Center for Drug Evaluation and Research DATE

TO: File FROM: Center for Drug Evaluation and Research DATE: March 24, 2021 SUBJECT: Nomination and Review of Clinical Need for Quinacrine Hydrochloride to be Included on the 503B Bulk Drug Substances List This memorandum reflects the discussions of the 503B Working Group, comprised of representatives from the following: CDER Office of New Drugs, Office of Pharmaceutical Quality, Office of Regulatory Policy, Office of Compliance, and Office of Regulatory Affairs. The Food and Drug Administration (FDA or Agency) is developing a list of bulk drug substances that can be used in compounding by outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 353b). 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 requirements concerning FDA approval prior to marketing (section 505 (21 U.S.C. 355)); labeling of drugs with adequate directions for use (section 502(f)(1) (21 U.S.C. 352(f)(1))); and drug supply chain security requirements (section 1 582 (21 U.S.C. 360eee-1)). To qualify for the exemptions available in section 503B of the FD&C Act, a drug product must be compounded in an outsourcing facility that does not compound using bulk drug substances unless: (1) the bulk drug substance appears on a list established by the Secretary of Health and Human Services identifying bulk drug substances for which there is a clinical need (the 503B Bulks List), or (2) the drug compounded from such bulk drug substances appears on the drug shortage list in effect under section 506E of the FD&C Act (21 U.S.C. 356e) at the time of compounding, distribution, and dispensing. Quinacrine hydrochloride (referred to as “quinacrine” in this document) is nominated by FDA for inclusion on the list of bulk drug substances for use in compounding under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) based on the Agency’s identification of 1 In general, drug products compounded under the conditions in section 503B must meet current good manufacturing practice (CGMP) requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)). Outsourcing facilities are also subject to FDA 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. 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. U.S. Food & Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 w ww.fda.gov a potential clinical need for its use in treating cutaneous lupus erythematosus (CLE). We evaluated quinacrine for potential inclusion on the 503B Bulks List under the clinical need standard in section 503B, consistent with the interpretation and policies described in FDA’s March 2019 guidance, “Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act” (the Clinical Need Guidance). Because quinacrine is not a component of an FDA-approved drug, we did not ask the questions in the Part 1 analysis described in the Clinical Need Guidance. Consistent with the Part 2 analysis in the Clinical Need Guidance, we have considered data and information regarding the physical and chemical characterization of quinacrine, safety issues raised by use of this substance in compounding, available evidence of effectiveness or lack of effectiveness, and historical and current use in compounding.2 For the reasons stated below, we conclude that the Agency should propose adding the bulk drug substance quinacrine to the 503B Bulks List with a limitation for oral use only. I. Background A. Nominated Product Quinacrine was previously reviewed in 2016 as part of FDA’s consideration of this bulk drug substance for inclusion on the list of bulk drug substances for use in compounding under section 503A of the FD&C Act (503A Bulks List).3 As part of this review: The Division of Anti-Infective Products (DAIP), now the Division of Anti-Infectives (DAI), recommended that quinacrine not be added to the 503A Bulks List for nominated uses as an antimalarial, antiprotozoal and anti-tapeworm drug (see Appendix A). Due to the effectiveness of other drugs and non-drug treatments for those indications, as well as safety concerns associated with quinacrine, the review identified treatment of refractory giardiasis as the primary anti-infective use of quinacrine, and this use occurred almost exclusively outside the U.S. The review noted that the risk-benefit considerations of this substance might be weighted differently for other treatment areas. The Division of Pulmonary, Allergy and Rheumatology Products (DPARP), now the Division of Rheumatology and Transplant Medicine (DRTM), recommended that quinacrine be added to the 503A Bulks List because of the data supporting the effectiveness of quinacrine in treating CLE and systemic lupus erythematosus (SLE) and 2 See Federal Food, Drug, and Cosmetic Act §503B(a)(2)(a) and FDA’s guidance titled “Evaluation of bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act” available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluation-bulk-drug- substances-nominated-use-compounding-under-section-503b-federal-food-drug-and). 