provisions is given below with an annual reporting
burden. Included in the estimate is the time for reviewing
instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing the
collection of information.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Permanent Discontinuance or Interruption in Manufacturing of
Certain Drug or Biological Products; Proposed Rule
Description: Under the proposed rule, applicants with an approved
NDA or ANDA for a covered drug product, manufacturers of a covered drug
product marketed without an approved application, and applicants with
an approved BLA for a covered biological product (including certain
applications of blood or blood components) would be required to notify
FDA in writing of a permanent discontinuance of the manufacture of the
drug or biological product or an interruption in manufacturing of the
drug or biological product that is likely to lead to a meaningful
disruption in the applicant's supply (or a significant disruption for
blood or blood components) of that product. The notification would be
required if the drug or biological product is life supporting, life
sustaining, or intended for use in the prevention or treatment of a
debilitating disease or condition, including use in emergency medical
care or during surgery, and if the drug or biological product is not a
radiopharmaceutical drug product.
The proposed rule would require the notification to include the
following information: (1) The name of the drug or biological product
subject to the notification, including the NDC (or, for a biological
product that does not have an NDC, an alternative standard for
identification and labeling that has been recognized as acceptable by
the Center Director); (2) the name of each applicant of the drug or
biological product; (3) whether the notification relates to a permanent
discontinuance of the drug or biological product or an interruption in
manufacturing of the product; (4) a description of the reason for the
permanent discontinuance or interruption in manufacturing; and (5) the
estimated duration of the interruption in manufacturing.
Under the proposed rule, the notification would be required to be
submitted to FDA electronically at least 6 months prior to the date of
the permanent discontinuance or interruption in manufacturing. If 6
months' advance notice is not possible because the permanent
discontinuance or interruption in manufacturing was unanticipated 6
months in advance, the applicant would be required to notify FDA as
soon as practicable, but in no case later than 5 business days after
the permanent discontinuance or interruption in manufacturing occurs.
If an applicant fails to submit the required notification, the
proposed rule would require FDA to issue a letter informing the
applicant or manufacturer of its noncompliance. The applicant would be
required to submit to FDA, not later than 30 calendar days after FDA
issues the letter, a written response setting forth the basis for
noncompliance and providing the required notification.
Description of Respondents: Applicants of prescription drugs and
biological products subject to an approved NDA, ANDA, or BLA, and
manufacturers of prescription drug products marketed without an
approved ANDA or NDA, if the product is life supporting, life
sustaining, or intended for use in the prevention or treatment of a
debilitating disease or condition, including use in emergency medical
care or during surgery, and is not a radiopharmaceutical product. If
the BLA applicant is a manufacturer of blood or blood components, it is
only subject to this rule if it manufactures a significant percentage
of the nation's blood supply.
Burden Estimates: Based on the number of drug and biological
product shortage related notifications we have seen during the past 12
months, we estimate that annually a total of approximately 75
respondents (``number of respondents'' in table 3) would notify us of a
permanent discontinuance of the manufacture of a drug or biological
product or an interruption in manufacturing of a drug or biological
product that is likely to lead to a meaningful disruption in the
respondent's supply of that product under the proposed rule. We
estimate that these respondents would submit annually a total of
approximately 305 notifications as required under proposed Sec. Sec.
310.306, 314.81(b)(3)(iii), and 600.82. Approximately 80 of these
notifications are notifications that we currently receive under OMB
control number 0910-0699 for the IFR, thus we expect to receive
approximately 225 new notifications under the proposed rule (``total
annual responses'' in table 3).\10\ We estimate three notifications per
respondent, because a respondent may experience multiple
discontinuances or interruptions in manufacturing in a year that
require notification (``no. of responses per respondent'' in table 3).
We also estimate that preparing and submitting these notifications to
FDA would take approximately 2 hours per respondent (``hours per
response'' in table 3).
---------------------------------------------------------------------------

