46688

Proposed Rules Federal Register Vol. 84, No. 172

Thursday, September 5, 2019

This section of the FEDERAL REGISTER 11:59 p.m. Eastern Time on the Received comments, those filed in a contains notices to the public of the proposed comment due date provided in the timely manner (see ADDRESSES), will be issuance of rules and regulations. The DATES section. Comments received by placed in the docket and, except for purpose of these notices is to give interested mail/hand delivery/courier (for written/ those submitted as ‘‘Confidential persons an opportunity to participate in the paper submissions) will be considered Submissions,’’ publicly viewable at rule making prior to the adoption of the final rules. timely if they are postmarked or the https://www.regulations.gov or at the delivery service acceptance receipt is on Dockets Management Staff between 9 or before that date. a.m. and 4 p.m., Monday through DEPARTMENT OF HEALTH AND Electronic Submissions Friday. HUMAN SERVICES • Confidential Submissions—To Submit electronic comments in the submit a comment with confidential Food and Drug Administration following way: information that you do not wish to be • Federal eRulemaking Portal: made publicly available, submit your 21 CFR Part 216 https://www.regulations.gov. Follow the comments only as a written/paper instructions for submitting comments. submission. You should submit two [Docket No. FDA–2018–N–4845] Comments submitted electronically, copies total. One copy will include the RIN 0910–AH81 including attachments, to https:// information you claim to be confidential www.regulations.gov will be posted to with a heading or cover note that states Amendments to the List of Bulk Drug the docket unchanged. Because your ‘‘THIS DOCUMENT CONTAINS Substances That Can Be Used to comment will be made public, you are CONFIDENTIAL INFORMATION.’’ The Compound Drug Products in solely responsible for ensuring that your Agency will review this copy, including Accordance With Section 503A of the comment does not include any the claimed confidential information, in Federal Food, Drug, and Cosmetic Act confidential information that you or a its consideration of comments. The third party may not wish to be posted, AGENCY: Food and Drug Administration, second copy, which will have the such as medical information, your or claimed confidential information HHS. anyone else’s Social Security number, or ACTION: Proposed rule. redacted/blacked out, will be available confidential business information, such for public viewing and posted on SUMMARY: The Food and Drug as a manufacturing process. Please note https://www.regulations.gov. Submit Administration (FDA or Agency) has that if you include your name, contact both copies to the Dockets Management issued a regulation creating a list of bulk information, or other information that Staff. If you do not wish your name and drug substances (active pharmaceutical identifies you in the body of your contact information to be made publicly ingredients) that can be used to comments, that information will be available, you can provide this compound drug products in accordance posted on https://www.regulations.gov. information on the cover sheet and not • If you want to submit a comment with certain compounding provisions of in the body of your comments and you with confidential information that you the Federal Food, Drug, and Cosmetic must identify this information as do not wish to be made available to the Act (FD&C Act), although they are ‘‘confidential.’’ Any information marked public, submit the comment as a neither the subject of an applicable as ‘‘confidential’’ will not be disclosed written/paper submission and in the United States Pharmacopeia (USP) or except in accordance with 21 CFR 10.20 manner detailed (see ‘‘Written/Paper National Formulary (NF) monograph and other applicable disclosure law. For Submissions’’ and ‘‘Instructions’’). nor components of FDA-approved more information about FDA’s posting drugs. This proposed rule would amend Written/Paper Submissions of comments to public dockets, see 80 that list by placing five additional bulk Submit written/paper submissions as FR 56469, September 18, 2015, or access drug substances on the list. This follows: the information at: https://www.gpo.gov/ proposed rule also identifies 26 bulk • Mail/Hand Delivery/Courier (for fdsys/pkg/FR-2015-09-18/pdf/2015- drug substances that FDA has written/paper submissions): Dockets 23389.pdf. considered and proposes not to include Management Staff (HFA–305), Food and Docket: For access to the docket to on the list. Additional substances Drug Administration, 5630 Fishers read background documents or the nominated by the public for inclusion Lane, Rm. 1061, Rockville, MD 20852. electronic and written/paper comments on this list are currently under • For written/paper comments received, go to https:// consideration and will be the subject of submitted to the Dockets Management www.regulations.gov and insert the a future rulemaking. Staff, FDA will post your comment, as docket number, found in brackets in the DATES: Submit either electronic or well as any attachments, except for heading of this document, into the written comments on the proposed rule information submitted, marked and ‘‘Search’’ box and follow the prompts by December 4, 2019. See section VI for identified, as confidential, if submitted and/or go to the Dockets Management the proposed effective date of a final as detailed in ‘‘Instructions.’’ Staff, 5630 Fishers Lane, Rm. 1061, rule based on this proposed rule. Instructions: All submissions received Rockville, MD 20852. ADDRESSES: You may submit comments must include the Docket No. FDA– FOR FURTHER INFORMATION CONTACT: as follows. Please note that late, 2018–N–4845 for ‘‘Amendments to the Rosilend Lawson, Center for Drug untimely filed comments will not be List of Bulk Drug Substances That Can Evaluation and Research, Office of considered. The https:// Be Used to Compound Drug Products in Unapproved Drugs and Labeling www.regulations.gov electronic filing Accordance With Section 503A of the Compliance, Food and Drug system will accept comments until Federal Food, Drug, and Cosmetic Act.’’ Administration, 10903 New Hampshire

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Ave., Bldg. 51, Rm. 5197, Silver Spring, in compounding under section 503A of (NAD), nicotinamide adenine MD 20993, 240–402–6223, the FD&C Act (21 U.S.C. 353a) (referred dinucleotide disodium reduced [email protected]. to as ‘‘the 503A Bulks List’’). Bulk drug (NADH), rubidium chloride, sodium SUPPLEMENTARY INFORMATION: substances that appear on the 503A dichloroacetate, vanadyl sulfate, and Bulks List can be used to compound vasoactive intestinal peptide (VIP). Table of Contents drug products subject to the conditions C. Legal Authority I. Executive Summary of section 503A, even though those A. Purpose of the Proposed Rule substances are not the subject of an Section 503A of the FD&C Act, in B. Summary of the Major Provisions of the applicable USP or NF monograph or conjunction with our general Proposed Rule components of approved drug products. rulemaking authority in section 701(a) C. Legal Authority of the FD&C Act (21 U.S.C. 371(a)), D. Costs and Benefits B. Summary of the Major Provisions of serves as our principal legal authority II. Table of Abbreviations/Commonly Used the Proposed Rule for this proposed rule. Acronyms in This Document Based on the results of its evaluation III. Background of nominated bulk drug substances to D. Costs and Benefits IV. Legal Authority V. Description of the Proposed Rule date, as well as consultation with the FDA evaluated 31 bulk drug A. Criteria for Evaluating Bulk Drug Pharmacy Compounding Advisory substances for this proposed rule, Substances for the 503A Bulks List Committee (PCAC), and the United proposing to place 5 bulk drug B. Methodology for Developing the 503A States Pharmacopoeia Convention, substances on the 503A Bulks List, and Bulks List Incorporated, FDA is proposing to not to place 26 substances on the 503A C. Substances Proposed for Inclusion on amend the 503A Bulks List to include Bulks List. The primary estimate of the the 503A Bulks List five additional bulk drug substances: present value of the costs over 10 years D. Substances Considered and Not Glutaraldehyde, glycolic acid, L- is $1.03 million. The primary estimate Proposed for Inclusion on the 503A citrulline, pyruvic acid, and of the annualized costs is $0.15 million Bulks List VI. Proposed Effective Date trichloroacetic acid (TCA). FDA is also at a 7 percent discount rate and $0.12 VII. Preliminary Economic Analysis of proposing that 26 other substances not million at a 3 percent discount rate. Impacts be included on the list: 7-keto Because we lack sufficient information VIII. Analysis of Environmental Impact dehydroepiandrosterone (DHEA), to quantify most of the costs and IX. Paperwork Reduction Act of 1995 acetyl-L-carnitine (ALC), alanyl-L- benefits of this proposed rule, we also X. Federalism glutamine, Aloe vera 200:1 freeze dried, include a qualitative description of XI. Consultation and Coordination With artemisinin, astragalus extract 10:1, potential benefits and potential costs. Indian Tribal Governments boswellia serrata extract (BWSE), We expect that the rule will affect XII. References cesium chloride, chondroitin sulfate, compounding pharmacies and other I. Executive Summary chrysin, curcumin, D-ribose, deoxy-D- producers that market the affected glucose, diindolylmethane, substances or drug products made from A. Purpose of the Proposed Rule domperidone, epigallocatechin gallate the affected substances, consumers of FDA is proposing to amend its (EGCG), germanium sesquioxide, drug products containing the affected regulations to add substances to the list glycyrrhizin, kojic acid, nettle, substances, and payers that cover these of bulk drug substances that can be used nicotinamide adenine dinucleotide drug products or alternative treatments.

II. TABLE OF ABBREVIATIONS/COMMONLY USED ACRONYMS IN THIS DOCUMENT

Abbreviation/acronym What it means

ALC ...... Acetyl-L-carnitine. BWSE ...... Boswellia serrata extract. CFR ...... Code of Federal Regulations. CFS ...... Chronic fatigue syndrome. CIRS ...... Chronic inflammatory response syndrome. DHEA ...... Dehydroepiandrosterone. EGCG ...... Epigallocatechin gallate. FD&C Act ...... Federal Food, Drug, and Cosmetic Act. FDA ...... Food and Drug Administration. GAIT ...... Glucosamine/Chondroitin Arthritis Intervention Trial. GRAS ...... Generally recognized as safe. HSV ...... Herpes simplex virus. IND ...... Investigational new drug. IV ...... Intravenous. MS ...... Multiple sclerosis. NAICS ...... North American Industry Classification System. NAD ...... Nicotinamide adenine dinucleotide. NADH ...... Nicotinamide adenine dinucleotide disodium reduced. NF ...... National Formulary. NPRM ...... Notice of proposed rulemaking. OA ...... Osteoarthritis. PCAC ...... Pharmacy Compounding Advisory Committee. RA ...... Rheumatoid arthritis. RFA ...... Regulatory Flexibility Analysis. SBA ...... Small Business Administration. TCA ...... Trichloroacetic acid. UCD ...... Urea cycle disorder. USP ...... United States Pharmacopeia.

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II. TABLE OF ABBREVIATIONS/COMMONLY USED ACRONYMS IN THIS DOCUMENT—Continued

Abbreviation/acronym What it means

VIP ...... Vasoactive intestinal peptide.