3 See: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompounding AdvisoryCommittee/UCM486146.pdf for the Background Package that FDA prepared for the March 8-9, 2016 PCAC meeting. More information about the PCAC meeting can be found at: https://www.fda.gov/advisorycommittees/pharmacy-compounding-advisory-committee/2016-meeting-materials-pharmacy-compounding- advisory-committee. 2 the expectation that serious safety issues, including aplastic anemia, could be addressed with appropriate dosing and monitoring by clinical specialty prescribers (see Appendix B).4 The Division of Bone, Reproductive and Urologic Products (DBRUP), now the Division of Urology, Obstetrics and Gynecology (DUOG), evaluated the nomination of quinacrine for intrauterine administration for non-surgical female sterilization and recommended that quinacrine should not be included on the 503A Bulks List this use (see Appendix C). This recommendation was based on the lack of information on efficacy comparable to other available methods of female sterilization and serious safety concerns of mutagenicity, cytotoxicity and possible carcinogenicity in use of quinacrine for this indication and route of administration. An OND summary memo recommended that quinacrine not be added to the 503A Bulks List (see Appendix D). In “balancing” four criteria as required by regulation (physical and chemical characterization, safety, efficacy, and history of use),5 the memo cites serious adverse effects that can be associated with quinacrine. The summary noted that, while OND believed many rheumatologists are familiar with quinacrine’s serious adverse effects, placing quinacrine on the 503A Bulks List would allow prescribers without the same specialized knowledge to use it as well. OND also expressed concern with the fact that safety labeling would not be required for compounded quinacrine under 503A. The memo therefore recommended that quinacrine be available to patients under an expanded access investigational new drug (IND) application. Quinacrine was presented to the Pharmacy Compounding Advisory Committee (PCAC) on March 8, 2016. The PCAC vote in response to the question “Should quinacrine hydrochloride be placed on the (503A) list?” was YES: 5, NO: 6, ABSTAIN: 0. The public record from the PCAC meeting contains support by individual clinical specialists, patients and associations, including the American Academy of Dermatology Association, for the availability of compounded quinacrine for the treatment of CLE.6 As of the date of this memo, FDA has not issued a proposed rule addressing whether quinacrine should be included on the 503A Bulks List. FDA is nominating quinacrine HCl in oral dosage forms at strengths of 25 – 100 mg for the treatment of cutaneous lupus erythematosus.7 FDA believes that there is a well-defined population who appear to benefit from quinacrine (patients with CLE). As described in the review below, there is a significant body of evidence in the scientific literature regarding the safety profile of quinacrine, including compounded quinacrine and data supporting the potential 4 The DPARP memo is a general statement about the available evidence supporting the effectiveness of different drug products for the treatment of CLE and SLE based on studies reported in the literature that were performed under a variety of conditions and with differing evidentiary value. While these data support the conclusion that there may be a clinical need for drug products compounded from quinacrine, it does not reflect a judgment that any particular drug product is safe and effective and would thus meet the approval standard under section 505 of the FDCA. 5 21 CFR 216.23(c). See also 84 FR 4696 for additional information. 6 Appendix F: Comments submitted for the March 8 and 9, 2016 PCAC Meeting 7 Appendix G: FDA’s nomination of quinacrine for the 503B Bulks List 3 effectiveness of compounded drug products containing quinacrine, especially in patients with CLE, and patients who are not fully clinically responsive to, or are intolerant of, treatment with FDA approved products alone. These patients may respond to use of quinacrine with other drugs, or to the use of quinacrine alone. The historic use of quinacrine in such cases, as documented in the scientific literature, provides support for a finding that there is a clinical need for quinacrine. Quinacrine has a long history of being used in compounded products, appears to be effective in this distinct population of patients, and it has a well characterized safety profile.

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