\10\ This estimate is based on the number of new notifications
we would receive under the proposed rule as compared to
notifications we currently receive under the IFR. The IFR is our
baseline for comparison for purposes of estimating the burden under
the PRA, because additional notifications that we may currently
receive, but that are not required under the IFR (e.g., as requested
in the draft guidance for industry on Notification to the Food and
Drug Administration of Issues That May Result in a Prescription Drug
Shortage) are not covered under any existing OMB control number, and
thus must be captured in this PRA estimate. In contrast, the
preliminary analysis of impacts of the proposed rule estimates the
costs and benefits of the proposed rule as compared to current
practice. As a result of the use of different baselines for
comparison, the estimate of new notifications under the PRA does not
match the estimate of new notifications included in the preliminary
analysis of impacts (see Table 2B of Ref. 3, which estimates the
number of new notifications we would receive under the proposed
rule, as compared to the number of notifications the Agency receives
currently, including all voluntary notifications not specifically
required by the IFR).
---------------------------------------------------------------------------

We base these estimates on our experience with the reporting of
similar information to FDA since the issuance of the President's
Executive Order 13588 of October 31, 2011 (Ref. 1 of this proposed
rule), and under the interim final rule entitled ``Applications for
Food and Drug Administration Approval To Market a New Drug; Revision of
Postmarketing Reporting Requirements--Permanent'' (76 FR 78530;
December 19, 2011), and the draft guidance entitled ``Draft Guidance
for Industry on Notification to Food and Drug Administration of Issues
That May Result in a Prescription Drug Shortage'' (77 FR 11550;
February 27, 2012).
FDA estimates the burden of this collection of information as
follows:

[[Page 65920]]

Table 3--Estimated Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Number of responses per Total annual Hours per Total hours
respondents respondent responses response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notifications required under proposed Sec. Sec. 310.306 75 3 225 2 450
(unapproved drugs), 314.81(b)(3)(iii) (products approved under an
NDA or ANDA), and 600.82 (products approved under a BLA)..........
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this information collection.

The information collection provisions of this proposed rule have
been submitted to OMB for review. Interested persons are requested to
fax comments regarding the information collection by December 4, 2013,
to the Office of Information and Regulatory Affairs, OMB. 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: 202-395-7245,
or emailed to oira_submission@omb.eop.gov. All comments should be
identified with the title of this information collection and should
include the FDA docket number found in brackets in the heading of this
document.

VII. Federalism

FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, does not contain policies that have
substantial direct effects on the States, on the relationship between
the National Government and the States, or on the distribution of power
and responsibilities among the various levels of government.
Accordingly, the Agency tentatively concludes that the proposed rule
does not contain policies that have federalism implications as defined
in the Executive order and, consequently, a federalism summary impact
statement is not required.

VIII. Environmental Impact

The Agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

IX. Comments

Interested persons may submit either electronic comments regarding
this document to https://www.regulations.gov or written comments to the
Division of Dockets Management (see ADDRESSES). It is only necessary to
send one set of comments. Identify comments with the docket number
found in brackets in the heading of this document. Received comments
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at https://www.regulations.gov.

X. References

The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday,
and are available electronically at https://www.regulations.gov. (FDA
has verified all the Web site addresses in this reference section, but
we are not responsible for any subsequent changes to the Web sites
after this document publishes in the Federal Register).

1. Executive Order 13588, Reducing Prescription Drug Shortages,
October 31, 2011, available at https://www.gpo.gov/fdsys/pkg/FR-2011-11-03/pdf/2011-28728.pdf, accessed November 2012.
2. Center for Drug Evaluation and Research, Manual of Policies and
Procedures 6003.1, Drug Shortage Management, September 26, 2006,
available at https://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/ucm079936.pdf, accessed November
2012.
3. Preliminary Regulatory Impact Analysis, Initial Regulatory
Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for
Permanent Discontinuance or Interruption in Manufacturing of Certain
Drug or Biological Products; Proposed Rule, available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

List of Subjects

21 CFR Part 20

Confidential business information, Courts, Freedom of information,
Government employees.

21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.

21 CFR Part 314

Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

Biologics, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 20,
310, 314, and 600 be amended as follows:

PART 20--PUBLIC INFORMATION

0
1. The authority citation for 21 CFR part 20 continues to read as
follows:

Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 21
U.S.C. 321-393; 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n,
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.

0
2. Revise Sec. 20.100 by adding paragraph (c)(45) to read as follows:

Sec. 20.100 Applicability; cross-reference to other regulations.