III. Background bulk drug substance means any physician compounds the drug product Section 503A of the FD&C Act substance that is represented for use in using bulk drug substances that: (1) describes the conditions under which a a drug and that, when used in the Comply with the standards of an compounded drug product may qualify manufacturing, processing, or packaging applicable USP or NF monograph, if a for an exemption from certain sections of a drug, becomes an active ingredient monograph exists, and the USP chapter of the FD&C Act. Those conditions or a finished dosage form of the drug, on pharmacy compounding; (2) if such include that a licensed pharmacist in a but the term does not include a monograph does not exist, are drug State-licensed pharmacy or Federal intermediates used in the synthesis of substances that are components of drugs facility or a licensed physician such substances. approved by the Secretary; or (3) if such compounds the drug product using bulk On August 31, 2016, FDA published a monograph does not exist and the drug substances that: (1) Comply with a final rule in the Federal Register to drug substance is not a component of a the standards of an applicable USP or update its registration and listing drug approved by the Secretary, appear NF monograph,1 if a monograph exists, regulations in part 207 (21 CFR part on the 503A Bulks List. (See section and the USP chapter on pharmacy 207), which included minor changes to 503A(b)(1)(A)(i) of the FD&C Act.) compounding; (2) if such a monograph the definition of bulk drug substance Section 503A(c)(1) of the FD&C Act also does not exist, are drug substances that and moved the definition to § 207.3 (see states that the Secretary shall issue are components of drugs approved by 81 FR 60170 at 60175). This definition regulations to implement section 503A, the Secretary of the Department of became effective on November 29, 2016. and that before issuing regulations to Health and Human Services (Secretary); As set forth in § 207.3, ‘‘bulk drug implement section 503A(b)(1)(A)(i)(III) or (3) if such a monograph does not substance,’’ as referenced in section pertaining to the 503A bulks list, among exist and the drug substance is not a 503A(b)(1)(A) of the FD&C Act, means other sections, the Secretary shall component of a drug approved by the the same as ‘‘active pharmaceutical convene and consult an advisory Secretary, appear on the 503A Bulks ingredient’’ as defined in § 207.1 (21 committee on compounding unless the List. (See section 503A(b)(1)(A)(i) of the CFR 207.1). An ‘‘active pharmaceutical Secretary determines that the issuance FD&C Act.) ingredient’’ is any substance that is of such regulations before consultation On February 19, 2019, FDA published intended for incorporation into a is necessary to protect the public health. a final rule establishing the criteria for finished drug product and is intended to Section 503A(c)(2) of the FD&C Act evaluating substances for inclusion on furnish pharmacological activity or requires the Secretary to issue the the 503A Bulks List, placing six other direct effect in the diagnosis, cure, regulations in consultation with the substances on the list, and identifying mitigation, treatment, or prevention of USP, and to include in the regulation four other substances that were disease, or to affect the structure or any the criteria for such substances that evaluated and not included on the 503A function of the body. The term ‘‘active shall include historical use, reports in Bulks List (84 FR 4696). That final rule pharmaceutical ingredient’’ does not peer-reviewed journals, or other criteria noted that additional substances were include intermediates used in the the Secretary identifies. Thus, section under evaluation, and that new synthesis of the substance (§ 207.1). 503A of the FD&C Act, in conjunction substances may be added to the list Inactive ingredients used in with our general rulemaking authority through subsequent rulemaking. This compounded drug products, such as in section 701(a) of the FD&C Act, proposed rule would amend that list by flavorings, dyes, or diluents, need not serves as our principal legal authority adding five additional substances. It appear on the 503A Bulks List to be for this proposed rule. eligible for use in compounding drug also identifies 26 other substances that V. Description of the Proposed Rule FDA has evaluated and proposes not to products and will not be included on include on the list. the list. FDA proposes to amend § 216.23 (21 Section 503A of the FD&C Act adopts For regulatory history of the 503A CFR 216.23) to include 5 of the bulk the definition of ‘‘bulk drug substance’’ Bulks List, see 81 FR 91071 (December drug substances that were considered on in FDA’s drug establishment registration 16, 2016). the 503A Bulks List and to identify 26 substances that were considered and and listing regulations, which was IV. Legal Authority would not be included on the list. The codified at § 207.3(a)(4) (21 CFR As described in Section III. 207.3(a)(4)) at the time section 503A criteria and methodology for evaluating Background, section 503A of the FD&C was enacted. (See section 503A(b)(1)(A) bulk drug substances for inclusion on Act describes the conditions that must of the FD&C Act.) Under the definition, the list, and FDA’s proposals regarding be satisfied for human drug products the substances addressed in this notice compounded by a licensed pharmacist 1 FDA has interpreted the statutory language of proposed rulemaking (NPRM) are ‘‘applicable United States Pharmacopoeia or or licensed physician to be exempt from described in the paragraphs that follow. National Formulary monograph’’ to refer only to three sections of the FD&C Act (sections official USP or NF monographs for drug substances. 501(a)(2)(B), 502(f)(1), and 505 (21 A. Criteria for Evaluating Bulk Drug Therefore, a substance that is the subject of a U.S.C. 351(a)(2)(B), 352(f)(1), and 355)). Substances for the 503A Bulks List dietary supplement monograph, but not a USP or NF drug substance monograph, does not satisfy the One of the conditions that must be Section 503A(c)(2) of the FD&C Act condition regarding bulk drug substances in section satisfied for a compounded drug to provides that the criteria for 503A(b)(1)(A)(i)(I) of the FD&C Act. Such a qualify for the exemptions under section determining which substances should substance may only be used as a bulk drug substance under section 503A of the FD&C Act if 503A of the FD&C Act is that a licensed appear on the 503A Bulks List shall it is a component of an FDA-approved drug product pharmacist in a State-licensed pharmacy include historical use, reports in peer- or is on the 503A Bulks List. or Federal facility or a licensed reviewed medical literature, or other

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criteria the Secretary may identify. limited its review to a sample of the best Section 503A of the FD&C Act also Under § 216.23, the following criteria literature sources available (e.g., review requires that FDA create the 503A Bulks are used to evaluate the nominated articles in widely known, peer-reviewed List in consultation with the USP. (See substances: journals; meta-analyses; reports of section 503A(c)(2) of the FD&C Act.) To • The physical and chemical randomized controlled trials). this end, FDA has consulted with USP characterization of the substance; FDA’s evaluation of the nominated about the substances that are the subject • Any safety issues raised by the use substances was, necessarily, far less of this proposed rule (Refs. 12 to 16). of the substance in compounded drug rigorous and less comprehensive than After publication of this NPRM, the products; the Agency’s review of drugs as part of public will have an opportunity to • The available evidence of the new drug approval process. The new submit comments on the proposed rule effectiveness or lack of effectiveness of drug approval process is conducted to the docket. After considering those a drug product compounded with the based on extensive data compiled and comments, FDA will publish a final rule substance, if any such evidence exists; submitted with new drug and amending the 503A Bulks List codified and abbreviated new drug applications, • at § 216.23. The final version of the rule Historical use of the substance in which are not available for the may include all, none, or only some of compounded drug products, including nominated substances. Additionally, the the substances proposed here for information about the medical Agency’s review during the drug inclusion on the 503A Bulks List, based condition(s) the substance has been approval process includes premarket upon the Agency’s consideration of the used to treat and any references in peer- evaluation of a specific drug comments received, and will also reviewed medical literature. formulation, the applicant’s chemistry identify those substances the Agency In evaluating candidates for the 503A and manufacturing controls, and has determined should not be included Bulks List under these criteria, the inspection of the establishments where Agency uses a balancing test. on the list. The Agency may amend the approved drugs will be manufactured. 503A Bulks List to add or delete Specifically, the Agency considers each In contrast, these bulk drug substances criterion in the context of the others and substances after further notice and will be evaluated only for possible use comment rulemaking. balance them, on a substance-by- in compounded drugs. With respect to any substance already substance basis, to decide whether a Therefore, the proposed inclusion of a particular substance is appropriate for drug substance on the 503A Bulks List addressed in a final rule, individuals inclusion on the 503A Bulks List. The should not, in any way, be equated with and organizations may petition FDA to criteria are discussed in further detail in or considered an FDA approval, amend the 503A Bulks List (to add or the Agency’s previous rulemaking on endorsement, or recommendation of any delete those bulk drug substances or to the 503A Bulks List (81 FR 91071; 84 FR drug compounded using the substance. consider information about those bulk 4696). Nor should it be assumed that a drug drug substances that is different from compounded using the substances on that which FDA presented to the PCAC) B. Methodology for Developing the 503A (see 21 CFR 10.30). With respect to Bulks List the proposed list has been proven to be safe and effective under the standards substances that have not been addressed FDA reviewed the substances required for Agency approval. Any in rulemaking, individuals and addressed in this proposed rule in the person who represents that a organizations may submit nominations context of adequately supported uses compounded drug made with a bulk of new substances or comments on that were proposed with the drug substance that appears on this list nominated substances to Docket No. nomination. In certain circumstances, is approved by FDA, or otherwise FDA–2015–N–3534. FDA also reviewed substances in the endorsed by FDA generally, or for a C. Substances Proposed for Inclusion on context of uses that were not proposed particular indication, will cause the the 503A Bulks List with the nomination or proposed uses drug to be misbranded under section that were inadequately supported 502(a) (labeling) and/or 502(bb) Under section 503A(c)(2) of the FD&C because, for example, such uses appear (advertising or promotion) of the FD&C Act, FDA is proposing that the following to be widespread, are intended to treat Act. five bulk drug substances, which are serious conditions, or pose serious risks On October 27 and 28, 2015, March 8, neither the subject of an applicable USP to patients. The information that FDA 2016, June 23, 2016, November 3, 2016, or NF monograph nor components of assessed to evaluate the substances May 8 and 9, 2017, and November 20, FDA-approved drugs, be included on addressed in this proposed rule under 2017, FDA consulted with the PCAC the 503A Bulks List, and the drug each of the evaluation criteria was created under section 503A(c)(1) of the products compounded with those obtained from publicly available FD&C Act about the 31 substances that substances may qualify for the sources, including peer-reviewed are addressed in this proposed rule exemptions provided for in section medical literature. Some of this (Refs. 1 to 11). The Agency considered 503A of the FD&C Act (i.e., from information was referenced in the the PCAC’s recommendations in sections 501(a)(2)(B), 502(f)(1), and 505 nominations, and the remainder FDA developing this proposed rule, and the of the FD&C Act). When a salt or ester gathered through independent searches Agency intends to continue to consult of an active moiety is listed, only that of medical and pharmaceutical with the PCAC in evaluating future particular salt or ester may be used for databases. FDA did not review raw data. candidates for the 503A Bulks List. compounding under section 503A of the The nature, quantity, and quality of the Going forward, FDA intends to publish FD&C Act. The base compound and information FDA assessed varied NPRMs proposing additional substances other salts or esters of the same active considerably from substance to be included on the list or not included moiety must be evaluated separately for substance. In some cases, there were on the list on a rolling basis as inclusion on the 503A Bulks List. very little data. For other substances, evaluations are completed. Depending Additionally, when a bulk drug reports in the literature were more on the length of time it takes to substance is included on the 503A plentiful and sometimes comprised complete a rulemaking, multiple Bulks List subject to certain restrictions hundreds or thousands of articles. In rulemakings may be ongoing (for example, for a particular route of those cases, generally the Agency simultaneously. administration (e.g., topical)), only drug

