List of Bulk Drug Substances for Which There is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act, 43877-43882 [2018-18614]

Download as PDF 43877 Federal Register / Vol. 83, No. 167 / Tuesday, August 28, 2018 / Notices laboratories can ensure high-quality laboratory testing, resulting in accurate and reliable testing results. By providing an evaluation program to assess the ability of the laboratories to test for drug resistant M. tuberculosis strains, laboratories also have a selfassessment tool to aid in optimizing their skills in susceptibility testing. The information obtained from the laboratories on susceptibility practices drug concentrations, and test methods performed by laboratories on a set of performance evaluation (PE) samples. The PE samples are sent to participants twice a year. Participants also report demographic data such as laboratory type and the number of tests performed annually. The total estimated annual burden hours are 129. There is no cost to respondents to participate other than their time. and procedures is used to establish variables related to good performance, assessing training needs, and aid with the development of practice standards. Participants in this program include domestic clinical and public health laboratories. Data collection from laboratory participants occurs twice per year. The data collected in this program will include the susceptibility test results of primary and secondary drugs, ESTIMATED ANNUALIZED BURDEN HOURS Domestic Laboratory ......................... Participant Biosafety Compliance Letter of Agreement. MPEP Mycobacterium tuberculosis Results Worksheet. Online Survey Instrument ................ MPEP Mycobacterium tuberculosis Minimum Inhibitory Concentration Results Form. 80 1 5/60 7 80 2 30/60 80 80 4 2 2 15/60 15/60 40 2 ........................................................... ........................ ........................ ........................ 129 Jeffrey M. Zirger, Acting Chief, Information Collection Review Office, Office of Scientific Integrity, Office of the Associate Director for Science, Office of the Director, Centers for Disease Control and Prevention. [FR Doc. 2018–18589 Filed 8–27–18; 8:45 am] BILLING CODE 4163–18–P DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2018–N–3240] List of Bulk Drug Substances for Which There is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act AGENCY: Food and Drug Administration, HHS. ACTION: Notice. The Food and Drug Administration (FDA or Agency) is developing a list of bulk drug substances (active pharmaceutical ingredients) for which there is a clinical need (the 503B Bulks List). Drug products that outsourcing facilities compound using bulk drug substances on the 503B Bulks List qualify for certain exemptions from the Federal Food, Drug, and Cosmetic Act (FD&C Act) provided certain conditions are met. This notice identifies three bulk drug substances that FDA has considered and is proposing not to SUMMARY: VerDate Sep<11>2014 20:00 Aug 27, 2018 Jkt 244001 Number of respondents Average burden per response (in hours) Form name Total ........................................... daltland on DSKBBV9HB2PROD with NOTICES Number of responses per respondent Type of respondents include on the list: Bumetanide, nicardipine hydrochloride, and vasopressin. Additional bulk drug substances nominated by the public for inclusion on this list are currently under consideration and will be the subject of future notices. DATES: Submit either electronic or written comments on the notice by October 29, 2018 to ensure that the Agency considers your comment on this notice before it begins work on a notice reflecting the Agency’s final decision about whether to include these substances on the 503B Bulks List. ADDRESSES: You may submit comments at any time as follows: Electronic Submissions Submit electronic comments in the following way: • Federal eRulemaking Portal: https://www.regulations.gov. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to https:// www.regulations.gov will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else’s Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that PO 00000 Frm 00036 Fmt 4703 Sfmt 4703 Total burden (in hours) identifies you in the body of your comments, that information will be posted on https://www.regulations.gov. • If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see ‘‘Written/Paper Submissions’’ and ‘‘Instructions’’). Written/Paper Submissions Submit written/paper submissions as follows: • Mail/Hand Delivery/Courier (for Written/Paper Submissions): Dockets Management Staff (HFA–305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. • For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in ‘‘Instructions.’’ Instructions: All submissions received must include the Docket No. FDA– 2018–N–3240 for ‘‘List of Bulk Drug Substances For Which There Is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act.’’ Received comments will be placed in the docket and, except for those submitted as ‘‘Confidential Submissions,’’ publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 E:\FR\FM\28AUN1.SGM 28AUN1 43878 Federal Register / Vol. 83, No. 167 / Tuesday, August 28, 2018 / Notices a.m. and 4 p.m., Monday through Friday. • Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states ‘‘THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.’’ The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on https://www.regulations.gov. Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as ‘‘confidential.’’ Any information marked as ‘‘confidential’’ will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA’s posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at: https://www.gpo.gov/ fdsys/pkg/FR-2015-09-18/pdf/201523389.pdf. Docket: For access to the docket to read background documents or the electronic and written/paper 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 Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. FOR FURTHER INFORMATION CONTACT: Elizabeth Hankla, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5216, Silver Spring, MD 20993, 301–796– 3110. SUPPLEMENTARY INFORMATION: daltland on DSKBBV9HB2PROD with NOTICES I. Background A. Drug Compounding Compounded drug products can serve an important role for patients whose clinical needs cannot be met by FDAapproved drug products, such as patients who have an allergy and need a medication to be made without a certain inactive ingredient (e.g., a dye) or hospital inpatients who need VerDate Sep<11>2014 20:00 Aug 27, 2018 Jkt 244001 infusions of a drug combined with a particular diluent. However, they also pose a higher risk to patients than FDAapproved drugs. In 2012, contaminated injectable drug products that a Statelicensed compounding pharmacy shipped to patients and healthcare practitioners across the country caused a fungal meningitis outbreak that resulted in more than 60 deaths and 750 cases of infection.1 This was the most serious of a long history of outbreaks and other serious adverse events, including overdoses, associated with contaminated, superpotent, or otherwise poor quality compounded drugs. In response to this outbreak, Congress enacted the Drug Quality and Security Act (Pub. L. 113–54), which, among other things, added new section 503B to the FD&C Act (21 U.S.C. 353b) and created a new category of compounders known as outsourcing facilities.2 Drug products compounded by outsourcing facilities in accordance with the conditions of section 503B are exempt from FDA drug approval requirements and the requirement that they be labeled with adequate directions for use. Because compounded drug products are not FDA-approved, they have not undergone FDA premarket review for safety, effectiveness, and quality. Although outsourcing facilities must comply with current good manufacturing practice (CGMP) requirements and are inspected by FDA according to a risk-based schedule, their drug products have not been determined to be safe or effective for conditions of use reflected in drug product labeling and lack a premarket inspection and finding of manufacturing quality, all of which are part of the drug approval process. Because compounded drug products are subject to a lower regulatory standard than FDA-approved drug products, they should only be used by patients whose medical needs cannot 1 See https://www.cdc.gov/HAI/outbreaks/ meningitis.html. 2 See Public Law 113–54, section 102(a), 127 Stat. 587, 587–588 (2013). Other compounders, which are not the subject of this notice, are regulated under section 503A of the FD&C Act (21 U.S.C. 353a). These include licensed pharmacists in Statelicensed pharmacies or Federal facilities, and licensed physicians, who have not registered an outsourcing facility with FDA. Drug products compounded by section 503A compounders are exempt from sections 505 (new drug approval requirements), 502(f)(1) (labeling with adequate directions for use), and 501(a)(2)(B) (CGMP requirements) if the conditions of section 503A are met, including that compounding is based on the receipt of valid prescriptions for identified individual patients (section 503A(a)). In general, section 503A compounders do not register with and are not routinely inspected by FDA, and they are primarily overseen by the States. PO 00000 Frm 00037 Fmt 4703 Sfmt 4703 be met by an FDA-approved drug product. Outsourcing facilities sometimes compound drug products using bulk drug substances and other times using finished drug products as the starting materials. In general, compounding using bulk drug substances presents a greater risk to patients than compounding using FDA-approved drug products. FDA-approved drug products provide certain assurances not provided by bulk drug substances, including assurances associated with premarket review by FDA for safety, effectiveness, and quality. Further, using a bulk drug substance in compounding when an FDA-approved drug product would be suitable would undermine the premarket approval process by reducing the incentive for applicants to invest in and seek FDA approval of drug products. The drug approval process is critical to ensure patient access to pharmaceuticals whose quality, safety, and effectiveness have been established. The conditions that section 503B of the FD&C Act places on compounding by outsourcing facilities, including conditions on compounding using bulk drug substances, help to mitigate the risks associated with compounded drug products and protect patient health. Among these is the condition that directs FDA to place a bulk drug substance on the list of bulk drug substances that outsourcing facilities can use in compounding (503B Bulks List) only if there is a clinical need for outsourcing facilities to compound drug products using the bulk drug substance. B. Statutory and Regulatory Background Section 503B of the FD&C Act describes the conditions that must be satisfied for drug products compounded by an outsourcing facility to be exempt from section 505 (21 U.S.C. 355) (concerning the approval of drugs under new drug applications (NDAs) or abbreviated new drug applications (ANDAs)); section 502(f)(1) (21 U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate directions for use); and section 582 (21 U.S.C. 360eee–1) (concerning drug supply chain security requirements).3 Drug products compounded under the conditions in section 503B are not exempt from CGMP requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)).4 Outsourcing facilities are also subject to FDA 3 Section 503B(a) of the FD&C Act. section 503A(a) of the FD&C Act (exempting drugs compounded in accordance with that section) with section 503B(a) of the FD&C Act (not providing the exemption from CGMP requirements). 