* * * * *
(c) * * *
(45) Postmarket notifications of a permanent discontinuance or an
interruption in manufacturing of certain drugs or biological products,
in Sec. Sec. 310.306, 314.81(b)(3)(iii), and 600.82 of this chapter.

PART 310--NEW DRUGS

0
3. The authority citation for 21 CFR part 310 is revised to read as
follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356c, 356e,
360b-360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241,
242(a), 262, 263b-263n.

0
4. Add Sec. 310.306 to subpart D to read as follows:

[[Page 65921]]

Sec. 310.306 Notification of a permanent discontinuance or an
interruption in manufacturing of marketed prescription drugs for human
use without approved new drug applications.

(a) Applicability. Marketed prescription drug products that are not
the subject of an approved new drug or abbreviated new drug application
are subject to this section.
(b) Notification of a permanent discontinuance or an interruption
in manufacturing. The manufacturer of each product subject to this
section must make the notifications required under Sec.
314.81(b)(3)(iii) of this chapter and otherwise comply with Sec.
314.81(b)(3)(iii) of this chapter. If the manufacturer of a product
subject to this section fails to provide notification as required under
Sec. 314.81(b)(3)(iii), FDA will send a letter to the manufacturer and
otherwise follow the procedures set forth under Sec.
314.81(b)(3)(iii)(e).
(c) Drug Shortages List. FDA will include on the drug shortages
list required by Sec. 314.81(b)(3)(iii)(d) drug products that are
subject to this section that it determines to be in shortage. For such
drug products, FDA will provide the names of each manufacturer rather
than the names of each applicant. With respect to information collected
under this paragraph FDA will observe the confidentiality and
disclosure provisions set forth in Sec. 314.81(b)(3)(iii)(d)(2).

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
5. The authority citation for 21 CFR part 314 is revised to read as
follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a,
356b, 356c, 356e, 371, 374, 379e.

0
6. Revise Sec. 314.81 paragraph (b)(3)(iii) to read as follows:

Sec. 314.81 Other postmarketing reports.

* * * * *
(b) * * *
(3) * * *
(iii) Notification of a permanent discontinuance or an interruption
in manufacturing.
(a) An applicant of a prescription drug product must notify FDA in
writing of a permanent discontinuance of manufacture of the drug
product or an interruption in manufacturing of the drug product that is
likely to lead to a meaningful disruption in supply of that drug in the
United States if:
(1) The drug product is life supporting, life sustaining, or
intended for use in the prevention or treatment of a debilitating
disease or condition, including any such drug used in emergency medical
care or during surgery; and
(2) The drug product is not a radiopharmaceutical drug product.
(b) Notifications required by paragraph (b)(3)(iii)(a) of this
section must be submitted to FDA electronically in a format that FDA
can process, review, and archive:
(1) At least 6 months prior to the date of the permanent
discontinuance or interruption in manufacturing; or
(2) If 6 months' advance notice is not possible because the
permanent discontinuance or interruption in manufacturing was not
reasonably anticipated 6 months in advance, as soon as practicable
thereafter, but in no case later than 5 business days after the
permanent discontinuance or interruption in manufacturing occurs.
(c) Notifications required by paragraph (b)(3)(iii)(a) of this
section must include the following information:
(1) The name of the drug subject to the notification, including the
NDC for such drug;
(2) The name of the applicant;
(3) Whether the notification relates to a permanent discontinuance
of the drug or an interruption in manufacturing of the drug;
(4) A description of the reason for the permanent discontinuance or
interruption in manufacturing; and
(5) The estimated duration of the interruption in manufacturing.
(d)(1) FDA will maintain a publicly available list of drugs that
are determined by FDA to be in shortage. This drug shortages list will
include the following information:
(i) The names and NDC(s) for such drugs;
(ii) The name of each applicant for such drugs;
(iii) The reason for the shortage, as determined by FDA from the
following categories: Requirements related to complying with good
manufacturing practices; regulatory delay; shortage of an active
ingredient; shortage of an inactive ingredient component;
discontinuation of the manufacture of the drug; delay in shipping of
the drug; demand increase for the drug; or other reason; and
(iv) The estimated duration of the shortage.
(2) FDA may choose not to make information collected to implement
this paragraph available on the drug shortages list or available under
section 506C(c) of the FD&C Act if FDA determines that disclosure of
such information would adversely affect the public health (such as by
increasing the possibility of hoarding or other disruption of the
availability of drug to patients). FDA will also not provide
information on the public drug shortages list or under section 506C(c)
of the FD&C Act that is protected by 18 U.S.C. 1905 or 5 U.S.C.
552(b)(4), including trade secrets and commercial or financial
information that is considered confidential or privileged under Sec.
20.61.
(e) If an applicant fails to submit a notification as required
under paragraph (b)(3)(iii)(a) of this section and in accordance with
paragraph (b)(3)(iii)(b) of this section, FDA will issue a letter to
the applicant informing it of such failure.
(1) Not later than 30 calendar days after the issuance of such a
letter, the applicant must submit to FDA a written response setting
forth the basis for noncompliance and providing the required
notification under paragraph (b)(3)(iii)(a) of this section and
including the information required under paragraph (b)(3)(iii)(c) of
this section; and
(2) Not later than 45 calendar days after the issuance of a letter
under paragraph (b)(3)(iii)(e) of this section, FDA will make the
letter and the applicant's response to the letter public, unless, after
review of the applicant's response, FDA determines that the applicant
had a reasonable basis for not notifying FDA as required under
paragraph (b)(3)(iii)(a) of this section.
(f) The following definitions of terms apply to paragraph
(b)(3)(iii) of this section:
Drug shortage or shortage means a period of time when the demand or
projected demand for the drug within the United States exceeds the
supply of the drug.
Intended for use in the prevention or treatment of a debilitating
disease or condition means a drug product intended for use in the
prevention or treatment of a disease or condition associated with
mortality or morbidity that has a substantial impact on day-to-day
functioning.
Life supporting or life sustaining means a drug product that is
essential to, or that yields information that is essential to, the
restoration or continuation of a bodily function important to the
continuation of human life.
Meaningful disruption means a change in production that is
reasonably likely to lead to a reduction in the supply of a drug by a
manufacturer that is more than negligible and affects the ability of
the manufacturer to fill orders or meet expected demand for its
product, and does not include interruptions in manufacturing due to
matters such as routine maintenance or