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products that conform to that restriction have also consulted with USP regarding adverse events have been linked to its may qualify for the 503A exemptions. placement of this substance on the 503A use. The following bulk drug substances Bulks List, and USP did not identify any Regarding effectiveness, we found no are being proposed for placement on the additional quality concerns related to clinical trials supporting the 503A Bulks List, to appear in § 216.23(a) this substance (Ref. 14). This proposed effectiveness of the use of L-citrulline of title 21 of the CFR: rule would place glutaraldehyde on the for UCDs. This lack of data is expected (1) Glutaraldehyde. Glutaraldehyde 2 503A Bulks List for topical use at given the small number of patients with was evaluated for topical use in the concentrations of 10 percent or lower. UCDs. However, there is a strong treatment of warts. Glutaraldehyde is (2) Glycolic Acid. Glycolic acid for mechanistic rationale supporting the well characterized physically and topical use was evaluated for use in the use of L-citrulline for UCDs, based on chemically. Glutaraldehyde is treatment of hyperpigmentation and the pathophysiology of the disorder and reasonably safe to use topically in 0.1 photodamaged skin. Glycolic acid, also the goals of treatment. There have also percent to 10 percent solutions for the known as hydroxyacetic acid, is been anecdotal reports of successful treatment of warts. Nonclinical studies physically and chemically well treatment of certain UCDs with L- do not show safety issues in vivo other characterized. When used in high citrulline. Historically, the duration of than irritation and skin sensitization. concentrations, glycolic acid causes use of L-citrulline in compounded drug Skin discoloration has been observed local effects that are typical of a strong products is not clear. L-citrulline has with the use of glutaraldehyde in the acid, such as dermal and eye irritation. been used clinically in the treatment of treatment of warts, which eventually Reported adverse reactions were certain UCDs for approximately 30 to 40 subsides after treatment. Other risks, generally limited in duration and years. Oral L-citrulline is part of the such as allergic contact dermatitis, skin readily manageable. There is no standard of care for certain UCDs. ulceration, and necrosis, were observed information available on long-term On balance, the physiochemical when high strengths of glutaraldehyde outcomes. The available data on short- characteristics, safety, effectiveness, and were used. These risks should be term outcomes do not raise major safety historical use of L-citrulline weigh in managed by the use of glutaraldehyde in concerns associated with the topical use favor of inclusion of this substance on strengths of 10 percent or lower. of glycolic acid. the list. FDA recommended to the PCAC Although there is no standard Data from controlled clinical trials that this substance, for oral use, be regimen for its use, there is available have shown consistently positive results included on the 503A Bulks List (Ref. evidence from uncontrolled clinical in the treatment of epidermal melasma 19). At its meeting on November 20, studies and one randomized controlled or other forms of hyperpigmentation. 2017, the PCAC voted to include L- trial demonstrating the effectiveness of The available evidence suggests that citrulline for oral use on the list (Ref. glutaraldehyde in nongenital cutaneous there is a role for glycolic acid in the 10). We have also consulted with USP wart treatment. There are no approved treatment of melasma, typically as a regarding placement of this substance prescription therapies for warts outside second line treatment. There is also on the 503A Bulks List, and USP did not of the genital area. Glutaraldehyde has some evidence indicating that glycolic identify any additional quality concerns been used in compounded drug acid may be effective for the mitigation related to this substance (Ref. 15). This products for over 40 years, primarily in of manifestations of photodamaged skin. proposed rule would place L-citrulline the treatment of nongenital warts. Historically, glycolic acid has been used for oral use on the 503A Bulks List. On balance, the physiochemical in compounded drug products for (4) Pyruvic Acid. Pyruvic acid for characteristics, safety, effectiveness, and several decades. topical use was evaluated for use in the historical use of glutaraldehyde weigh On balance, the physiochemical treatment of acne, melasma, and warts. in favor of inclusion of this substance characteristics, safety, effectiveness, and It is physically and chemically well on the list. FDA recommended to the historical use of glycolic acid weigh in characterized, but it is unlikely to be PCAC that this substance be included favor of inclusion of this substance on stable in ambient conditions. Stability on the 503A Bulks List for topical use, the list. FDA recommended to the PCAC concerns can be addressed by carefully at concentrations of 10 percent or lower that this substance be included on the sealing the drug product and isolating it (Ref. 17). At its meeting on October 28, 503A Bulks List, for topical use in from moisture and light. Regarding 2015, the PCAC voted to include concentrations up to 70 percent (Ref. safety, we identified no significant glutaraldehyde on the list (Ref. 3). We 18). At its meeting on November 3, safety concerns related to the topical use 2016, the PCAC voted to include of pyruvic acid in compounded drug 2 Note that there is a USP monograph for glutaral glycolic acid for topical use on the list products. The available data indicate concentrate (glutaraldehyde in a 50 percent aqueous (Ref. 8). We have also consulted with that the topical use of pyruvic acid is solution), which is a different concentration than USP regarding placement of this associated with local irritancy, but that proposed in the nominations. USP Guidelines substance on the 503A Bulks List, and reported adverse reactions were state that ‘‘[s]ome drug substances are available as concentrated solutions . . . and are intended to be USP did not identify any additional generally limited in duration and used as intermediates for final formulations.’’ USP quality concerns related to this readily manageable. The most serious Nomenclature Guideline Outline, available at substance (Ref. 15). This proposed rule risk reported was upper respiratory tract https://www.usp.org/sites/default/files/usp/ would place glycolic acid for topical irritation due to inhaled vapors, which document/about/expert-volunteers/expert- committees/nomenclature-guideline.pdf. The use, in concentrations up to 70 percent, can be avoided when patients and glutaral concentrate that is the subject of the USP on the 503A Bulks List. healthcare providers take appropriate monograph is intended to be used as an (3) L-citrulline. L-citrulline for oral precautionary measures (e.g., ensuring intermediate for a final formulation; the USP use was evaluated for use in the the product is administered in a room monograph for glutaral concentrate states that it should be labeled with the statement that it is not treatment of certain urea cycle disorders with adequate ventilation) to protect intended for direct administration to humans or (UCDs). L-citrulline, a non-essential against inhalation. animals. Under § 207.3(a)(4), the definition of ‘‘bulk amino acid, is well characterized Regarding effectiveness, limited data drug substance’’ excludes intermediates used in the physically and chemically. The derived from small, open-label trials synthesis of the bulk drug substance. Therefore, we indicate that the topical use of pyruvic are proposing glutaraldehyde for inclusion on the available nonclinical and clinical data list in forms or concentrations other than those are inadequate to evaluate the safety of acid might be somewhat effective in the provided in the USP monograph. L-citrulline for oral use, but no serious treatment of acne, melasma, and warts,

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which are not serious or life-threatening On balance, the physiochemical included on the 503A Bulks List (Ref. conditions. There are no approved characteristics, safety, effectiveness, and 19). At its meeting on November 20, prescription therapies for warts outside historical use of TCA weigh in favor of 2017, the PCAC voted not to include 7- of the genital area. Pyruvic acid has inclusion of this substance on the list. keto DHEA on the list (Ref. 11). We have been used in compounded drug FDA recommended to the PCAC that also consulted with USP regarding products for approximately 30 years. this substance be included on the 503A placement of this substance on the 503A On balance, the physiochemical Bulks List for topical use (Ref. 18). At Bulks List, and USP did not identify any characteristics, safety, effectiveness, and its meeting on November 3, 2016, the additional quality concerns related to historical use of pyruvic acid weigh in PCAC voted to include TCA on the list this substance (Ref. 15). The proposed favor of inclusion of this substance on for topical use (Ref. 8). We have also rule would not place 7-keto DHEA on the list. FDA recommended to the PCAC consulted with USP regarding the 503A Bulks List. that this substance be included on the placement of this substance on the 503A (2) ALC. ALC was evaluated for use in 503A Bulks List for topical Bulks List, and USP did not identify any the treatment of Alzheimer’s disease, administration (Ref. 20). At its meeting additional quality concerns related to chemotherapy-induced peripheral on June 23, 2016, the PCAC voted to this substance (Ref. 15). This proposed neuropathy, and hepatic include pyruvic acid for topical use on rule would place TCA on the 503A encephalopathy. ALC is well the list (Ref. 7). We have also consulted Bulks List for topical use. characterized physically and chemically but given that hydrolysis may occur on with USP regarding placement of this D. Substances Considered and Not substance on the 503A Bulks List, and its ester group in aqueous solutions, it Proposed for Inclusion on the 503A is unlikely to be stable when formulated USP did not identify any additional Bulks List quality concerns related to this as an aqueous solution. But it is likely FDA is proposing that 26 of the bulk substance (Ref. 14). This proposed rule to be stable in solid dosage forms. drug substances that it has evaluated not would place pyruvic acid for topical use Regarding safety, the available be included on the 503A Bulks List. on the 503A Bulks List. information, which is limited, did not Bulk drug substances that are indicate toxicity, and it appears to be (5) TCA. TCA for topical use was considered for the 503A Bulks list, but well-tolerated when given orally up to evaluated for the treatment of warts and not placed on the list, cannot be used to 3 grams daily. However, the labeling of as a chemical peeling agent. TCA is well compound drug products that would FDA-approved products that contain L- characterized physically and chemically qualify for the exemptions in section carnitine, a closely related drug and is likely to be stable when 503A.3 substance, indicates that those products refrigerated. The safety profile shows The 26 bulk drug substances that have may affect blood clotting and pose a risk that TCA commonly causes erythema, been evaluated and that FDA is for seizures. There may be similar risks crusting, hyperpigmentation and proposing not be placed on the list, and with the use of ALC. hypopigmentation, burning, and pain at the reasons for that proposal, are as There is insufficient evidence to the application site. The reported follows: indicate that ALC is effective for the incidents of adverse effects have (1) 7-keto DHEA. 7-keto DHEA was treatment of the evaluated conditions. increased in correlation with the evaluated for use in the treatment of FDA-approved drug products have been concentration of TCA used (e.g., adverse Raynaud’s phenomena and weight loss. demonstrated to be safe and effective reactions were observed more frequently 7-keto DHEA is physically and under the conditions of use set forth in with a 95 percent TCA solution as chemically well characterized. Although their labeling for the treatment of compared with 85 percent or 50 percent we did not identify a safety signal from Alzheimer’s disease, chemotherapy- solutions), and more adverse effects available information, there are minimal induced peripheral neuropathy, and have been reported when TCA was used data available, and we could not hepatic encephalopathy, which are in the facial and genital areas. At higher adequately assess whether it is safe to serious conditions. The history of ALC concentrations, the potential for use 7-keto DHEA in compounded drug use in compounded drug products is ulceration and subsequent absorption products. Similarly, there are unknown. through open wounds increases. insufficient data to establish whether 7- On balance, the physiochemical Ulcerations have been reported in most keto DHEA would be effective in the characteristics, safety, effectiveness, and studies of TCA in the treatment of treatment of Raynaud’s phenomena or historical use of ALC weigh against genital warts. obesity. Historically, it appears that 7- inclusion of this substance on the list. Regarding effectiveness, the available keto DHEA has been used in FDA recommended to the PCAC that information suggests that TCA may have compounded drug products for this substance not be included on the some effectiveness for the treatment of approximately 7 years. 503A Bulks List (Ref. 21), and at its warts when used at higher On balance, the physiochemical meeting on March 8, 2016, the PCAC concentrations (e.g., in one comparative characteristics, safety, effectiveness, and voted not to include ALC on the list study, more subjects had a ‘‘good’’ historical use of 7-keto DHEA weigh (Ref. 6). We have also consulted with response with an 80 percent TCA against inclusion of this substance on USP regarding placement of this solution as compared with a 35 percent the 503A Bulks List. FDA proposed to substance on the 503A Bulks List, and solution) or in conjunction with an the PCAC that this substance not be USP did not identify any additional additional wart treatment, and thus may quality concerns related to this have a role in treating refractory warts 3 If a prescribing practitioner nevertheless substance (Ref. 14). This proposed rule or patients intolerant of other therapies. believes that a patient should be treated with a drug would not place ALC on the 503A Bulks product compounded from such a bulk drug Warts generally are not a serious or life- substance, it may be possible to obtain the drug List. threatening condition. There are no under an investigational new drug (IND) (3) Alanyl-L-Glutamine. Alanyl-L- approved prescription therapies for application. For information about the requirements glutamine was evaluated for use in warts outside of the genital area. for proceeding under an IND application, visit nutritional support and reducing rates FDA’s website at https://www.fda.gov/drugs/ Historically, TCA has been used in developmentapprovalprocess/howdrugsare of infectious complications in critically compounded drug products for at least developedandapproved/approvalapplications/ ill and surgical patients. Alanyl-L- 20 years. investigationalnewdrugindapplication/default.htm. glutamine is well characterized