4 Compare E:\FR\FM\28AUN1.SGM 28AUN1 Federal Register / Vol. 83, No. 167 / Tuesday, August 28, 2018 / Notices inspections according to a risk-based schedule, specific adverse event reporting requirements, and other conditions that help to mitigate the risks of the drug products they compound.5 Outsourcing facilities may or may not obtain prescriptions for identified individual patients and can, therefore, distribute compounded drugs to healthcare practitioners for ‘‘office stock,’’ to hold in their offices in advance of patient need.6 One of the conditions that must be met for a drug product compounded by an outsourcing facility to qualify for exemptions under section 503B is that the outsourcing facility may not compound a drug using a bulk drug substance unless (a) the bulk drug substance appears on a list established by the Secretary identifying bulk drug substances for which there is a clinical need (the 503B Bulks List); or (b) the drug compounded from such bulk drug substances appears on the drug shortage list in effect under section 506E of the FD&C Act (FDA’s drug shortage list) (21 U.S.C. 356e) at the time of compounding, distribution, and dispensing.7 For purposes of section 503B, bulk drug substance means an active pharmaceutical ingredient as defined in 21 CFR 207.1(b).8 Active pharmaceutical ingredient means any substance that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body, but the term does not include intermediates used in the synthesis of the substance.9 10 II. Methodology for Developing the 503B Bulks List A. Process for Developing the List In the Federal Register of December 4, 2013 (78 FR 72838), FDA requested nominations for specific bulk drug substances for the Agency to consider for inclusion on the 503B Bulks List. In response to that request, interested groups and individuals nominated a 5 Section 503B(b)(4) and (5) of the FD&C Act. 503B(d)(4)(C) of the FD&C Act. 7 Section 503B(a)(2)(A) of the FD&C Act. 8 21 CFR 207.3. 9 Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1. 10 Inactive ingredients are not subject to section 503B(a)(2) of the FD&C Act and will not be included in the 503B Bulks List because they are not included within the definition of a bulk drug substance. Pursuant to section 503B(a)(3), inactive ingredients used in compounding must comply with the standards of an applicable United States Pharmacopeia or National Formulary monograph, if a monograph exists. daltland on DSKBBV9HB2PROD with NOTICES 6 Section VerDate Sep<11>2014 20:00 Aug 27, 2018 Jkt 244001 wide variety of substances. However, many of those nominations were not for substances used in compounding as active pharmaceutical ingredients or did not include sufficient information to allow FDA to evaluate the nominated substance. To improve the efficiency of the process for the development of the list of bulk drug substances, FDA reopened the nomination process in the Federal Register of July 2, 2014 (79 FR 37750), and provided more detailed information on what it needs to evaluate nominations for the list. On October 27, 2015 (80 FR 65770), the Agency opened a new docket, FDA–2015–N–3469, to provide an opportunity for interested persons to submit new nominations of bulk drug substances or to re-nominate substances with sufficient information. As FDA evaluates bulk drug substances, it intends to publish notices for public comment in the Federal Register that describe its proposed position on each substance along with the rationale for that position.11 After considering any comments on FDA’s proposals regarding whether to include nominated substances on the 503B Bulks List, FDA intends to consider whether input from the Pharmacy Compounding Advisory Committee (PCAC) on the nominations would be helpful to the Agency in making its determination, and if so, it will seek PCAC input.12 Depending on its review of the docket comments and other relevant information before the Agency, FDA may finalize its proposed determination without change, or it may finalize a modification to its proposal to reflect new evidence or analysis regarding clinical need. FDA will then publish in the Federal Register a list identifying the bulk drug substances for which it has determined there is a clinical need and FDA’s rationale in making that final determination. FDA will also publish in the Federal Register a list of those substances it considered but found that there is no clinical need to use in compounding and FDA’s rationale in making this decision. FDA intends to maintain a current list of all bulk drug substances it has evaluated on its website, with separate lists for bulk drug substances it has placed on the 503B Bulks List and those it has decided not to place on the 503B 11 This is consistent with procedure set forth in section 503B(a)(2)(A)(i). Although the statute only directs FDA to issue a Federal Register notice and seek public comment when it proposes to include bulk drug substances on the 503B Bulks List, we intend to seek comment when the Agency has evaluated a nominated substance and proposes either to include or not to include the substance on the list. 12 Section 503B does not require FDA to consult the PCAC before developing a 503B Bulks List. PO 00000 Frm 00038 Fmt 4703 Sfmt 4703 43879 Bulks List. FDA will only place a bulk drug substance on the 503B Bulks List where it has determined there is a clinical need for outsourcing facilities to compound drug products using the bulk drug substance. If a clinical need to compound drug products using the bulk drug substance has not been demonstrated, based on the information submitted by the nominator and any other information considered by the Agency, FDA will not place a bulk drug substance on the 503B Bulks List. FDA intends to evaluate the bulk drug substances nominated for the 503B Bulks List on a rolling basis. FDA will evaluate and publish in the Federal Register its proposed and final determinations in groups of bulk drug substances until all nominated substances that were sufficiently supported have been evaluated and either placed on the 503B Bulks List or identified as bulk drug substances that were considered but determined not to be appropriate for inclusion on the 503B Bulks List.13 B. Analysis of Substances Nominated for the List As noted above, the 503B Bulks List will include bulk drug substances for which there is a clinical need. The Agency is beginning its evaluation of some of the bulk drug substances that were nominated for inclusion on the 503B Bulks List, proceeding case by case, under the standard provided by the statute.14 In applying this standard to develop the proposals in this notice, FDA is interpreting the phrase ‘‘bulk drug substances for which there is a clinical need’’ to mean that the 503B Bulks List may include a bulk drug substance if: (1) There is a clinical need for an outsourcing facility to compound 13 On June 10, 2016, FDA announced the availability of a guidance for industry that provides additional information regarding FDA’s policies for bulk drug substances nominated for the 503B Bulks List pending our review of nominated substances under the ‘‘clinical need’’ standard entitled ‘‘Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act’’ (81 FR 37502); available at https://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/UCM469122.pdf. 14 On March 26, 2018, FDA announced the availability of a draft guidance entitled ‘‘Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act’’ (503B Bulks Evaluation Guidance) (83 FR 12952); available at https://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/ UCM602276.pdf. The draft guidance proposes policies for developing the 503B Bulks List, including the interpretation of the phrase ‘‘bulk drug substances for which there is a clinical need,’’ as it is used in section 503B. The Agency is considering comments it received on this draft guidance and is working to finalize the guidance. E:\FR\FM\28AUN1.SGM 28AUN1 daltland on DSKBBV9HB2PROD with NOTICES 43880 Federal Register / Vol. 83, No. 167 / Tuesday, August 28, 2018 / Notices the drug product and (2) the drug product must be compounded using the bulk drug substance. FDA is not interpreting supply issues, such as backorders, to be within the meaning of ‘‘clinical need’’ for compounding with a bulk drug substance. Section 503B separately provides for compounding from bulk drug substances under the exemptions from the FD&C Act discussed above if the drug product compounded from the bulk drug substance is on the FDA drug shortage list at the time of compounding, distribution, and dispensing. Additionally, we are not considering cost of the compounded drug product as compared with an FDA-approved drug product to be within the meaning of ‘‘clinical need.’’ The bulk drug substances that we are addressing in this notice are components of FDA-approved drug products, and we therefore began our evaluation by asking the following questions: (a) Is there a basis to conclude, for each FDA-approved product that includes the nominated bulk drug substance, that (i) an attribute of the FDA-approved drug product makes it medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation, and (ii) the drug product proposed to be compounded is intended to address that attribute? (b) Is there a basis to conclude that the drug product proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product? The reason for question (a) is that unless an attribute of the FDA-approved drug is medically unsuitable for certain patients, and a drug product compounded using a bulk drug substance that is a component of the approved drug is intended to address that attribute, there is no clinical need to compound a drug product using that bulk drug substance. Rather, such compounding would unnecessarily expose patients to the risks associated with drug products that do not meet the standards applicable to FDA-approved drug products for safety, effectiveness, quality, and labeling and would undermine the drug approval process. The reason for question (b) is that to place a bulk drug substance on the 503B Bulks List, FDA must determine that there is a clinical need for outsourcing facilities to compound a drug product using the bulk drug substance rather than starting with an FDA-approved drug product. If the answer to both of these questions is ‘‘yes,’’ there may be clinical VerDate Sep<11>2014 20:00 Aug 27, 2018 Jkt 244001 need for outsourcing facilities to compound using the bulk drug substance, and we would analyze the question further.15 If the answer to either of these questions is ‘‘no,’’ we generally would not include the bulk drug substance on the 503B Bulks List, because there would not be a basis to conclude that there may be a clinical need to compound drug products using the bulk drug substance instead of administering or starting with an approved drug product. III. Substances Proposed for the 503B Bulks List The three bulk drug substances that have been evaluated to date and that FDA is proposing not to place on the list, and the reasons for those proposals, are as follows: 1. Bumetanide Bumetanide has been nominated for inclusion on the 503B Bulks List to compound a drug product that manages edema associated with congestive heart failure, cirrhosis, and renal disease.16 The proposed route of administration is intravenous infusion, the proposed dosage form is injection, and the proposed strength is 0.1 milligrams per milliliter (mg/mL). The nominated bulk drug substance is a component of FDAapproved drug products (e.g., ANDAs 074332 and 079196). FDA-approved bumetanide is available as a 0.25 mg/mL injection that may be administered parenterally (intravenously or intramuscularly) to patients in whom gastrointestinal absorption may be impaired or in whom oral administration is not practical.17 18 Because bumetanide is a component of an FDA-approved drug product, we considered whether there is a basis to conclude that the drug product proposed to be compounded must be compounded using a bulk drug substance. The nomination does not provide a basis to conclude that a bulk drug substance must be used to prepare a drug product containing bumetanide 15 According to FDA’s proposal in its 503B Bulks Evaluation Guidance, the additional analysis would consist of the application of four additional factors. We did not answer ‘‘yes’’ to both of the threshold questions for bumetanide, nicardipine hydrochloride, or vasopressin, and we did not consider these four additional factors in our proposal not to include bumetanide, nicardipine hydrochloride, or vasopressin on the 503B Bulks List. 16 See Docket No. FDA–2015–N–3469, document no. FDA–2015–N–3469–0013. 17 See, e.g., labeling available as of the date of this notice at https://www.accessdata.fda.gov/spl/data/ f983b4df-996d-4558-adf7-ee4be1b3a03a/f983b4df996d-4558-adf7-ee4be1b3a03a.xml. 18 Bumetanide is also approved as an oral tablet. See, e.g., ANDA 074225. PO 00000 Frm 00039 Fmt 4703 Sfmt 4703 at concentrations below the concentration of the FDA-approved drug product (0.25 mg/mL). The nomination states that it may not be safer to prepare a drug product at such concentrations by starting with the approved drug; however, the nomination also recognizes that doing so would only require a dilution. It does not take the position or provide support for a position that a bulk drug substance must be used to prepare these concentrations of bumetanide.19 20 Accordingly, FDA finds no basis to conclude that the drug products proposed to be compounded at a lower concentration than FDA-approved bumetanide must be compounded using a bulk drug substance rather than the approved drug product. We also find no basis to conclude that there is a clinical need for an outsourcing facility to compound a drug product using the bulk drug substance bumetanide and, therefore, we propose to not include bumetanide on the 503B Bulks List. Because we are proposing not to include bumetanide on the 503B Bulks List for this reason, we do not consider question (a) in the analysis described above—whether an attribute of the FDAapproved drug product makes it medically unsuitable to treat certain patients and whether the drug product proposed to be compounded is intended to address that attribute. 2. Nicardipine Hydrochloride Nicardipine hydrochloride has been nominated for inclusion on the 503B Bulks List.21 The proposed route of administration is intravenous, the proposed dosage form is injection, and the proposed strength is 0.1–2.5 mg/mL. This nominated bulk drug substance is a component of FDA-approved drug products (e.g., NDAs 022276 and 019734). FDA has approved nicardipine hydrochloride drug products as 0.1 mg/ mL and 0.2 mg/mL ready-to-use solutions for intravenous administration 19 For example, the nomination does not take the position or provide support for a position that a drug product prepared by starting with the approved drug would be unsuitable for administration. 20 The nomination also states that bumetanide should be added to the 503B Bulks List because compounding from the bulk drug substance could allow outsourcing facilities to address issues such as drug shortages, product accessibility, and/or affordability. As noted above, section 503B contains a separate provision for compounding from bulk drug substances to address a drug shortage, and we do not interpret the other price- and supply-related reasons advanced by the nomination to fall within the statutory definition of ‘‘clinical need.’’ 21 See Docket No. FDA–2015–N–3469, document no. FDA–2015–N–3469–0002. E:\FR\FM\28AUN1.SGM 28AUN1 Federal Register / Vol. 83, No. 167 / Tuesday, August 28, 2018 / Notices daltland on DSKBBV9HB2PROD with NOTICES and as a 2.5 mg/mL single-dose vial that must be diluted prior to infusion.22 23 Because nicardipine hydrochloride is a component of an FDA-approved drug product, we considered whether there is a basis to conclude that the drug product proposed to be compounded must be compounded using a bulk drug substance. The nomination does not provide a basis to conclude that a bulk drug substance must be used to prepare drug products containing nicardipine hydrochloride at concentrations at or below the concentrations of the FDAapproved products (0.1, 0.2, and 2.5 mg/ mL) and for the same route of administration (intravenous) as that described in the approved drug product labeling. Initially, we note that two nicardipine drug products are approved in ready-to-administer form (e.g., no further dilutions needed) at concentrations within the range described in the nominations. The nomination does not present a reason to compound a drug product from a bulk drug substance at these concentrations. With respect to other concentrations, the nomination asserts, without support, that it would be safer to use a bulk drug substance than to start with the approved drug product. However, the nomination does not take the position or provide support for the position that a bulk drug substance must be used to prepare these concentrations of nicardipine hydrochloride.24 In fact, the approved labeling of another nicardipine hydrochloride drug product directs the drug product to be diluted to a concentration within that range.25 Accordingly, FDA finds no basis to conclude that the drug products proposed to be compounded at a concentration at or lower than FDAapproved nicardipine hydrochloride 22 See, e.g., labeling available as of the date of this notice at https://www.accessdata.fda.gov/spl/data/ 32756b4e-a977-47ac-9620-0c1ed74d7606/ 32756b4e-a977-47ac-9620-0c1ed74d7606.xml (ready-to-administer) and https:// www.accessdata.fda.gov/spl/data/5444784f-fefe4352-afd1-b4c487165f3a/5444784f-fefe-4352-afd1b4c487165f3a.xml (for dilution). 23 Nicardipine hydrochloride is also approved as an oral capsule. See, e.g., ANDA 074642. 24 For example, the nomination does not take the position or provide support for a position that a drug product prepared by starting with the approved drug product would be unsuitable for patient administration. 25 The nomination also states that nicardipine hydrochloride should be added to the 503B Bulks List because compounding from bulk could help outsourcing facilities to address drug shortages and inconsistencies in supply of generic injections. As noted in section II., section 503B of the FD&C Act already provides for compounding from bulk drug substances to address a drug shortage, and we do not interpret the other price- and supply-related reasons stated in the nomination to constitute clinical need. VerDate Sep<11>2014 20:00 Aug 27, 2018 Jkt 244001 must be compounded using a bulk drug substance rather than the approved drug product. We also find no basis to conclude that there is clinical need for an outsourcing facility to compound using the bulk drug substance nicardipine hydrochloride and, therefore, we propose to not include nicardipine hydrochloride on the 503B Bulks List. Because we are proposing not to include nicardipine hydrochloride on the 503B Bulks List for this reason, we do not consider question (a) in the analysis described above—whether an attribute of the FDAapproved drug product makes it medically unsuitable to treat certain patients and whether the drug product proposed to be compounded is intended to address that attribute. 