[[Page 65922]]

insignificant changes in manufacturing so long as the manufacturer
expects to resume operations in a short period of time.
* * * * *

Sec. 314.91 [Removed]

0
7. Remove Sec. 314.91.

PART 600--BIOLOGICAL PRODUCTS: GENERAL

0
8. The authority citation for 21 CFR part 600 is revised to read as
follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356c, 356e, 360,
360i, 371, 374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

0
9. Add Sec. 600.82 to subpart D to read as follows:

Sec. 600.82 Notification of a permanent discontinuance or an
interruption in manufacturing.

(a) Notification of a permanent discontinuance or an interruption
in manufacturing.
(1) An applicant of a biological product, other than blood or blood
components for transfusion, which is licensed under section 351 of the
Public Health Service Act, and which may be dispensed only under
prescription under section 503(b)(1) of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 353(b)(1)), must notify FDA in writing of a
permanent discontinuance of manufacture of the biological product or an
interruption in manufacturing of the biological product that is likely
to lead to a meaningful disruption in supply of that biological product
in the United States if:
(i) The biological product is life supporting, life sustaining, or
intended for use in the prevention or treatment of a debilitating
disease or condition, including any such biological product used in
emergency medical care or during surgery; and
(ii) The biological product is not a radiopharmaceutical biological
product.
(2) An applicant of blood or blood components for transfusion,
which is licensed under section 351 of the Public Health Service Act,
and which may be dispensed only under prescription under section 503(b)
of the Federal Food, Drug, and Cosmetic Act, must notify FDA in writing
of a permanent discontinuance of manufacture of any product listed in
its license or an interruption in manufacturing of any such product
that is likely to lead to a significant disruption in supply of that
product in the United States if:
(i) The product is life supporting, life sustaining, or intended
for use in the prevention or treatment of a debilitating disease or
condition, including any such product used in emergency medical care or
during surgery; and
(ii) The applicant is a manufacturer of a significant percentage of
the U.S. blood supply.
(b) Submission and timing of notification. Notifications required
by paragraph (a) of this section must be submitted to FDA
electronically in a format that FDA can process, review, and archive:
(1) At least 6 months prior to the date of the permanent
discontinuance or interruption in manufacturing; or
(2) If 6 months' advance notice is not possible because the
permanent discontinuance or interruption in manufacturing was not
reasonably anticipated 6 months in advance, as soon as practicable
thereafter, but in no case later than 5 business days after such a
permanent discontinuance or interruption in manufacturing occurs.
(c) Information included in notification. Notifications required by
paragraph (a) of this section must include the following information:
(1) The name of the biological product subject to the notification,
including the National Drug Code for such biological product, or an
alternative standard for identification and labeling that has been
recognized as acceptable by the Center Director;
(2) The name of the applicant of the biological product;
(3) Whether the notification relates to a permanent discontinuance
of the biological product or an interruption in manufacturing of the
biological product;
(4) A description of the reason for the permanent discontinuance or
interruption in manufacturing; and
(5) The estimated duration of the interruption in manufacturing.
(d)(1) Public list of biological product shortages. FDA will
maintain a publicly available list of biological products that are
determined by FDA to be in shortage. This biological product shortages
list will include the following information:
(i) The names and National Drug Codes for such biological products,
or the alternative standards for identification and labeling that have