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physically and chemically, but there are dried’’ from other Aloe vera extracts. artemisinin has clinically significant toxicity concerns with potential Aloe vera extract is not well effects on different cytochrome P450 impurities, specifically, solvents, characterized physically and enzymes. It is possible that artemisinin endotoxins, bioburden, and heavy metal chemically. Rather, it is a complex acts as a perpetrator to change the impurities linked to the source of the mixture that may contain various exposure of other concomitantly starting material and the reagents used classes of chemical compounds, such as administered drug products that are in processing. Exposure to elemental polysaccharides, organic acids, and substrates of these cytochrome P450 impurities such as heavy metals has anthraquinones. isoforms in patients. These effects may been associated with proven toxicities, Regarding safety, nonclinical data lead to significant drug-drug such as irreversible neurological show that Aloe vera has abortifacient interactions when artemisinin is used impairment and hepatotoxicity. We activity when taken orally and induced with other concomitant medications could not adequately assess whether the skeletal malformations in an oral that are substrates of these cytochrome substance would be sufficiently free of embryofetal toxicity study in rats. P450 isoforms on a daily basis. For use such impurities to be suitable for Clinical data indicate that the topical in the treatment of malaria, when dosing compounding into parenteral solutions use of Aloe vera gel can be tolerated for is limited to 1 or 2 days, we did not for intravenous (IV) administration, short durations without serious toxicity, identify significant safety concerns which would result in 100 percent although it is unclear whether those associated with the use of artemisinin in bioavailability of impurities. data are based on 200:1 freeze dried compounded drug products. However, Additionally, safety concerns were Aloe vera. The anthraquinone derivative with repeat dosing (as would be used in observed in a large, randomized in Aloe vera latex can pose safety the treatment of the other conditions controlled trial of critically ill patients concerns, including potential evaluated), there is evidence of serious who received glutamine carcinogenicity, particularly when used adverse events, the most concerning supplementation, the results of which repeatedly at high doses. We found no being drug-induced hepatitis. There are demonstrated the potential toxicity of data on the safety of the long-term use numerous reports in the literature of alanyl-L-glutamine, including increased of Aloe vera. elevations of transaminases and frequency of increased serum urea Regarding effectiveness, there is bilirubin in patients taking repetitive levels and an increase of in-hospital, 28- limited and conflicting information doses of artemisinin leading to day, and 6-month mortality rates. from controlled clinical trials regarding hospitalization. Regarding effectiveness, a meta- the effectiveness of Aloe vera topical Regarding effectiveness, there is analysis published in the literature products in the treatment of cuts, burns, evidence indicating that artemisinin is suggests that parenteral and wounds. It is not clear whether likely an effective therapy for the supplementation with alanyl-L- these trials used 200: 1 freeze dried Aloe treatment of malaria. However, there are glutamine may benefit certain vera. Historically, Aloe vera has been numerous FDA-approved drug products populations, including through used in herbal remedies in many parts that have been demonstrated to be safe potential decrease in rates of infection of the world. However, we do not have and effective under the conditions of or infectious complications; however, sufficient information to evaluate the use set forth in their labeling for the the available data are limited, and some historical use of compounded drug treatment of malaria. Additionally, other analyses indicated unfavorable products that include 200:1 freeze dried because of concerns about resistance, outcomes. Alanyl-L-glutamine has been Aloe vera. artemisinin is not appropriate for use for used in compounded drug products for On balance, the physiochemical prophylaxis of malaria when traveling approximately 15 years. characteristics, safety, effectiveness, and to countries where malaria is endemic. On balance, the physiochemical historical use of 200:1 freeze dried Aloe For the other uses evaluated, there is characteristics, safety, effectiveness, and vera weigh against inclusion of this insufficient information to evaluate the historical use of alanyl-L-glutamine substance on the list. FDA effectiveness of artemisinin. We found weigh against inclusion of this recommended to the PCAC that this no information regarding the historical substance on the list. FDA substance not be included on the 503A use of artemisinin in compounded drug recommended to the PCAC that this Bulks List (Ref. 21), and at its meeting products. It does not appear to be substance not be included on the 503A on March 8, 2016, the PCAC voted not currently used in compounding in the Bulks List (Ref. 17), and at its meeting to include 200:1 freeze dried Aloe vera United States. on October 27, 2015, the PCAC voted on the list (Ref. 6). We have also On balance, the physiochemical not to include alanyl-L-glutamine on the consulted with USP regarding characteristics, safety, effectiveness, and list (Ref. 2). We have also consulted placement of this substance on the 503A historical use of artemisinin weigh with USP regarding placement of this Bulks List, and USP did not identify any against inclusion of this substance on substance on the 503A Bulks List, and additional quality concerns related to the 503A Bulks List. FDA proposed to USP did not identify any additional this substance (Ref. 14). This proposed the PCAC that this substance not be quality concerns related to this rule proposes not to include Aloe vera included on the 503A Bulks List (Ref. substance (Ref. 14). This proposed rule 200:1 freeze dried on the 503A Bulks 22). At its meeting on May 9, 2017, the would not place alanyl-L-glutamine on List. PCAC voted not to include artemisinin the 503A Bulks List. (5) Artemisinin. Artemisinin was on the list (Ref. 9). We have also (4) Aloe Vera 200:1 Freeze Dried. Aloe evaluated for use in the treatment of consulted with USP regarding vera 200:1 freeze dried 4 was evaluated malaria, helminthic infections, placement of this substance on the 503A as treatment for burns, cuts, and protozoal (particularly toxoplasmosis) Bulks List, and USP did not identify any wounds. We found no information to infections, stomach ulcers, and cancer. additional quality concerns related to differentiate ‘‘Aloe vera 200:1 freeze Artemisinin is well characterized this substance (Ref. 15). The proposed physically and chemically. However, it rule would not place artemisinin on the 4 A USP dietary supplement monograph exists for has a short half-life and poor oral 503A Bulks List. Aloe (USP 38–NF33, Aloe). However, no USP or NF bioavailability due to excess first pass (6) Astragalus Extract 10:1. Astragalus monograph exist for Aloe vera 200:1 freeze-dried or Aloe vera gel 200:1 freeze-dried. See Ref. 21 for metabolism and is poorly soluble in Extract 10:1 (astragalus) was evaluated additional information. water and oil. Regarding safety, for use in the treatment of diabetes

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mellitus, allergic rhinitis, wound materials and manufacturing processes. discussing studies of the substance date healing, asthma, and herpes simplex Regarding safety, there are reports that back to the 1980s keratitis. It is not physically or resin from Boswellia may be an On balance, the physiochemical chemically well characterized. Rather, it emmenagogue and induce abortion. characteristics, safety, effectiveness, and contains hundreds of known and BWSE has also been associated with historical use of cesium chloride weigh unknown chemical entities, particularly gastrointestinal adverse events, against inclusion of this substance on polysaccharides, most of which would including diarrhea, abdominal pain, and the 503A Bulks List. FDA proposed to be difficult to characterize and quantify. nausea. There are reports of an increase the PCAC that this substance not be Nonclinical data regarding the safety of in anticoagulant effect when BWSE included on the 503A Bulks List (Ref. astragalus are limited, and the interacts with oral anticoagulants. 20). At its meeting on June 23, 2016, the significance of the available data is There is some evidence that BWSE PCAC voted not to include cesium unknown given the variability between might improve symptoms of OA in some chloride on the list (Ref. 7). We have astragalus compounds. Based on limited patients, but BWSE has not been shown also consulted with USP regarding clinical data, it appears that astragalus to be effective in inhibiting radiographic placement of this substance on the 503A may be well-tolerated; however, the progression of RA. There are numerous Bulks List, and USP did not identify any limited data are insufficient to allow FDA-approved drug products that have additional quality concerns related to evaluation of potential adverse been demonstrated to be safe and this substance (Ref. 14). The proposed outcomes associated with the use of effective under the conditions of use set rule would not place cesium chloride on astragalus. forth in their labeling for both RA and the 503A Bulks List. Regarding effectiveness, there have OA. Regarding its historical use, (9) Chondroitin Sulfate. Chondroitin been numerous investigations of Boswellia has been used for millennia, sulfate was evaluated for use in the astragalus extracts in the treatment of particularly in Ayurvedic and treatment of OA. Chondroitin sulfate is diabetes. Some of these studies indicate traditional Chinese medicine, for a an unspecified mixture, composed that some formulations of astragalus variety of uses, including wound care, mainly of chondroitin 4-sulfate and extracts reduced plasma glucose and pain, and arthritis, although we don’t chondroitin 6-sulfate in varying insulin sensitivity. However, as noted know how long it has been used in percentages. The relative amounts of above, the significance of the data from compounded drug products. chondroitin sulfate A and chondroitin these studies is unknown given the On balance, the physiochemical sulfate C in the mixture are not well variability between astragalus characteristics, safety, effectiveness, and defined and can vary. compounds. Studies in allergic rhinitis, historical use of BWSE weigh against The data available are inadequate to wound healing, and asthma were inclusion of this substance on the list. evaluate the safety of the use of inadequate to assess effectiveness, and FDA recommended to the PCAC that chondroitin sulfate in compounded no studies in herpes simplex keratitis this substance not be included on the drug products, although there have been were found that assessed clinically 503A Bulks List (Ref. 21), and at its no significant safety signals associated meaningful endpoints. Historically, meeting on March 8, 2016, the PCAC with the use of topical chondroitin astragalus has been used as an herbal voted not to include BWSE on the list sulfate. While most adverse events treatment for a variety of conditions, but (Ref. 6). We have also consulted with reported in the literature with the use of there is insufficient information to USP regarding placement of this chondroitin sulfate orally have not been determine whether astragalus has been substance on the 503A Bulks List, and serious in nature, there have been used in compounded drug products. USP did not identify any additional adverse event reports of concern, On balance, the physiochemical quality concerns related to this including reports of increased characteristics, safety, effectiveness, and substance (Ref. 14). This proposed rule effectiveness of anticoagulants (leading historical use of astragalus weigh would not place BWSE on the 503A to a risk of bleeding) when given in against inclusion of this substance on Bulks List. combination with chondroitin sulfate the 503A Bulks List. FDA proposed to (8) Cesium Chloride. Cesium chloride, and reports of abnormal liver function. the PCAC that this substance not be an inorganic chloride salt, was Regarding effectiveness, a large, well- included on the 503A Bulks List (Ref. evaluated for use in the treatment of controlled trial, the NIH-sponsored 19). At its meeting on November 20, cancer. It is well characterized ‘‘Glucosamine/chondroitin Arthritis 2017, the PCAC voted not to include physically and chemically. Both Intervention Trial (GAIT)’’ (Ref. 21), astragalus on the list (Ref. 11). We have nonclinical and clinical studies give rise showed that, whether alone or in also consulted with USP regarding to significant safety concerns related to combination with glucosamine, the oral placement of this substance on the 503A the use of cesium chloride in use of chondroitin sulfate appears to be Bulks List, and USP did not identify any compounded drug products. Those ineffective for the treatment of pain additional quality concerns related to concerns include links between cesium associated with OA. Other trials this substance (Ref. 15). The proposed chloride use and hypokalemia, seizures, reported positive results, including with rule would not place astragalus on the QT prolongation, and cardiac the topical use of chondroitin sulfate, 503A Bulks List. arrhythmias. There is no evidence that but those trials were generally smaller (7) BWSE. BWSE was evaluated as cesium chloride would be effective in and of shorter duration, and suggest treatment for rheumatoid arthritis (RA) the prevention or treatment of cancer. In that, at best, any effect may be transient. and osteoarthritis (OA). BWSE is not contrast, there are numerous FDA- As noted above, there are numerous physically or chemically well approved drug products that have been FDA-approved drug products that have characterized. Rather, because it is a demonstrated to be safe and effective been demonstrated to be safe and naturally derived, botanical substance, under the conditions of use set forth in effective under the conditions of use set BWSE’s physical and chemical their labeling for the treatment of forth in their labeling for the treatment characteristics can vary according to the cancer. We found no evidence regarding of OA. source and extraction method and the historical use of cesium chloride in Regarding historical use, the use of cannot adequately be controlled to compounded drug products, although it chondroitin sulfate has been reported in ensure a consistent composition absent appears to have been used for the medical literature dating back to the proper controls of the botanical raw treatment of cancer. Literature 1980s, but that discussion was not