3. Vasopressin Vasopressin was nominated for inclusion on the 503B Bulks List to compound a drug product that treats septic shock, post-cardiotomy shock, diabetes insipidus, and hypotension.26 The proposed route of administration is intravenous; the proposed dosage form is injection. The nominators proposed a range of specific concentrations (0.1, 0.2, 0.4, and 1 units/mL (U/mL)), and also concentrations above that of the approved drug product without identifying any specific concentration. This nominated bulk drug substance is the active ingredient of the FDAapproved drug VASOSTRICT (NDA 204485). VASOSTRICT is approved as a 20 U/mL intravenous infusion that, per its labeling, should be diluted with normal saline or 5 percent dextrose in water to either 0.1 U/mL or 1 U/mL for intravenous administration.27 Because vasopressin is a component of an FDA-approved drug product, we considered the nominations under questions (a) and (b) of the analysis described previously. One of the nominations proposes vasopressin for the 503B Bulks List so that it can be used to compound a drug product whose concentration of vasopressin is higher than undiluted VASOSTRICT. The nomination does not identify an attribute of VASOSTRICT that makes it medically unsuitable for patients and that such highconcentration products are intended to address. The nomination does not identify any data or information as to the need for a higher concentration than the approved product, nor does the 26 See Docket No. FDA–2015–N–3469, documents nos. FDA–2015–N–3469–0012 and –0023. 27 The labeling as of the date of this notice is available at https://www.accessdata.fda.gov/spl/ data/4166e423-659e-4fe4-8a3c-2394434d00dd/ 4166e423-659e-4fe4-8a3c-2394434d00dd.xml. PO 00000 Frm 00040 Fmt 4703 Sfmt 4703 43881 nomination identify specific higher concentrations it proposes to compound. In addition, the information provided in the nomination does not identify patients for whom a concentration at or below 20 U/mL is medically unsuitable and who would therefore require a higher concentration, and FDA is not aware of patients who would need concentrations above 20 U/ mL. Both nominations propose vasopressin for the 503B Bulks List so that it can be used to compound drug products whose concentrations of vasopressin are lower than undiluted VASOSTRICT. The nominations do not provide a basis to conclude that a bulk drug substance must be used to prepare a drug product that contains vasopressin at concentrations below the concentration of VASOSTRICT (20 U/mL) and uses the same diluents (dextrose and sodium chloride) and the same route of administration (intravenous) as that described in the approved product labeling. The nominations do not take the position or provide support for the position that a bulk drug substance rather than the FDA-approved drug product must be used to prepare these lower concentrations of vasopressin.28 In fact, VASOSTRICT’s approved labeling directs VASOSTRICT to be diluted using the diluents described in the nominations to concentrations within which the drug products proposed to be compounded fall.29 Accordingly, FDA finds no basis to conclude that an attribute of VASOSTRICT makes it medically unsuitable to treat patients such that patients would need a higher concentration higher than that of VASOSTRICT. FDA also finds no basis to conclude that the drug products proposed to be compounded at a lower concentration than VASOSTRICT must be compounded using a bulk drug substance rather than the approved drug. Further, we find no basis to conclude that there is a clinical need for an outsourcing facility to compound 28 For example, the nomination does not take the position or provide support for a position that a drug product prepared by starting with the approved drug product would be unsuitable for patient administration. 29 One of the nominations also states that vasopressin should be added to the 503B Bulks List because compounding from the bulk drug substance could allow outsourcing facilities to address issues such as drug shortages, product accessibility, and/ or affordability. As noted above, section 503B contains a separate provision for compounding from bulk drug substances to address a drug shortage, and we do not interpret the other priceand supply-related reasons advanced by the nomination to fall within the statutory definition of ‘‘clinical need.’’ E:\FR\FM\28AUN1.SGM 28AUN1 43882 Federal Register / Vol. 83, No. 167 / Tuesday, August 28, 2018 / Notices using the bulk drug substance vasopressin and, therefore, we propose to not include vasopressin on the 503B Bulks List. DEPARTMENT OF HEALTH AND HUMAN SERVICES Dated: August 23, 2018. Leslie Kux, Associate Commissioner for Policy. Agency Information Collection Request. 60-Day Public Comment Request [FR Doc. 2018–18614 Filed 8–27–18; 8:45 am] AGENCY: BILLING CODE 4164–01–P ACTION: Office of the Secretary Notice of Interest Rate on Overdue Debts Section 30.18 of the Department of Health and Human Services’ claims collection regulations (45 CFR part 30) provides that the Secretary shall charge an annual rate of interest, which is determined and fixed by the Secretary of the Treasury after considering private consumer rates of interest on the date that the Department of Health and Human Services becomes entitled to recovery. The rate cannot be lower than the Department of Treasury’s current value of funds rate or the applicable rate determined from the ‘‘Schedule of Certified Interest Rates with Range of Maturities’’ unless the Secretary waives interest in whole or part, or a different rate is prescribed by statute, contract, or repayment agreement. The Secretary of the Treasury may revise this rate quarterly. The Department of Health and Human Services publishes this rate in the Federal Register. The current rate of 101⁄4%, as fixed by the Secretary of the Treasury, is certified for the quarter ended June 30, 2018. This rate is based on the Interest Rates for Specific Legislation, ‘‘National Health Services Corps Scholarship Program (42 U.S.C. 254o(b)(1)(A))’’ and ‘‘National Research Service Award Program (42 U.S.C. 288(c)(4)(B)).’’ This interest rate will be applied to overdue debt until the Department of Health and Human Services publishes a revision. Dated: August 23, 2018. David C. Horn, Director, Office of Financial Policy and Reporting. [FR Doc. 2018–18648 Filed 8–27–18; 8:45 am] daltland on DSKBBV9HB2PROD with NOTICES BILLING CODE 4150–04–P 20:00 Aug 27, 2018 Jkt 244001 Office of the Secretary, HHS. Notice. In compliance with the requirement of the Paperwork Reduction Act of 1995, the Office of the Secretary (OS), Department of Health and Human Services, is publishing the following summary of a proposed collection for public comment. DATES: Comments on the ICR must be received on or before October 29, 2018. ADDRESSES: Submit your comments to Sherrette.Funn@hhs.gov or by calling (202) 795–7714. FOR FURTHER INFORMATION CONTACT: When submitting comments or requesting information, please include the document identifier 0990–New— 60D and project title for reference., to Sherrette.funn@hhs.gov, or call 202– 795–7714, Sherrette Funn, the Reports Clearance Officer. SUPPLEMENTARY INFORMATION: Interested persons are invited to send comments regarding this burden estimate or any other aspect of this collection of information, including any of the following subjects: (1) The necessity and utility of the proposed information collection for the proper performance of the agency’s functions; (2) the accuracy of the estimated burden; (3) ways to enhance the quality, utility, and clarity of the information to be collected; and (4) the use of automated collection techniques or other forms of information technology to minimize the information collection burden. Title of the Collection: Cross-Site Evaluation on the Women’s Health College Sexual Assault Policy and Prevention Initiative. Type of Collection: New. OMB No. 0990–XXXX: Office of Women’s Health within OS. Abstract: The Office of Women’s Health is seeking an approval by OMB on a new information collection, CrossSite Evaluation on the Women’s Health College Sexual Assault. The purpose of SUMMARY: DEPARTMENT OF HEALTH AND HUMAN SERVICES VerDate Sep<11>2014 [Document Identifier: OS–0990—New] PO 00000 Frm 00041 Fmt 4703 Sfmt 4703 this data collection is to gather qualitative data across the nine grantee organizations and partners via interviews to gain a full understanding of grantee and partner perceived success over the course of the three-year project; grantee and partner experiences with the initiative; barriers and facilitators to project implementation; sustainability of grantee efforts; and anecdotal or other evidence of reductions in campus sexual violence. Interviews conducted with individuals representing the grantee organizations and campus partners, and will occur once per respondent in the spring of 2019. The CDC estimates that 23 million women have experienced completed or attempted rape in their lifetimes. (National Intimate Partner and Sexual Violence Survey, https://www.cdc.gov/ mmwr/preview/mmwrhtml/ ss6308a1.htm). A September 2015 Association of American Universities (AAU) survey of 150,000 students across 27 colleges and universities indicated that 23% of female undergraduate students reported experiencing sexual assault since enrolling in college (AAU Campus Climate Survey on Sexual Assault and Sexual Misconduct, https:// www.aau.edu/sites/default/files/ %40%20Files/Climate%20Survey/ Executive%20Summary%2012-1415.pdf). The College Sexual Assault Policy, and Prevention Initiative of the Department of Health and Human Services, Office of Women’s Health, has three main goals: (1) Disseminate sexual assault policy and prevention information to organizations in a position to influence and implement policies and practices at post-secondary schools; (2) provide technical assistance to post-secondary schools to establish policies and practices that prevent sexual assault; and (3) assess the success of policy establishment and sustained prevention strategies enacted by partnering organizations and postsecondary schools. E:\FR\FM\28AUN1.SGM 28AUN1