been recognized as acceptable by the Center Director;
(ii) The name of each applicant for such biological products;
(iii) The reason for the shortage, as determined by FDA, selecting
from the following categories: Requirements related to complying with
good manufacturing practices; regulatory delay; shortage of an active
ingredient; shortage of an inactive ingredient component;
discontinuation of the manufacture of the biological product; delay in
shipping of the biological product; demand increase for the biological
product; or other reason; and
(iv) The estimated duration of the shortage.
(2) Confidentiality. FDA may choose not to make information
collected to implement this paragraph available on the biological
product shortages list or available under section 506C(c) of the FD&C
Act if FDA determines that disclosure of such information would
adversely affect the public health (such as by increasing the
possibility of hoarding or other disruption of the availability of the
biological product to patients). FDA will also not provide information
on the public shortages list or under section 506C(c) of the FD&C Act
that is protected by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4), including
trade secrets and commercial or financial information that is
considered confidential or privileged under Sec. 20.61 of this
chapter.
(e) Noncompliance letters. If an applicant fails to submit a
notification as required under paragraph (a) of this section and in
accordance with paragraph (b) of this section, FDA will issue a letter
to the applicant informing it of such failure.
(1) Not later than 30 calendar days after the issuance of such a
letter, the applicant must submit to FDA a written response setting
forth the basis for noncompliance and providing the required
notification under paragraph (a) of this section and including the
information required under paragraph (c) of this section; and
(2) Not later than 45 calendar days after the issuance of a letter
under this paragraph, FDA will make the letter and the applicant's
response to the letter public, unless, after review of the applicant's
response, FDA determines that the applicant had a reasonable basis for
not notifying FDA as required under paragraph (a) of this section.
(f) Definitions. The following definitions of terms apply to this
section:
Biological product shortage or shortage means a period of time when
the demand or projected demand for the biological product within the
United States exceeds the supply of the biological product.
Intended for use in the prevention or treatment of a debilitating
disease or condition means a biological product intended for use in the
prevention or treatment of a disease or condition associated with
mortality or morbidity that has a substantial impact on day-to-day
functioning.
Life supporting or life sustaining means a biological product that
is

[[Page 65923]]

essential to, or that yields information that is essential to, the
restoration or continuation of a bodily function important to the
continuation of human life.
Meaningful disruption means a change in production that is
reasonably likely to lead to a reduction in the supply of a biological
product by a manufacturer that is more than negligible and affects the
ability of the manufacturer to fill orders or meet expected demand for
its product, and does not include interruptions in manufacturing due to
matters such as routine maintenance or insignificant changes in
manufacturing so long as the manufacturer expects to resume operations
in a short period of time.
Significant disruption means a change in production that is
reasonably likely to lead to a reduction in the supply of blood or
blood components by a manufacturer that substantially affects the
ability of the manufacturer to fill orders or meet expected demand for
its product, and does not include interruptions in manufacturing due to
matters such as routine maintenance or insignificant changes in
manufacturing so long as the manufacturer expects to resume operations
in a short period of time.

Dated: October 28, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-25956 Filed 10-31-13; 11:15 am]
BILLING CODE 4160-01-P

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