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specific to its use in compounded drug (Ref. 7). We have also consulted with with USP regarding placement of this products. We found no information USP regarding placement of this substance on the 503A Bulks List, and regarding how long chondroitin sulfate substance on the 503A Bulks List, and USP did not identify any additional has been used in compounded drug USP did not identify any additional quality concerns related to this products. quality concerns related to this substance (Ref. 14). This proposed rule On balance, the physiochemical substance (Ref. 14). The proposed rule would not place curcumin on the 503A characteristics, safety, effectiveness, and would not place chrysin on the 503A Bulks List. historical use of chondroitin sulfate Bulks List. (12) D-Ribose. D-Ribose was evaluated weigh against inclusion of this (11) Curcumin. Curcumin, a dye as treatment for heart disease and substance on the list. FDA obtained from turmeric, was evaluated chronic fatigue syndrome (CFS).6 D- recommended to the PCAC that this as treatment for familial adenomatous ribose is well characterized physically substance not be included on the 503A polyposis, gastric metaplasia, and oral and chemically. It is commercially Bulks List (Ref. 21), and at its meeting leukoplakia. Although curcumin and its available for use as a food additive and on March 8, 2016, the PCAC voted not major components are well has been designated as Generally to include chondroitin sulfate on the list characterized physically and Recognized as Safe (GRAS). However, a (Ref. 6). We have also consulted with chemically, the term ‘‘curcumin’’ is substance that is safe when used as a USP regarding placement of this used to refer to a wide range of food might not be safe as an active substance on the 503A Bulks List, and substances comprised of different ingredient in a drug product, for USP did not identify any additional amounts of different curcuminoids, example, when used for a route of quality concerns related to this which might have different physical and administration other than oral. In substance (Ref. 14). This proposed rule chemical characteristics. addition, a GRAS determination does would not place chondroitin sulfate on Curcumin appears to be mostly well not indicate that a substance would the 503A Bulks List. tolerated for short durations, and the have any effectiveness for a proposed (10) Chrysin. Chrysin was evaluated most common adverse events were use when used in a compounded drug for use as an aromatase inhibitor.5 mild. However, the evaluated product. When used as a drug product Chrysin is well characterized physically conditions can be chronic, requiring D-ribose may cause a false and chemically. Regarding safety, treatment for years. There are limited hypoglycemia if the dose constitutes a limited nonclinical studies show data about the safety of curcumin in substantial fraction of total daily caloric chrysin has the potential for compounded drug products given its intake.7 The use of D-ribose in mutagenicity and neurotoxicity. poor bioavailability, lack of exposure- compounded drug products poses a Clinically, systemic exposure to chrysin response for safety, lack of uniformity of particular safety concern to patients is low due to poor oral bioavailability the curcumin used, and lack of with diabetes mellitus, since they often and rapid metabolism and elimination. information from well-designed clinical have concomitant coronary artery We found insufficient information about trials. Although preliminary signs of disease or ischemic cardiac myopathy/ the topical or oral use of chrysin to activity related to curcumin (generally ischemic heart failure. Hypoglycemia, evaluate its safety. related to biomarkers or effects on detected with glucose monitoring, could Regarding effectiveness, in vitro data disease processes) have been reported in complicate the titration of insulin in shows that chrysin inhibits aromatase at small and uncontrolled studies, there is patients with diabetes, particularly high concentrations, but we found no insufficient evidence that it would be when high pharmacologic doses of D- clinical data indicating that chrysin effective for the proposed conditions. ribose and insulin are administered would be effective in the treatment of Further, there is a risk that patients close in time. cancer, which is the use for which FDA- might use curcumin to treat the Regarding effectiveness, there is a lack approved aromatase inhibitors are conditions reviewed in lieu of FDA- of proven benefit associated with D- approved products that have been indicated, specifically, for the treatment ribose for the treatment of either heart demonstrated to be safe and effective disease or CFS. The reported studies of of breast cancer in women. There are under the conditions of use set forth in the utility of D-ribose for the treatment also FDA-approved products indicated their labeling, or that they might delay of cardiovascular disease provide no for testosterone replacement, another the use of such products. Familial convincing evidence of a meaningful common use of compounded chrysin adenomatous polyposis in particular is clinical benefit. There are many FDA- products. We found insufficient a serious condition; virtually all patients approved drug products that have been information to evaluate the historical will develop colon cancer if it is left demonstrated to be safe and effective use of chrysin in compounded drug untreated. Turmeric has historically under the conditions of use set forth in products. It is currently being been used in traditional Indian their labeling for the treatment of heart compounded for use in drug products medicine, but we found no information disease, which is a serious condition. promoted for bodybuilding and ‘‘men’s on the length of time curcumin has been While we recognize that there are no health.’’ used in compounded drug products. It FDA-approved therapies indicated for On balance, the physiochemical has been used in an IV dosage form to CFS, the treatment of CFS with D-ribose characteristics, safety, effectiveness, and treat eczema and thrombocytopenia has been evaluated in only a single historical use of chrysin weigh against (Ref. 23). inclusion of this substance on the 503A On balance, the physiochemical 6 Currently, FDA does not recognize a particular Bulks List. FDA proposed to the PCAC characteristics, safety, effectiveness, and definition or name as appropriate for use in clinical that this substance not be included on historical use of curcumin weigh against trials of drug products for CFS, which is also referred to as myalgic encephalomyelitis or the 503A Bulks List (Ref. 20). At its inclusion of this substance on the list. meeting on June 23, 2016, the PCAC systemic exertion intolerance disease. CFS is used FDA recommended to the PCAC that in this NPRM because it was the term used in the voted not to include chrysin on the list this substance not be included on the nomination for D-ribose. 503A Bulks List (Ref. 17), and at its 7 Food products that contain D-ribose as a food 5 Chrysin was proposed for use ‘‘as an aromatase additive at ≥1 percent per volume or weight also inhibitor which prevents the conversion of meeting on October 27, 2015, the PCAC contain other sources of carbohydrates (and thus testosterone to estrogen’’ for the treatment of ‘‘high voted not to include curcumin on the glucose), and thus might not pose the same risk of estrogen and low testosterone.’’ (Ref. 20). list (Ref. 2). We have also consulted false hypoglycemia.

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small uncontrolled, unblinded study On balance, the physiochemical USP regarding placement of this (Ref. 24). We do not believe that this characteristics, safety, effectiveness, and substance on the 503A Bulks List, and study demonstrates that there is a historical use of deoxy-D-glucose weigh USP did not identify any additional benefit to CFS patients that would against inclusion of this substance on quality concerns related to this outweigh the risks of using D-ribose the list. FDA recommended to the PCAC substance (Ref. 15). The proposed rule outlined above. that this substance not be included on would not place diindolylmethane on Regarding the historical use of D- the 503A Bulks List (Ref. 17), and at its the 503A Bulks List. ribose, we do not know how long it has meeting on October 27, 2015, the PCAC (15) Domperidone. Domperidone was been used as a compounded drug voted not to include deoxy-D-glucose on evaluated as treatment for gastroparesis, product. It first appeared in the medical the list (Ref. 2). We have also consulted nausea and vomiting, and to enhance literature in 1946. with USP regarding placement of this lactation. Domperidone is well On balance, the physiochemical substance on the 503A Bulks List, and characterized physically and characteristics, safety, effectiveness, and USP did not identify any additional chemically. Serious concerns about the historical use of D-ribose weigh against quality concerns related to this safety of domperidone are raised by inclusion of this substance on the list. substance (Ref. 14). This proposed rule both clinical and nonclinical studies. At FDA recommended to the PCAC that would not place deoxy-D-glucose on the therapeutic doses approved outside the this substance not be included on the 503A Bulks List. United States, domperidone carries a 503A Bulks List (Ref. 21), and at its (14) Diindolylmethane. serious risk of life-threatening cardiac meeting on March 8, 2016, the PCAC Diindolylmethane was evaluated for use arrhythmias and sudden cardiac death voted not to include D-ribose on the list in the treatment of cancer. It is well in all populations, including healthy (Ref. 6). We have also consulted with characterized physically and lactating women, and potentially, their USP regarding placement of this chemically. Oral administration of infants. Domperidone has known risks substance on the 503A Bulks List, and diindolylmethane caused white pulp of QT interval prolongation, and the USP did not identify any additional atrophy and decreased immune cell dose and exposure at which quality concerns related to this counts in the spleen of neonatal mice domperidone can cause serious cardiac substance (Ref. 14). This proposed rule and increased serum cytokines in adult arrhythmias are not well characterized would not place D-ribose on the 503A mice. Diindolylmethane induced in patients. The effectiveness of domperidone as a Bulks List. hepatic CYP1A1, CYP1A2, and CYP3A2 in rats, suggesting that drug-drug galactagogue is unknown given the (13) Deoxy-D-Glucose. Deoxy-D- interactions might occur with its use in limited evidence available, and glucose, also known as 2-deoxy-D- patients. While the nonclinical data are evidence suggesting that domperidone glucose, was evaluated for use in the limited, the available data suggest that may be beneficial for nausea and treatment of cancer and herpes simplex there may be a safety concern with the vomiting and gastroparesis is limited virus (HSV). Deoxy-D-glucose is use of diindolylmethane in due to the small size of the clinical trials physically and chemically well compounded drug products. Although that have been conducted for these uses characterized. Regarding safety, in rats, we identified no serious adverse events or design flaws with those trials. dietary supplementation with deoxy-D- reports related to the use of Domperidone has been compounded in glucose showed cardiac toxicity, diindolylmethane in humans, the the United States for at least a decade developmental and reproductive available clinical data are too limited to and has been used in other jurisdictions toxicity, carcinogenicity, and decreased draw conclusions regarding the safety of since at least the 1970s. median survival. In humans, the safety diindolylmethane. On balance, the physiochemical profile of deoxy-D-glucose was only Clinical studies published to date characteristics, safety, effectiveness, and manageable at lower doses used with show changes in biomarkers, but no historical use of domperidone weigh combination treatments; when used as a clinical publication to date describes an against inclusion of this substance on single agent, based on limited clinical effect of diindolylmethane on any the list. FDA recommended to the PCAC evidence, the high dose of deoxy-D- endpoint generally accepted in clinical that this substance not be included on glucose required was unacceptably oncology as being of clinical benefit. the 503A Bulks List (Ref. 17), and at its toxic. There is no evidence that meeting on October 28, 2015, the PCAC Regarding effectiveness, we found no diindolylmethane would be effective in voted not to include domperidone on evidence indicating that deoxy-D- the treatment of cancer. In contrast, the list (Ref. 4). We have also consulted glucose would be effective as a there are numerous FDA-approved drug with USP regarding placement of this treatment for cancer or HSV. In the products that have been demonstrated substance on the 503A Bulks List, and reported clinical trials that studied the to be safe and effective under the USP did not identify any additional use of deoxy-D-glucose for the treatment conditions of use set forth in their quality concerns related to this of cancer, toxicity was reached before labeling for the treatment of cancer. We substance (Ref. 16). This proposed rule there was evidence of effectiveness. We found no evidence regarding the would not place domperidone on the located only one clinical trial that historical use of diindolylmethane in 503A Bulks List. studied deoxy-D-glucose in the compounded drug products. (16) EGCG. EGCG, or treatment of HSV, from which no On balance, the physiochemical (-)-epigallocatechin-3-gallate, was conclusions regarding efficacy could be characteristics, safety, effectiveness, and evaluated for use in the treatment of drawn due to the quality of the study. historical use of diindolylmethane obesity, type 1 and type 2 diabetes, Each of these serious conditions has a weigh against inclusion of this cardiac hypertrophy, corneal number of FDA-approved drug products substance on the 503A Bulks List. FDA neovascularization, non-alcoholic fatty that have been demonstrated to be safe proposed to the PCAC that this liver disease, Parkinson’s disease, and and effective under the conditions of substance not be included on the 503A wound healing. EGCG is the most use set forth in their labeling. We found Bulks List (Ref. 18). At its meeting on abundant type of catechin in green tea. insufficient evidence to evaluate the November 3, 2016, the PCAC voted not It is well characterized physically and historical use of deoxy-D-glucose in to include diindolylmethane on the list chemically, but degrades significantly compounded drug products. (Ref. 8). We have also consulted with within 1 month. It was nominated for