Agencies

[Federal Register Volume 83, Number 167 (Tuesday, August 28, 2018)]
[Notices]
[Pages 43877-43882]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-18614]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-3240]


List of Bulk Drug Substances for Which There is a Clinical Need 
Under Section 503B of the Federal Food, Drug, and Cosmetic Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is developing 
a list of bulk drug substances (active pharmaceutical ingredients) for 
which there is a clinical need (the 503B Bulks List). Drug products 
that outsourcing facilities compound using bulk drug substances on the 
503B Bulks List qualify for certain exemptions from the Federal Food, 
Drug, and Cosmetic Act (FD&C Act) provided certain conditions are met. 
This notice identifies three bulk drug substances that FDA has 
considered and is proposing not to include on the list: Bumetanide, 
nicardipine hydrochloride, and vasopressin. Additional bulk drug 
substances nominated by the public for inclusion on this list are 
currently under consideration and will be the subject of future 
notices.

DATES: Submit either electronic or written comments on the notice by 
October 29, 2018 to ensure that the Agency considers your comment on 
this notice before it begins work on a notice reflecting the Agency's 
final decision about whether to include these substances on the 503B 
Bulks List.

ADDRESSES: You may submit comments at any time as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for Written/Paper 
Submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2018-N-3240 for ``List of Bulk Drug Substances For Which There Is a 
Clinical Need Under Section 503B of the Federal Food, Drug, and 
Cosmetic Act.'' Received comments will be placed in the docket and, 
except for those submitted as ``Confidential Submissions,'' publicly 
viewable at https://www.regulations.gov or at the Dockets Management 
Staff between 9

[[Page 43878]]

a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper 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 Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Elizabeth Hankla, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5216, Silver Spring, MD 20993, 301-796-
3110.

SUPPLEMENTARY INFORMATION: 

I. Background

A. Drug Compounding

    Compounded drug products can serve an important role for patients 
whose clinical needs cannot be met by FDA-approved drug products, such 
as patients who have an allergy and need a medication to be made 
without a certain inactive ingredient (e.g., a dye) or hospital 
inpatients who need infusions of a drug combined with a particular 
diluent. However, they also pose a higher risk to patients than FDA-
approved drugs. In 2012, contaminated injectable drug products that a 
State-licensed compounding pharmacy shipped to patients and healthcare 
practitioners across the country caused a fungal meningitis outbreak 
that resulted in more than 60 deaths and 750 cases of infection.\1\ 
This was the most serious of a long history of outbreaks and other 
serious adverse events, including overdoses, associated with 
contaminated, superpotent, or otherwise poor quality compounded drugs.
---------------------------------------------------------------------------

    \1\ See https://www.cdc.gov/HAI/outbreaks/meningitis.html.
---------------------------------------------------------------------------

    In response to this outbreak, Congress enacted the Drug Quality and 
Security Act (Pub. L. 113-54), which, among other things, added new 
section 503B to the FD&C Act (21 U.S.C. 353b) and created a new 
category of compounders known as outsourcing facilities.\2\ Drug 
products compounded by outsourcing facilities in accordance with the 
conditions of section 503B are exempt from FDA drug approval 
requirements and the requirement that they be labeled with adequate 
directions for use. Because compounded drug products are not FDA-
approved, they have not undergone FDA premarket review for safety, 
effectiveness, and quality. Although outsourcing facilities must comply 
with current good manufacturing practice (CGMP) requirements and are 
inspected by FDA according to a risk-based schedule, their drug 
products have not been determined to be safe or effective for 
conditions of use reflected in drug product labeling and lack a 
premarket inspection and finding of manufacturing quality, all of which 
are part of the drug approval process. Because compounded drug products 
are subject to a lower regulatory standard than FDA-approved drug 
products, they should only be used by patients whose medical needs 
cannot be met by an FDA-approved drug product.
---------------------------------------------------------------------------

    \2\ See Public Law 113-54, section 102(a), 127 Stat. 587, 587-
588 (2013). Other compounders, which are not the subject of this 
notice, are regulated under section 503A of the FD&C Act (21 U.S.C. 
353a). These include licensed pharmacists in State-licensed 
pharmacies or Federal facilities, and licensed physicians, who have 
not registered an outsourcing facility with FDA. Drug products 
compounded by section 503A compounders are exempt from sections 505 
(new drug approval requirements), 502(f)(1) (labeling with adequate 
directions for use), and 501(a)(2)(B) (CGMP requirements) if the 
conditions of section 503A are met, including that compounding is 
based on the receipt of valid prescriptions for identified 
individual patients (section 503A(a)). In general, section 503A 
compounders do not register with and are not routinely inspected by 
FDA, and they are primarily overseen by the States.
---------------------------------------------------------------------------

    Outsourcing facilities sometimes compound drug products using bulk 
drug substances and other times using finished drug products as the 
starting materials. In general, compounding using bulk drug substances 
presents a greater risk to patients than compounding using FDA-approved 
drug products. FDA-approved drug products provide certain assurances 
not provided by bulk drug substances, including assurances associated 
with premarket review by FDA for safety, effectiveness, and quality. 
Further, using a bulk drug substance in compounding when an FDA-
approved drug product would be suitable would undermine the premarket 
approval process by reducing the incentive for applicants to invest in 
and seek FDA approval of drug products. The drug approval process is 
critical to ensure patient access to pharmaceuticals whose quality, 
safety, and effectiveness have been established.
    The conditions that section 503B of the FD&C Act places on 
compounding by outsourcing facilities, including conditions on 
compounding using bulk drug substances, help to mitigate the risks 
associated with compounded drug products and protect patient health. 
Among these is the condition that directs FDA to place a bulk drug 
substance on the list of bulk drug substances that outsourcing 
facilities can use in compounding (503B Bulks List) only if there is a 
clinical need for outsourcing facilities to compound drug products 
using the bulk drug substance.