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use in capsules, topical gels, and particularly given the risk of of IV administration of glycyrrhizin in ophthalmic solutions, but it is not contamination with highly toxic patients with chronic hepatitis C have expected to be stable in formulations inorganic forms of germanium salts. The shown no demonstrable antiviral effect. other than solid oral dosage forms. nephrotoxicity of inorganic forms of Regarding its historical use, Regarding safety, in several nonclinical germanium, such as germanium dioxide Glycyrrhiza (licorice) has been used for models, liver and gastrointestinal or germanium citrate lactate, is well curative and flavoring purposes for toxicities were noted. In humans, there established, and prolonged use of 4,000 years, and glycyrrhizin has been are numerous case reports of germanium products has been used to treat chronic hepatitis in Japan hepatotoxicity, including fulminant associated with cases of renal failure for over 30 years. However, we found no hepatic failure, the need for liver and death. There is currently a evidence of the use of glycyrrhizin in IV transplantation, or death associated restriction on the importation of all compounded drugs products in the with products that contain EGCG, which germanium compounds, except those United States. is typically administered as one used for semiconductors (Ref. 26). On balance, the physiochemical component of a multicomponent dietary There are very little clinical data characteristics, safety, effectiveness, and supplement/botanical product. regarding the effectiveness of historical use of glycyrrhizin weigh Establishing whether EGCG has a causal germanium sesquioxide in the treatment against inclusion of this substance on link with these existing cases is not of cancer. We located only a single case the list. FDA recommended to the PCAC feasible, and additional data are needed report, from which no conclusions that this substance not be included on to evaluate the safety of the use of EGCG regarding the effectiveness of the 503A Bulks List (Ref. 17), and at its in compounded drug products. A germanium sesquioxide could be drawn. meeting on October 28, 2015, the PCAC review by Health Canada published in In contrast, there are numerous FDA- voted not to include glycyrrhizin on the December 2017 concluded that there approved drug products that have been list (Ref. 3). We have also consulted may be a link between the use of green demonstrated to be safe and effective with USP regarding placement of this tea extract and a risk of rare and under the conditions of use set forth in substance on the 503A Bulks List, and unpredictable liver injury (Ref. 25). their labeling for the treatment of USP did not identify any additional Regarding effectiveness, there are various types of cancer. We found little quality concerns related to this hypotheses regarding the potential information regarding the history of the substance (Ref. 14). This proposed rule therapeutic utility of EGCG, as well as use of germanium sesquioxide in would not place glycyrrhizin on the nonclinical and clinical pharmacologic compounded drug products and could 503A Bulks List. data identifying potential mechanisms not determine whether or how long it (19) Kojic Acid. Kojic acid was of action in various disease states. has been used in compounded drug evaluated for use in the treatment of However, clinical data for EGCG have products. melasma and as an iron chelator in not been identified to support the On balance, the physiochemical wound healing and photodamage effectiveness of EGCG for any of the characteristics, safety, effectiveness, and prevention. Kojic acid is well uses evaluated. We found insufficient historical use of germanium sesquioxide characterized physically and information to determine how long weigh against inclusion of this chemically, but it is a very reactive and EGCG has been used in compounded substance on the list. FDA unstable compound. Nonclinical data drug products. recommended to the PCAC that this suggest that kojic acid is potentially On balance, the physiochemical substance not be included on the 503A genotoxic, and data about its characteristics, safety, effectiveness, and Bulks List (Ref. 17), and at its meeting carcinogenicity are equivocal. Data historical use of EGCG weigh against on October 27, 2015, the PCAC voted suggest that the use of kojic acid may be inclusion of this substance on the 503A not to include germanium sesquioxide associated with local irritancy, but Bulks List. FDA proposed to the PCAC on the list (Ref. 2). We have also reported adverse reactions appear to that this substance not be included on consulted with USP regarding have been transient and manageable. the 503A Bulks List (Ref. 19). At its placement of this substance on the 503A There have been no reports of systemic meeting on November 20, 2017, the Bulks List, and USP did not identify any adverse reactions. We identified no PCAC voted not to include EGCG on the additional quality concerns related to major safety concerns related to the use list (Ref. 11). We have also consulted this substance (Ref. 14). This proposed of kojic acid to treat melasma, but we with USP regarding placement of this rule would not place germanium found no data evaluating the safety of substance on the 503A Bulks List, and sesquioxide on the 503A Bulks List. the use of kojic acid in open wounds or USP did not identify any additional (18) Glycyrrhizin. Glycyrrhizin, also the prevention of photodamage. quality concerns related to this known as glycyrrhizic acid or Regarding effectiveness, there is substance (Ref. 15). The proposed rule glycyrihizinic acid, is a triterpene insufficient evidence to show that kojic would not place EGCG on the 503A saponin extracted from licorice. It was acid would be an effective treatment for Bulks List. evaluated for use in the treatment of any of the evaluated uses. Most trials (17) Germanium Sesquioxide. hepatitis C by intravenous evaluating the use of kojic acid for Germanium sesquioxide was evaluated administration. Although glycyrrhizin’s melasma or hyperpigmentation as treatment for cancer. It is physically molecular structure can be disorders used kojic acid in and chemically well characterized. It characterized, the term ‘‘glycyrrhizin’’ is combination with other topical can, however, include impurities with used to refer to a variety of licorice therapies, and often flaws in trial design significant toxicities, specifically, extracts, which are often complex prevented the data from being potentially dangerous levels of mixtures that are not well characterized sufficiently reliable. Historically, kojic inorganic germanium salts (e.g., GeO2, physically or chemically. Glycyrrhizin acid has been used in compounded drug germanium lactate citrate, Ge-lac-cit), also poses safety concerns. The products for decades, often in which can accumulate in the body. The association between glycyrrhizin use combination with other substances. limited information available about the and serious pseudo-hyperaldosterone On balance, the physiochemical safety of germanium sesquioxide gives effects is well established and has been characteristics, safety, effectiveness, and rise to significant concerns about its use noted in over 100 case reports. historical use of kojic acid weigh against in compounded drug products, Regarding effectiveness, clinical studies inclusion of this substance on the 503A

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Bulks List. FDA proposed to the PCAC characterized physically and profile for NADH, particularly for use in that this substance not be included on chemically, but it degrades substantially a chronic disease such as CFS. the 503A Bulks List (Ref. 18). At its when exposed to light, moisture, Regarding effectiveness, there is meeting on November 3, 2016, the alkaline pH, or standard room insufficient information to indicate that PCAC voted not to include kojic acid on temperatures and would not be stable NADH would be effective for the the list (Ref. 8). We have also consulted under ordinary storage conditions evaluated use. The available clinical with USP regarding placement of this absent multiple compensatory effectiveness data regarding substance on the 503A Bulks List, and measures. Nonclinical data found in the administration of NADH to patients USP did not identify any additional literature are inadequate to characterize with CFS failed to provide an quality concerns related to this the potential toxicity profile for NAD, assessment of fatigue specifically, and it substance (Ref. 15). The proposed rule particularly for use in a chronic disease also failed to show statistically would not place kojic acid on the 503A such as MS. Similarly, we did not find significant improvement on assessment Bulks List. sufficient clinical data about NAD to scales of multiple other symptoms. We (20) Nettle. Nettle (Urtica dioica L.), a evaluate whether it is safe for use in do not have enough information to botanical substance, was evaluated for compounded drug products. determine how long NAD has been used use in glycemic control. Nettle is not We identified no published studies in compounded drug products. physically or chemically well that support the use of NAD for the On balance, the physiochemical characterized. The major and/or active treatment of fatigue in patients with characteristics, safety, effectiveness, and components of nettle are unknown. multiple sclerosis. Therefore, we have historical use of NADH weigh against There is a dearth of reliable information insufficient information on which to inclusion of this substance on the 503A regarding the safety of the use of nettle evaluate the effectiveness for NAD for Bulks List. FDA proposed to the PCAC in compounded drug products. The its proposed use. There are FDA- that this substance not be included on most frequent adverse effects appear to approved drug products that have been the 503A Bulks List (Ref. 22). At its be mild gastrointestinal irritation and demonstrated to be safe and effective meeting on May 8, 2017, the PCAC allergic reactions; however, the under the conditions of use set forth in voted not to include NADH on the list available information is based on their labeling for the treatment of MS. (Ref. 9). We have also consulted with formulations with poorly characterized We do not have enough information to USP regarding placement of this compositions. It is unclear how the determine how long NAD has been used substance on the 503A Bulks List, and formulations employed in the existing in compounded drug products. USP did not identify any additional literature might compare qualitatively or quality concerns related to this quantitatively to a bulk drug substance On balance, the physiochemical substance (Ref. 15). The proposed rule used in compounded drug products. characteristics, safety, effectiveness, and The effectiveness of nettle has not historical use of NAD weigh against would not place NADH on the 503A been adequately assessed with well- inclusion of this substance on the 503A Bulks List. characterized formulations. A small Bulks List. FDA proposed to the PCAC (23) Rubidium Chloride. Rubidium number of clinical effectiveness that this substance not be included on chloride, also known as rubidium investigations of nettle and some the 503A Bulks List (Ref. 22). At its monochloride or rubinorm, was nonclinical data in animal models for meeting on May 8, 2017, the PCAC evaluated for use in the treatment of diabetes suggest that nettle may have voted not to include NAD on the list cancer. Rubidium chloride is physically some effect in reducing fasting blood (Ref. 9). We have also consulted with and chemically well characterized. We sugar and other parameters related to USP regarding placement of this found insufficient information to diabetes. However, they do not provide substance on the 503A Bulks List, and determine whether the use of rubidium sufficient evidence that nettle would be USP did not identify any additional chloride in compounded drug products effective in providing glycemic control. quality concerns related to this would be safe or effective. Non-clinical Historically, nettle has been used for substance (Ref. 15). The proposed rule studies showed that the administration centuries as an herbal treatment for a would not place NAD on the 503A of rubidium in rats affected their variety of conditions. It has been used Bulks List. growth, survival times, and behavior. in compounded drug products for at (22) NADH. NADH was evaluated for Rubidium chloride in the treatment of least 7 years. use in the treatment of CFS.8 It is well cancer appears to have only been On balance, the physiochemical characterized physically and studied in clinical trials by one characteristics, safety, effectiveness, and chemically, but degrades substantially individual in the 1960s and 1970s, but historical use of nettle weigh against when exposed to light, moisture, the role of rubidium in the results of inclusion of this substance on the 503A alkaline pH, or standard room those studies is uncertain since data Bulks List. FDA proposed to the PCAC temperatures and would not be stable were reported in the aggregate. Since that this substance not be included on under ordinary storage conditions that time, there have been no the 503A Bulks List (Ref. 22). At its absent multiple compensatory documented studies of the safety or meeting on May 8, 2017, the PCAC measures. We found no reports of effectiveness of rubidium chloride in voted not to include nettle on the list serious adverse events; however, the the treatment of cancer. In contrast, (Ref. 9). We have also consulted with clinical safety data available for review there are numerous FDA-approved drug USP regarding placement of this were minimal. Nonclinical data products that have been demonstrated substance on the 503A Bulks List, and reported in the literature suggest that to be safe and effective under the USP did not identify any additional NADH is not stable in an acid medium conditions of use set forth in their quality concerns related to this and is likely to be degraded before labeling in the treatment of various substance (Ref. 15). The proposed rule absorption after oral dosing. Nonclinical types of cancer. Although rubidium would not place nettle on the 503A safety data are insufficient to chloride was first discussed in medical Bulks List. characterize the potential toxicity literature in the 1960s, we did not find (21) NAD. NAD was evaluated for use information regarding the history of use in the treatment of fatigue in patients 8 See footnote 5, above, regarding use of the term of rubidium chloride in compounded with multiple sclerosis (MS). It is well ‘‘CFS.’’ drug products.

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On balance, the physiochemical vanadium salt, is well characterized characterized physically and characteristics, safety, effectiveness, and physically and chemically. Regarding chemically, but absent sufficient historical use of rubidium chloride the safety of vanadyl sulfate in controls on its production, synthesis is weigh against inclusion of this compounded drug products, nonclinical likely to result in peptides of different substance on the list. FDA safety data, including toxicokinetic data, lengths or different amino acid recommended to the PCAC that this chronic toxicity data, reproductive data, sequencing. Although most adverse substance not be included on the 503A and carcinogenicity data, found in the reactions observed related to the use of Bulks List (Ref. 17), and at its meeting literature suggest the potential for a high VIP appear to be relatively mild, it has on October 27, 2015, the PCAC voted toxicity profile. Administration by been associated with severe not to include rubidium chloride on the injection, the proposed dosage form, immunologic reactions. Regarding list (Ref. 2). We have also consulted appears to be associated with greater effectiveness, we located only one with USP regarding placement of this toxicity than the oral route of published study of VIP in a condition substance on the 503A Bulks List, and administration. Human safety data are that appears to be related to CIRS (Ref. USP did not identify any additional limited and do not reveal the same types 28), which failed to clearly establish quality concerns related to this or degrees of toxicity that are shown in benefits of the administration of VIP. substance (Ref. 14). This proposed rule nonclinical testing. The differences We did not find sufficient information would not place rubidium chloride on between nonclinical and clinical safety to determine the historical use of VIP in the 503A Bulks List. findings may be explained by compounded drug products. However, it (24) Sodium Dichloroacetate. Sodium shortcomings in the available clinical appears that VIP is currently used in dichloroacetate, also known as data and limited duration of treatment. compounded nasal sprays. dichloroacetate sodium, was evaluated Regarding effectiveness, limited On balance, the physiochemical for use in the treatment of cancer. It is clinical effectiveness data provide characteristics, safety, effectiveness, and well characterized physically and preliminary evidence that vanadyl historical use of VIP weigh against chemically, but unlikely to be stable sulfate or other vanadium containing inclusion of this substance on the 503A when formulated as a solution for compounds could have an effect in Bulks List. FDA proposed to the PCAC injection. There are significant safety treating diabetes or hyperlipidemia. We that this substance not be included on concerns related to the use of sodium identified no clinical effectiveness data the 503A Bulks List (Ref. 18). At its dichloroacetate in compounded drug for the treatment of cancer or heart meeting on November 3, 2016, the products, primarily related to its disease with vanadyl sulfate. There is PCAC voted not to include VIP on the toxicity profile, as observed in both insufficient evidence to indicate that list (Ref. 8). We have also consulted nonclinical and clinical studies. One vanadyl sulfate has any effectiveness in with USP regarding placement of this study of sodium dichloroacetate treating any of the evaluated conditions. substance on the 503A Bulks List, and identified in the literature was closed Cancer and heart disease are serious USP did not identify any additional due to patient deaths and safety conditions for which there are FDA quality concerns related to this concerns (Ref. 27). There is no evidence approved drugs that have been found to substance (Ref. 15). The proposed rule that sodium dichloroacetate would be be safe and effective under the would not place VIP on the 503A Bulks effective in the prevention or treatment conditions of use set forth in their List. of cancer. In contrast, there are labeling. We do not have enough numerous FDA-approved drug products information to determine how long VI. Proposed Effective Date that have been demonstrated to be safe vanadyl sulfate has been used in The Agency proposes that any final and effective under the conditions of compounded drug products. rule based on this proposed rule will use set forth in their labeling for the On balance, the physiochemical become effective 30 days after the date treatment of cancer. We found no characteristics, safety, effectiveness, and of publication of the final rule in the evidence regarding the historical use of historical use of vanadyl sulfate weigh Federal Register. sodium dichloroacetate in compounded against inclusion of this substance on drug products. the 503A Bulks List. FDA proposed to VII. Preliminary Economic Analysis of On balance, the physiochemical the PCAC that this substance not be Impacts characteristics, safety, effectiveness, and included on the 503A Bulks List (Ref. We have examined the impacts of the historical use of sodium dichloroacetate 22). At its meeting on May 8, 2017, the proposed rule under Executive Order weigh against inclusion of this PCAC voted not to include vanadyl 12866, Executive Order 13563, substance on the 503A Bulks List. FDA sulfate on the list (Ref. 9). We have also Executive Order 13771, the Regulatory proposed to the PCAC that this consulted with USP regarding Flexibility Act (5 U.S.C. 601–612), and substance not be included on the 503A placement of this substance on the 503A the Unfunded Mandates Reform Act of Bulks List (Ref. 20). At its meeting on Bulks List, and USP did not identify any 1995 (Pub. L. 104–4). Executive Orders June 23, 2016, the PCAC voted not to additional quality concerns related to 12866 and 13563 direct us to assess all include sodium dichloroacetate on the this substance (Ref. 15). The proposed costs and benefits of available regulatory list (Ref. 7). We have also consulted rule would not place vanadyl sulfate on alternatives and, when regulation is with USP regarding placement of this the 503A Bulks List. necessary, to select regulatory substance on the 503A Bulks List, and (26) VIP. VIP, a 28-amino acid approaches that maximize net benefits USP did not identify any additional peptide, was evaluated for use in the (including potential economic, quality concerns related to this treatment of a condition described as environmental, public health and safety, substance (Ref. 14). The proposed rule ‘‘chronic inflammatory response and other advantages; distributive would not place sodium dichloroacetate syndrome’’ (CIRS).9 VIP is well impacts; and equity). Executive Order on the 503A Bulks List. 13771 requires that the costs associated (25) Vanadyl Sulfate. Vanadyl sulfate 9 CIRS is a term we located in three publications. with significant new regulations ‘‘shall, was evaluated for use in the treatment It appears to be the subject of research. It is not listed in the International Statistical Classification to the extent permitted by law, be offset of diabetes, hyperlipidemia, and heart of Diseases and Related Health Problems (ICD–10), disease, and for the prevention of a medical classification list by the World Health in the Medical Dictionary for Regulatory Activities cancer. Vanadyl sulfate, an inorganic Organization (Ref. 18). Further, CIRS is not listed (MedDRA) (id.).

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by the elimination of existing costs includes an assessment of anticipated producers that market the affected associated with at least two prior costs and benefits, before proposing substances or drug products made from regulations.’’ We have developed a ‘‘any rule that includes any Federal the affected substances, consumers of comprehensive Preliminary Economic mandate that may result in the drug products containing the affected Analysis of Impacts that assesses the expenditure by State, local, and tribal substances, and payers that cover these impacts of the proposed rule. We governments, in the aggregate, or by the drug products or alternative treatments. believe that this proposed rule is not a private sector, of $100,000,000 or more Because we lack sufficient information significant regulatory action as defined (adjusted annually for inflation) in any to quantify most of the costs and by Executive Order 12866. one year.’’ The current threshold after benefits of this proposed rule, we also The Regulatory Flexibility Act adjustment for inflation is $150 million, include a qualitative description of requires us to analyze regulatory options using the most current (2017) Implicit potential benefits and potential costs. that would minimize any significant Price Deflator for the Gross Domestic impact of a rule on small entities. Product. This proposed rule would not In table 1, we summarize the impacts Because we do not have enough result in an expenditure in any year that of the proposed rule. The estimated information about the effect of the meets or exceeds this amount. costs are derived from administrative proposed rule on small entities, we find We evaluated 31 bulk drug substances costs related to reading the rule. The that the proposed rule will have a for this proposed rule. We propose to primary estimate of the present value of significant economic impact on a place 5 bulk drug substances on the the costs over 10 years is $1.03 million. substantial number of small entities. 503A Bulks List, and we propose not to The primary estimate of the annualized The Unfunded Mandates Reform Act place 26 substances on the 503A Bulks costs is $0.15 million at a 7 percent of 1995 (section 202(a)) requires us to List. We expect that the rule will affect discount rate and $0.12 million at a 3 prepare a written statement, which compounding pharmacies and other percent discount rate. TABLE 1—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF THE PROPOSED RULE

Units Primary Low High Category estimate estimate estimate Discount Period Notes Year dollars rate covered

Benefits: Annualized Monetized ($m/year).

Annualized Quantified.

Qualitative ...... Potential gains or losses in consumer surplus, depending on consumer preferences for compounded drugs. Potential public health benefits from increased use of other drug products that may be more effective.

Costs: Annualized Monetized ($m/year) ...... $0.15 $0.10 $0.20 2017 7% 10 years. $0.12 $0.08 $0.16 2017 3% 10 years.

Annualized Quantified.

Qualitative ...... Costs to submit investigational new drug applications (INDs) for some compounded drug products.

Transfers: Federal Annualized Monetized ($m/year).

From: To:

Other Annualized Monetized ($m/year).

From: To:

Effects: ...... State, Local, or Tribal Government: None. Small Business: None. Wages: None. Growth: None.

We have developed a comprehensive does not individually or cumulatively X. Federalism Preliminary Economic Analysis of have a significant effect on the human Impacts that assesses the impacts of the environment. Therefore, neither an We have analyzed this proposed rule proposed rule. The full preliminary environmental assessment nor an in accordance with the principles set analysis of economic impacts is environmental impact statement is forth in Executive Order 13132. We available in the docket for this proposed required. have determined that this proposed rule (Ref. 29) and at https:// rule, if finalized, would not contain IX. Paperwork Reduction Act of 1995 www.fda.gov/AboutFDA/ policies that would have substantial ReportsManualsForms/Reports/ FDA tentatively concludes that this direct effects on the States, on the EconomicAnalyses/default.htm. proposed rule contains no collection of relationship between the National information. Therefore, clearance by the Government and the States, or on the VIII. Analysis of Environmental Impact Office of Management and Budget under distribution of power and We have determined under 21 CFR the Paperwork Reduction Act of 1995 is responsibilities among the various 25.30(h) that this action is of a type that not required. levels of government. Accordingly, we