B. Statutory and Regulatory Background

    Section 503B of the FD&C Act describes the conditions that must be 
satisfied for drug products compounded by an outsourcing facility to be 
exempt from section 505 (21 U.S.C. 355) (concerning the approval of 
drugs under new drug applications (NDAs) or abbreviated new drug 
applications (ANDAs)); section 502(f)(1) (21 U.S.C. 352(f)(1)) 
(concerning the labeling of drugs with adequate directions for use); 
and section 582 (21 U.S.C. 360eee-1) (concerning drug supply chain 
security requirements).\3\
---------------------------------------------------------------------------

    \3\ Section 503B(a) of the FD&C Act.
---------------------------------------------------------------------------

    Drug products compounded under the conditions in section 503B are 
not exempt from CGMP requirements in section 501(a)(2)(B) of the FD&C 
Act (21 U.S.C. 351(a)(2)(B)).\4\ Outsourcing facilities are also 
subject to FDA

[[Page 43879]]

inspections according to a risk-based schedule, specific adverse event 
reporting requirements, and other conditions that help to mitigate the 
risks of the drug products they compound.\5\ Outsourcing facilities may 
or may not obtain prescriptions for identified individual patients and 
can, therefore, distribute compounded drugs to healthcare practitioners 
for ``office stock,'' to hold in their offices in advance of patient 
need.\6\
---------------------------------------------------------------------------

    \4\ Compare section 503A(a) of the FD&C Act (exempting drugs 
compounded in accordance with that section) with section 503B(a) of 
the FD&C Act (not providing the exemption from CGMP requirements).
    \5\ Section 503B(b)(4) and (5) of the FD&C Act.
    \6\ Section 503B(d)(4)(C) of the FD&C Act.
---------------------------------------------------------------------------

    One of the conditions that must be met for a drug product 
compounded by an outsourcing facility to qualify for exemptions under 
section 503B is that the outsourcing facility may not compound a drug 
using a bulk drug substance unless (a) the bulk drug substance appears 
on a list established by the Secretary identifying bulk drug substances 
for which there is a clinical need (the 503B Bulks List); or (b) the 
drug compounded from such bulk drug substances appears on the drug 
shortage list in effect under section 506E of the FD&C Act (FDA's drug 
shortage list) (21 U.S.C. 356e) at the time of compounding, 
distribution, and dispensing.\7\
---------------------------------------------------------------------------

    \7\ Section 503B(a)(2)(A) of the FD&C Act.
---------------------------------------------------------------------------

    For purposes of section 503B, bulk drug substance means an active 
pharmaceutical ingredient as defined in 21 CFR 207.1(b).\8\ Active 
pharmaceutical ingredient means any substance that is intended for 
incorporation into a finished drug product and is intended to furnish 
pharmacological activity or other direct effect in the diagnosis, cure, 
mitigation, treatment, or prevention of disease, or to affect the 
structure or any function of the body, but the term does not include 
intermediates used in the synthesis of the substance.\9\ \10\
---------------------------------------------------------------------------

    \8\ 21 CFR 207.3.
    \9\ Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1.
    \10\ Inactive ingredients are not subject to section 503B(a)(2) 
of the FD&C Act and will not be included in the 503B Bulks List 
because they are not included within the definition of a bulk drug 
substance. Pursuant to section 503B(a)(3), inactive ingredients used 
in compounding must comply with the standards of an applicable 
United States Pharmacopeia or National Formulary monograph, if a 
monograph exists.
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II. Methodology for Developing the 503B Bulks List

A. Process for Developing the List

    In the Federal Register of December 4, 2013 (78 FR 72838), FDA 
requested nominations for specific bulk drug substances for the Agency 
to consider for inclusion on the 503B Bulks List. In response to that 
request, interested groups and individuals nominated a wide variety of 
substances. However, many of those nominations were not for substances 
used in compounding as active pharmaceutical ingredients or did not 
include sufficient information to allow FDA to evaluate the nominated 
substance. To improve the efficiency of the process for the development 
of the list of bulk drug substances, FDA reopened the nomination 
process in the Federal Register of July 2, 2014 (79 FR 37750), and 
provided more detailed information on what it needs to evaluate 
nominations for the list. On October 27, 2015 (80 FR 65770), the Agency 
opened a new docket, FDA-2015-N-3469, to provide an opportunity for 
interested persons to submit new nominations of bulk drug substances or 
to re-nominate substances with sufficient information.
    As FDA evaluates bulk drug substances, it intends to publish 
notices for public comment in the Federal Register that describe its 
proposed position on each substance along with the rationale for that 
position.\11\ After considering any comments on FDA's proposals 
regarding whether to include nominated substances on the 503B Bulks 
List, FDA intends to consider whether input from the Pharmacy 
Compounding Advisory Committee (PCAC) on the nominations would be 
helpful to the Agency in making its determination, and if so, it will 
seek PCAC input.\12\ Depending on its review of the docket comments and 
other relevant information before the Agency, FDA may finalize its 
proposed determination without change, or it may finalize a 
modification to its proposal to reflect new evidence or analysis 
regarding clinical need. FDA will then publish in the Federal Register 
a list identifying the bulk drug substances for which it has determined 
there is a clinical need and FDA's rationale in making that final 
determination. FDA will also publish in the Federal Register a list of 
those substances it considered but found that there is no clinical need 
to use in compounding and FDA's rationale in making this decision.
---------------------------------------------------------------------------

    \11\ This is consistent with procedure set forth in section 
503B(a)(2)(A)(i). Although the statute only directs FDA to issue a 
Federal Register notice and seek public comment when it proposes to 
include bulk drug substances on the 503B Bulks List, we intend to 
seek comment when the Agency has evaluated a nominated substance and 
proposes either to include or not to include the substance on the 
list.
    \12\ Section 503B does not require FDA to consult the PCAC 
before developing a 503B Bulks List.
---------------------------------------------------------------------------

    FDA intends to maintain a current list of all bulk drug substances 
it has evaluated on its website, with separate lists for bulk drug 
substances it has placed on the 503B Bulks List and those it has 
decided not to place on the 503B Bulks List. FDA will only place a bulk 
drug substance on the 503B Bulks List where it has determined there is 
a clinical need for outsourcing facilities to compound drug products 
using the bulk drug substance. If a clinical need to compound drug 
products using the bulk drug substance has not been demonstrated, based 
on the information submitted by the nominator and any other information 
considered by the Agency, FDA will not place a bulk drug substance on 
the 503B Bulks List.
    FDA intends to evaluate the bulk drug substances nominated for the 
503B Bulks List on a rolling basis. FDA will evaluate and publish in 
the Federal Register its proposed and final determinations in groups of 
bulk drug substances until all nominated substances that were 
sufficiently supported have been evaluated and either placed on the 
503B Bulks List or identified as bulk drug substances that were 
considered but determined not to be appropriate for inclusion on the 
503B Bulks List.\13\
---------------------------------------------------------------------------

    \13\ On June 10, 2016, FDA announced the availability of a 
guidance for industry that provides additional information regarding 
FDA's policies for bulk drug substances nominated for the 503B Bulks 
List pending our review of nominated substances under the ``clinical 
need'' standard entitled ``Interim Policy on Compounding Using Bulk 
Drug Substances Under Section 503B of the Federal Food, Drug, and 
Cosmetic Act'' (81 FR 37502); available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469122.pdf.
---------------------------------------------------------------------------

B. Analysis of Substances Nominated for the List

    As noted above, the 503B Bulks List will include bulk drug 
substances for which there is a clinical need. The Agency is beginning 
its evaluation of some of the bulk drug substances that were nominated 
for inclusion on the 503B Bulks List, proceeding case by case, under 
the standard provided by the statute.\14\ In applying this standard to 
develop the proposals in this notice, FDA is interpreting the phrase 
``bulk drug substances for which there is a clinical need'' to mean 
that the 503B Bulks List may include a bulk drug substance if: (1) 
There is a clinical need for an outsourcing facility to compound

[[Page 43880]]

the drug product and (2) the drug product must be compounded using the 
bulk drug substance. FDA is not interpreting supply issues, such as 
backorders, to be within the meaning of ``clinical need'' for 
compounding with a bulk drug substance. Section 503B separately 
provides for compounding from bulk drug substances under the exemptions 
from the FD&C Act discussed above if the drug product compounded from 
the bulk drug substance is on the FDA drug shortage list at the time of 
compounding, distribution, and dispensing. Additionally, we are not 
considering cost of the compounded drug product as compared with an 
FDA-approved drug product to be within the meaning of ``clinical 
need.''
---------------------------------------------------------------------------

    \14\ On March 26, 2018, FDA announced the availability of a 
draft guidance entitled ``Evaluation of Bulk Drug Substances 
Nominated for Use in Compounding Under Section 503B of the Federal 
Food, Drug, and Cosmetic Act'' (503B Bulks Evaluation Guidance) (83 
FR 12952); available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM602276.pdf. The 
draft guidance proposes policies for developing the 503B Bulks List, 
including the interpretation of the phrase ``bulk drug substances 
for which there is a clinical need,'' as it is used in section 503B. 
The Agency is considering comments it received on this draft 
guidance and is working to finalize the guidance.
---------------------------------------------------------------------------

    The bulk drug substances that we are addressing in this notice are 
components of FDA-approved drug products, and we therefore began our 
evaluation by asking the following questions:
    (a) Is there a basis to conclude, for each FDA-approved product 
that includes the nominated bulk drug substance, that (i) an attribute 
of the FDA-approved drug product makes it medically unsuitable to treat 
certain patients for a condition that FDA has identified for 
evaluation, and (ii) the drug product proposed to be compounded is 
intended to address that attribute?
    (b) Is there a basis to conclude that the drug product proposed to 
be compounded must be produced from a bulk drug substance rather than 
from an FDA-approved drug product?
    The reason for question (a) is that unless an attribute of the FDA-
approved drug is medically unsuitable for certain patients, and a drug 
product compounded using a bulk drug substance that is a component of 
the approved drug is intended to address that attribute, there is no 
clinical need to compound a drug product using that bulk drug 
substance. Rather, such compounding would unnecessarily expose patients 
to the risks associated with drug products that do not meet the 
standards applicable to FDA-approved drug products for safety, 
effectiveness, quality, and labeling and would undermine the drug 
approval process. The reason for question (b) is that to place a bulk 
drug substance on the 503B Bulks List, FDA must determine that there is 
a clinical need for outsourcing facilities to compound a drug product 
using the bulk drug substance rather than starting with an FDA-approved 
drug product.
    If the answer to both of these questions is ``yes,'' there may be 
clinical need for outsourcing facilities to compound using the bulk 
drug substance, and we would analyze the question further.\15\ If the 
answer to either of these questions is ``no,'' we generally would not 
include the bulk drug substance on the 503B Bulks List, because there 
would not be a basis to conclude that there may be a clinical need to 
compound drug products using the bulk drug substance instead of 
administering or starting with an approved drug product.
---------------------------------------------------------------------------

    \15\ According to FDA's proposal in its 503B Bulks Evaluation 
Guidance, the additional analysis would consist of the application 
of four additional factors. We did not answer ``yes'' to both of the 
threshold questions for bumetanide, nicardipine hydrochloride, or 
vasopressin, and we did not consider these four additional factors 
in our proposal not to include bumetanide, nicardipine 
hydrochloride, or vasopressin on the 503B Bulks List.
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III. Substances Proposed for the 503B Bulks List

    The three bulk drug substances that have been evaluated to date and 
that FDA is proposing not to place on the list, and the reasons for 
those proposals, are as follows:

1. Bumetanide

    Bumetanide has been nominated for inclusion on the 503B Bulks List 
to compound a drug product that manages edema associated with 
congestive heart failure, cirrhosis, and renal disease.\16\ The 
proposed route of administration is intravenous infusion, the proposed 
dosage form is injection, and the proposed strength is 0.1 milligrams 
per milliliter (mg/mL). The nominated bulk drug substance is a 
component of FDA-approved drug products (e.g., ANDAs 074332 and 
079196). FDA-approved bumetanide is available as a 0.25 mg/mL injection 
that may be administered parenterally (intravenously or 
intramuscularly) to patients in whom gastrointestinal absorption may be 
impaired or in whom oral administration is not practical.\17\ \18\
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    \16\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0013.
    \17\ See, e.g., labeling available as of the date of this notice 
at https://www.accessdata.fda.gov/spl/data/f983b4df-996d-4558-adf7-ee4be1b3a03a/f983b4df-996d-4558-adf7-ee4be1b3a03a.xml.
    \18\ Bumetanide is also approved as an oral tablet. See, e.g., 
ANDA 074225.
---------------------------------------------------------------------------

    Because bumetanide is a component of an FDA-approved drug product, 
we considered whether there is a basis to conclude that the drug 
product proposed to be compounded must be compounded using a bulk drug 
substance. The nomination does not provide a basis to conclude that a 
bulk drug substance must be used to prepare a drug product containing 
bumetanide at concentrations below the concentration of the FDA-
approved drug product (0.25 mg/mL). The nomination states that it may 
not be safer to prepare a drug product at such concentrations by 
starting with the approved drug; however, the nomination also 
recognizes that doing so would only require a dilution. It does not 
take the position or provide support for a position that a bulk drug 
substance must be used to prepare these concentrations of 
bumetanide.\19\ \20\
---------------------------------------------------------------------------

    \19\ For example, the nomination does not take the position or 
provide support for a position that a drug product prepared by 
starting with the approved drug would be unsuitable for 
administration.
    \20\ The nomination also states that bumetanide should be added 
to the 503B Bulks List because compounding from the bulk drug 
substance could allow outsourcing facilities to address issues such 
as drug shortages, product accessibility, and/or affordability. As 
noted above, section 503B contains a separate provision for 
compounding from bulk drug substances to address a drug shortage, 
and we do not interpret the other price- and supply-related reasons 
advanced by the nomination to fall within the statutory definition 
of ``clinical need.''
---------------------------------------------------------------------------

    Accordingly, FDA finds no basis to conclude that the drug products 
proposed to be compounded at a lower concentration than FDA-approved 
bumetanide must be compounded using a bulk drug substance rather than 
the approved drug product. We also find no basis to conclude that there 
is a clinical need for an outsourcing facility to compound a drug 
product using the bulk drug substance bumetanide and, therefore, we 
propose to not include bumetanide on the 503B Bulks List.
    Because we are proposing not to include bumetanide on the 503B 
Bulks List for this reason, we do not consider question (a) in the 
analysis described above--whether an attribute of the FDA-approved drug 
product makes it medically unsuitable to treat certain patients and 
whether the drug product proposed to be compounded is intended to 
address that attribute.