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conclude that the rule does not contain 20170404155221/https://www.fda.gov/ 12. *Memorandum to File on FDA policies that have federalism downloads/AdvisoryCommittees/ Consultations with United States implications as defined in the Executive CommitteesMeetingMaterials/Drugs/ Pharmacopeia, September 26, 2016. PharmacyCompoundingAdvisory 13. *Letter from the United States order and, consequently, a federalism Committee/UCM484907.pdf. Pharmacopeia to FDA, October 7, 2016. summary impact statement is not 4. *FDA, Transcript of the October 28, 2015, 14. *Letter I from the United States required. Meeting of the Pharmacy Compounding Pharmacopeia to FDA, August 17, 2018. XI. Consultation and Coordination With Advisory Committee (Afternoon 15. *Letter II from the United States Session), 2015. Available at https:// Pharmacopeia to FDA, August 17, 2018. Indian Tribal Governments wayback.archive-it.org/7993/ 16. *Letter III from the United States We have analyzed this proposed rule 20170404155222/https://www.fda.gov/ Pharmacopeia to FDA, August 17, 2018. in accordance with the principles set downloads/AdvisoryCommittees/ 17. *FDA Briefing Document for the October forth in Executive Order 13175. We CommitteesMeetingMaterials/Drugs/ 27–28, 2015, Meeting of the Pharmacy PharmacyCompoundingAdvisory Compounding Advisory Committee, have tentatively determined that the Committee/UCM484908.pdf. 2015. Available at https:// rule does not contain policies that 5. *FDA, Transcript of the March 8, 2016, wayback.archive-it.org/7993/ would have a substantial direct effect on Meeting of the Pharmacy Compounding 20170405230355/https://www.fda.gov/ one or more Indian Tribes, on the Advisory Committee (Morning Session), downloads/AdvisoryCommittees/ relationship between the Federal 2016. Available at https:// CommitteesMeetingMaterials/Drugs/ Government and Indian Tribes, or on wayback.archive-it.org/7993/ PharmacyCompoundingAdvisory the distribution of power and 20170403224125/https://www.fda.gov/ Committee/UCM466380.pdf. responsibilities between the Federal downloads/AdvisoryCommittees/ 18. *FDA Briefing Document for the CommitteesMeetingMaterials/Drugs/ November 3, 2016, Meeting of the Government and Indian Tribes. The PharmacyCompoundingAdvisory Pharmacy Compounding Advisory Agency solicits comments from tribal Committee/UCM507771.pdf. Committee, 2016. Available at https:// officials on any potential impact on 6. *FDA, Transcript of the March 8, 2016, www.fda.gov/downloads/Advisory Indian Tribes from this proposed action. Meeting of the Pharmacy Compounding Committees/CommitteesMeeting Advisory Committee (Afternoon Materials/Drugs/PharmacyCompounding XII. References Session), 2016. Available at https:// AdvisoryCommittee/UCM524613.pdf. The following references marked with wayback.archive-it.org/7993/ 19. *FDA Briefing Document for the an asterisk (*) are on display at the 20170404155209/https://www.fda.gov/ November 20, 2017, Meeting of the Dockets Management Staff (see downloads/AdvisoryCommittees/ Pharmacy Compounding Advisory CommitteesMeetingMaterials/Drugs/ Committee, 2017. Available at https:// ADDRESSES) and are available for PharmacyCompoundingAdvisory www.fda.gov/AdvisoryCommittees/ viewing by interested persons between Committee/UCM507772.pdf. CommitteesMeetingMaterials/Drugs/ 9 a.m. and 4 p.m., Monday through 7. *FDA, Transcript of the June 23, 2016, PharmacyCompoundingAdvisory Friday; they also are available Meeting of the Pharmacy Compounding Committee/ucm582868.htm. electronically at https:// Advisory Committee (Morning Session), 20. *FDA Briefing Document for the June 23, www.regulations.gov. References 2016. Available at https://www.fda.gov/ 2016, Meeting of the Pharmacy without asterisks are not on display at downloads/AdvisoryCommittees/ Compounding Advisory Committee, https://www.regulations.gov because CommitteesMeetingMaterials/Drugs/ 2016. Available at https://www.fda.gov/ PharmacyCompoundingAdvisory downloads/AdvisoryCommittees/ they have copyright restriction. Some Committee/UCM563843.pdf. CommitteesMeetingMaterials/Drugs/ may be available at the website address, 8. *FDA, Transcript of the November 3, 2016, PharmacyCompoundingAdvisory if listed. References without asterisks Meeting of the Pharmacy Compounding Committee/UCM505041.pdf. are available for viewing only at the Advisory Committee (Morning Session), 21. *FDA Briefing Document for the March Dockets Management Staff. FDA has 2016. Available at https://www.fda.gov/ 8–9, 2016, Meeting of the Pharmacy verified the website addresses, as of the downloads/AdvisoryCommittees/ Compounding Advisory Committee, date this document publishes in the CommitteesMeetingMaterials/Drugs/ 2016. Available at https://www.fda.gov/ Federal Register, but websites are PharmacyCompoundingAdvisory AdvisoryCommittees/Committees Committee/UCM563842.pdf. MeetingMaterials/Drugs/Pharmacy subject to change over time. 9. *FDA, Transcript of the May 8–9, 2017, CompoundingAdvisoryCommittee/ 1. *FDA, Transcript of the October 27, 2015, Meeting of the Pharmacy Compounding ucm486144.htm. Meeting of the Pharmacy Compounding Advisory Committee, 2017. Available at 22. *FDA Briefing Document for the May 8– Advisory Committee (Morning Session), https://www.fda.gov/downloads/ 9, 2017, Meeting of the Pharmacy 2015. Available at https:// AdvisoryCommittees/Committees Compounding Advisory Committee, wayback.archive-it.org/7993/ MeetingMaterials/Drugs/Pharmacy 2017. Available at https://www.fda.gov/ 20170404155219/https://www.fda.gov/ CompoundingAdvisoryCommittee/ downloads/AdvisoryCommittees/ downloads/AdvisoryCommittees/ UCM565933.pdf. CommitteesMeetingMaterials/Drugs/ CommitteesMeetingMaterials/Drugs/ 10. *FDA, Transcript of the November 20, PharmacyCompoundingAdvisory PharmacyCompoundingAdvisory 2017, Meeting of the Pharmacy Committee/UCM553368.pdf. Committee/UCM484905.pdf. Compounding Advisory Committee 23. *FDA, August 4, 2017, Statement, ‘‘FDA 2. *FDA, Transcript of the October 27, 2015, (Morning Session), 2017. Available at investigates two serious adverse events Meeting of the Pharmacy Compounding https://www.fda.gov/downloads/ associated with ImprimisRx’s Advisory Committee (Afternoon AdvisoryCommittees/Committees compounded curcumin emulsion Session), 2015. Available at https:// MeetingMaterials/Drugs/Pharmacy product for injection.’’ Available at wayback.archive-it.org/7993/ CompoundingAdvisoryCommittee/ https://www.fda.gov/Drugs/Guidance 20170404155220/https://www.fda.gov/ UCM604328.pdf. ComplianceRegulatoryInformation/ downloads/AdvisoryCommittees/ 11. *FDA, Transcript of the November 20, PharmacyCompounding/ CommitteesMeetingMaterials/Drugs/ 2017, Meeting of the Pharmacy ucm570192.htm. PharmacyCompoundingAdvisory Compounding Advisory Committee 24. Teitelbaum, J.E., et al. ‘‘The Use of D- Committee/UCM484906.pdf. (Afternoon Session), 2017. Available at Ribose in Chronic Fatigue Syndrome and 3. *FDA, Transcript of the October 28, 2015, https://www.fda.gov/downloads/ Fibromyalgia: A Pilot Study,’’ Journal of Meeting of the Pharmacy Compounding AdvisoryCommittees/Committees Alternative and Complementary Advisory Committee (Morning Session), MeetingMaterials/Drugs/Pharmacy Medicine, 12:857–862, 2006. 2015. Available at https:// CompoundingAdvisoryCommittee/ 25. *Government of Canada, ‘‘Summary wayback.archive-it.org/7993/ UCM604329.pdf. Safety Review-Green Tea Extract-

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Containing Natural Health Products- (1) Brilliant Blue G, also known as Dated: July 16, 2019. Assessing the Potential Risk of Liver Coomassie Brilliant Blue G–250. Norman E. Sharpless, Injury (Hepatotoxicity),’’ December 12, (2) Cantharidin (for topical use only). Acting Commissioner of Food and Drugs. 2017. Available at https:// www.canada.ca/en/health-canada/ (3) Diphenylcyclopropenone (for Dated: August 13, 2019. services/drugs-health-products/ topical use only). Eric D. Hargan, medeffect-canada/safety-reviews/green- (4) Glutaraldehyde (for topical use Deputy Secretary, Department of Health and tea-extract-containing-natural-health- only, in concentrations of 10 percent or Human Services. products-assessing-potential-risk-liver- lower). [FR Doc. 2019–18951 Filed 9–4–19; 8:45 am] injury.html. (5) Glycolic acid (for topical use only, 26. *FDA Import Alert 54–07. Available at BILLING CODE 4164–01–P _ in concentrations of 70 percent or https://www.accessdata.fda.gov/cms ia/ lower). importalert_139.html. 27. Garon, E.B., et al. ‘‘Dichloroacetate (6) L-citrulline (for oral DEPARTMENT OF INTERIOR Should be Considered with Platinum- administration only). based Chemotherapy in Hypoxic Tumors (7) N-acetyl-D-glucosamine (for Office of Surface Mining Reclamation Rather Than as a Single Agent in topical use only). and Enforcement Advanced Non-small Cell Lung Cancer,’’ (8) Pyruvic acid (for topical use only). Journal of Cancer Research and Clinical (9) Squaric acid dibutyl ester (for 30 CFR Part 935 Oncology, 140:443, 2014. topical use only). 28. Shoemaker, R.C., et al. ‘‘Vasoactive [OH–262–FOR; Docket ID: OSM–2019–0006 Intestinal Polypeptide (VIP) Corrects (10) Thymol iodide (for topical use S1D1S SS08011000 SX064A000 Chronic Inflammatory Response only). 190S180110; S2D2S SS08011000 Syndrome (CIRS) Acquired Following (11) Trichloroacetic acid (for topical SX064A000 19XS501520] Exposure to Water-Damaged Buildings,’’ use only). Health, 5:396–401, 2013. Available at (b) The following bulk drug Ohio Regulatory Program https://www.scirp.org/journal/health/. substances have been nominated and (Open Access) AGENCY: Office of Surface Mining evaluated for inclusion on the list of Reclamation and Enforcement (OSMRE), 29. *Amendments to the List of Bulk Drug substance that can be used in Substances that Can be Used to Interior. compounding set forth in paragraph (a) Compound Drug Products in Accordance ACTION: Proposed rule; public comment with Section 503A of the Federal Food, of this section, and FDA has determined that they do not meet the criteria for period and opportunity for public Drug, and Cosmetic Act, Preliminary hearing. Regulatory Impact Analysis, Initial inclusion set forth in paragraph (c) of Regulatory Flexibility Analysis, this section: SUMMARY: We, the Office of Surface Unfunded Mandates Reform Act (1) 7-keto dehydroepiandrosterone Mining Reclamation and Enforcement Analysis, 2018. Available at https:// (DHEA). (OSMRE), are announcing receipt of a www.fda.gov/AboutFDA/Reports (2) Acetyl L Carnitine. ManualsForms/Reports/Economic proposed amendment to the Ohio Analyses/default.htm. (3) Alanyl L Glutamine. regulatory program, hereinafter the Ohio (4) Aloe Vera 200:1 Freeze Dried. program, under the Surface Mining List of Subjects in 21 CFR Part 216 (5) Artemisinin. Control and Reclamation Act of 1977 Drugs, Prescription drugs. (6) Astragalus extract 10:1. (SMCRA or the Act). Ohio seeks to Therefore, under the Federal Food, (7) Boswellia. amend its program by revising a Drug, and Cosmetic Act, and under (8) Cesium Chloride. definition involving the transfer, authority delegated to the Commissioner (9) Chondroitin Sulfate. assignment, or sale of permit rights. of Food and Drugs, we propose that 21 (10) Chrysin. This document gives the times and CFR part 216 be amended as follows: (11) Curcumin. locations that the Ohio program and this (12) D-Ribose. proposed amendment to that program PART 216—HUMAN DRUG (13) Deoxy-D-Glucose. are available for your inspection, the COMPOUNDING (14) Diindolylmethane. comment period during which you may submit written comments, on the (15) Domperidone. ■ amendment and the procedures that we 1. The authority citation for part 216 (16) Epigallocatechin gallate (EGCG). continues to read as follows: will follow for the public hearing, if one (17) Germanium Sesquioxide. is requested. Authority: 21 U.S.C. 351, 352, 353a, 353b, (18) Glycyrrhizin. DATES: We will accept written 355, and 371. (19) Kojic acid. comments on this request until 4:00 ■ (20) Nettle. 2. In § 216.23, revise paragraphs (a) p.m., Eastern Standard Time (e.s.t.), and (b) to read as follows: (21) Nicotinamide adenine October 7, 2019. If requested, we will dinucleotide (NAD). hold a public hearing on the request on § 216.23 Bulk drug substances that can be (22) Nicotinamide adenine used to compound drug products in September 30, 2019. We will accept accordance with section 503A of the dinucleotide disodium reduced requests to speak at a hearing until 4:00 Federal Food, Drug, and Cosmetic Act. (NADH). p.m., e.s.t. on September 20, 2019. (23) Oxitriptan. (a) The following bulk drug ADDRESSES: You may submit comments, (24) Piracetam. substances, which are neither the identified by SATS No. OH–262–FOR, subject of a current applicable United (25) Rubidium Chloride. Docket ID: OSM–2019–0006, by any of States Pharmacopeia or National (26) Silver Protein Mild. the following methods: Formulary monograph nor components (27) Sodium dichloroacetate. • Mail/Hand Delivery: Mr. Ben of FDA-approved drugs, can be used in (28) Tranilast. Owens, Chief, Pittsburgh Field Division compounding under section (29) Vanadyl sulfate. Office of Surface Mining Reclamation 503A(b)(1)(A)(i)(III) of the Federal Food, (30) Vasoactive intestinal peptide. and Enforcement 3 Parkway Center, Drug, and Cosmetic Act. * * * * * Pittsburgh, Pa 15220.

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