2. Nicardipine Hydrochloride

    Nicardipine hydrochloride has been nominated for inclusion on the 
503B Bulks List.\21\ The proposed route of administration is 
intravenous, the proposed dosage form is injection, and the proposed 
strength is 0.1-2.5 mg/mL. This nominated bulk drug substance is a 
component of FDA-approved drug products (e.g., NDAs 022276 and 019734). 
FDA has approved nicardipine hydrochloride drug products as 0.1 mg/mL 
and 0.2 mg/mL ready-to-use solutions for intravenous administration

[[Page 43881]]

and as a 2.5 mg/mL single-dose vial that must be diluted prior to 
infusion.\22\ \23\
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    \21\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0002.
    \22\ See, e.g., labeling available as of the date of this notice 
at https://www.accessdata.fda.gov/spl/data/32756b4e-a977-47ac-9620-0c1ed74d7606/32756b4e-a977-47ac-9620-0c1ed74d7606.xml (ready-to-
administer) and https://www.accessdata.fda.gov/spl/data/5444784f-fefe-4352-afd1-b4c487165f3a/5444784f-fefe-4352-afd1-b4c487165f3a.xml 
(for dilution).
    \23\ Nicardipine hydrochloride is also approved as an oral 
capsule. See, e.g., ANDA 074642.
---------------------------------------------------------------------------

    Because nicardipine hydrochloride is a component of an FDA-approved 
drug product, we considered whether there is a basis to conclude that 
the drug product proposed to be compounded must be compounded using a 
bulk drug substance. The nomination does not provide a basis to 
conclude that a bulk drug substance must be used to prepare drug 
products containing nicardipine hydrochloride at concentrations at or 
below the concentrations of the FDA-approved products (0.1, 0.2, and 
2.5 mg/mL) and for the same route of administration (intravenous) as 
that described in the approved drug product labeling. Initially, we 
note that two nicardipine drug products are approved in ready-to-
administer form (e.g., no further dilutions needed) at concentrations 
within the range described in the nominations. The nomination does not 
present a reason to compound a drug product from a bulk drug substance 
at these concentrations. With respect to other concentrations, the 
nomination asserts, without support, that it would be safer to use a 
bulk drug substance than to start with the approved drug product. 
However, the nomination does not take the position or provide support 
for the position that a bulk drug substance must be used to prepare 
these concentrations of nicardipine hydrochloride.\24\ In fact, the 
approved labeling of another nicardipine hydrochloride drug product 
directs the drug product to be diluted to a concentration within that 
range.\25\
---------------------------------------------------------------------------

    \24\ For example, the nomination does not take the position or 
provide support for a position that a drug product prepared by 
starting with the approved drug product would be unsuitable for 
patient administration.
    \25\ The nomination also states that nicardipine hydrochloride 
should be added to the 503B Bulks List because compounding from bulk 
could help outsourcing facilities to address drug shortages and 
inconsistencies in supply of generic injections. As noted in section 
II., section 503B of the FD&C Act already provides for compounding 
from bulk drug substances to address a drug shortage, and we do not 
interpret the other price- and supply-related reasons stated in the 
nomination to constitute clinical need.
---------------------------------------------------------------------------

    Accordingly, FDA finds no basis to conclude that the drug products 
proposed to be compounded at a concentration at or lower than FDA-
approved nicardipine hydrochloride must be compounded using a bulk drug 
substance rather than the approved drug product. We also find no basis 
to conclude that there is clinical need for an outsourcing facility to 
compound using the bulk drug substance nicardipine hydrochloride and, 
therefore, we propose to not include nicardipine hydrochloride on the 
503B Bulks List. Because we are proposing not to include nicardipine 
hydrochloride on the 503B Bulks List for this reason, we do not 
consider question (a) in the analysis described above--whether an 
attribute of the FDA-approved drug product makes it medically 
unsuitable to treat certain patients and whether the drug product 
proposed to be compounded is intended to address that attribute.

3. Vasopressin

    Vasopressin was nominated for inclusion on the 503B Bulks List to 
compound a drug product that treats septic shock, post-cardiotomy 
shock, diabetes insipidus, and hypotension.\26\ The proposed route of 
administration is intravenous; the proposed dosage form is injection. 
The nominators proposed a range of specific concentrations (0.1, 0.2, 
0.4, and 1 units/mL (U/mL)), and also concentrations above that of the 
approved drug product without identifying any specific concentration. 
This nominated bulk drug substance is the active ingredient of the FDA-
approved drug VASOSTRICT (NDA 204485). VASOSTRICT is approved as a 20 
U/mL intravenous infusion that, per its labeling, should be diluted 
with normal saline or 5 percent dextrose in water to either 0.1 U/mL or 
1 U/mL for intravenous administration.\27\
---------------------------------------------------------------------------

    \26\ See Docket No. FDA-2015-N-3469, documents nos. FDA-2015-N-
3469-0012 and -0023.
    \27\ The labeling as of the date of this notice is available at 
https://www.accessdata.fda.gov/spl/data/4166e423-659e-4fe4-8a3c-2394434d00dd/4166e423-659e-4fe4-8a3c-2394434d00dd.xml.
---------------------------------------------------------------------------

    Because vasopressin is a component of an FDA-approved drug product, 
we considered the nominations under questions (a) and (b) of the 
analysis described previously.
    One of the nominations proposes vasopressin for the 503B Bulks List 
so that it can be used to compound a drug product whose concentration 
of vasopressin is higher than undiluted VASOSTRICT. The nomination does 
not identify an attribute of VASOSTRICT that makes it medically 
unsuitable for patients and that such high-concentration products are 
intended to address. The nomination does not identify any data or 
information as to the need for a higher concentration than the approved 
product, nor does the nomination identify specific higher 
concentrations it proposes to compound. In addition, the information 
provided in the nomination does not identify patients for whom a 
concentration at or below 20 U/mL is medically unsuitable and who would 
therefore require a higher concentration, and FDA is not aware of 
patients who would need concentrations above 20 U/mL.
    Both nominations propose vasopressin for the 503B Bulks List so 
that it can be used to compound drug products whose concentrations of 
vasopressin are lower than undiluted VASOSTRICT. The nominations do not 
provide a basis to conclude that a bulk drug substance must be used to 
prepare a drug product that contains vasopressin at concentrations 
below the concentration of VASOSTRICT (20 U/mL) and uses the same 
diluents (dextrose and sodium chloride) and the same route of 
administration (intravenous) as that described in the approved product 
labeling. The nominations do not take the position or provide support 
for the position that a bulk drug substance rather than the FDA-
approved drug product must be used to prepare these lower 
concentrations of vasopressin.\28\ In fact, VASOSTRICT's approved 
labeling directs VASOSTRICT to be diluted using the diluents described 
in the nominations to concentrations within which the drug products 
proposed to be compounded fall.\29\
---------------------------------------------------------------------------

    \28\ For example, the nomination does not take the position or 
provide support for a position that a drug product prepared by 
starting with the approved drug product would be unsuitable for 
patient administration.
    \29\ One of the nominations also states that vasopressin should 
be added to the 503B Bulks List because compounding from the bulk 
drug substance could allow outsourcing facilities to address issues 
such as drug shortages, product accessibility, and/or affordability. 
As noted above, section 503B contains a separate provision for 
compounding from bulk drug substances to address a drug shortage, 
and we do not interpret the other price- and supply-related reasons 
advanced by the nomination to fall within the statutory definition 
of ``clinical need.''
---------------------------------------------------------------------------

    Accordingly, FDA finds no basis to conclude that an attribute of 
VASOSTRICT makes it medically unsuitable to treat patients such that 
patients would need a higher concentration higher than that of 
VASOSTRICT. FDA also finds no basis to conclude that the drug products 
proposed to be compounded at a lower concentration than VASOSTRICT must 
be compounded using a bulk drug substance rather than the approved 
drug. Further, we find no basis to conclude that there is a clinical 
need for an outsourcing facility to compound

[[Page 43882]]

using the bulk drug substance vasopressin and, therefore, we propose to 
---------------------------------------------------------------------------
not include vasopressin on the 503B Bulks List.

    Dated: August 23, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-18614 Filed 8-27-18; 8:45 am]
BILLING CODE 4164-01-P

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