Source: https://www.federalregister.gov/documents/2016/12/16/2016-30109/list-of-bulk-drug-substances-that-can-be-used-to-compound-drug-products-in-accordance-with-section
Timestamp: 2017-08-20 18:49:44
Document Index: 38571474

Matched Legal Cases: ['§\u2009207', 'art 207', 'art 207', '§\u2009207', '§\u2009207', '§\u2009207', '§\u2009207', '§\u2009207', '§\u2009216', '§\u2009216']

A Proposed Rule by the Food and Drug Administration on 12/16/2016
91071-91082 (12 pages)
Reference 8 - FDA Briefing Document for the February 23-24,...
Reference 7 - FDA Briefing Document for the June 17-18, 2015,...
Reference 6 - Letter from USP to FDA, October 7, 2016
Reference 5 - Memorandum to File on FDA Consultations with...
B. Regulatory History of the 503A Bulks List
C. Requests for Nominations
1. Brilliant Blue G
3. Diphenylcyclopropenone (DPCP)
4. N-acetyl-D-glucosamine (NAG)
5. Squaric Acid Dibutyl Ester (SADBE)
6. Thymol Iodide
1. Oxitriptan
3. Silver Protein Mild
4. Tranilast
A. Summary of the Costs of the Rule
B. Summary of the Benefits of the Rule
C. Summary of the Impact on Small Entities
https://www.federalregister.gov/d/2016-30109 https://www.federalregister.gov/d/2016-30109
Instructions: All submissions received must include the Docket No. FDA-2016-N-3464 for “List of Bulk Drug Substances That Can Be Used To Compound Drug Products in Accordance With Section 503A of the Federal Food, Drug, and Cosmetic Act.” Received comments will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.Start Printed Page 91072
James Flahive, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5108, Silver Spring, MD 20993-0002, 301-796-9293.
FDA is proposing to amend its regulations to add a list of bulk drug substances that can be used in compounding under section 503A of the FD&C Act (21 U.S.C. 353a) (referred to as “the 503A Bulks List”). Bulk drug substances that appear on the 503A Bulks List can be used to compound drug products subject to the conditions of section 503A, although those substances are not the subject of a USP or NF monograph or components of approved drug products.
5-HTP 5-hydroxytryptophan
BLA Biologics License Application
CSA Controlled Substances Act
DPCP Diphenylcyclopropenone
DQSA Drug Quality and Security Act
IND Investigational New Drug
NAG N-acetyl-D-glucosamine
NF National Formulary
PCAC Pharmacy Compounding Advisory Committee
PRESTO Prevention of REStenosis with Tranilast and its Outcomes
RFA Regulatory Flexibility Analysis
SADBE Squaric acid dibutyl ester
UGT1A1 Uridine diphosphate glucuronosyltransferase 1A1
USP United States Pharmacopeia
Section 503A of the FD&C Act (21 U.S.C. 353a) describes the conditions under which a compounded drug product may qualify for an exemption from certain sections of the FD&C Act. Those conditions include that a licensed pharmacist in a State-licensed pharmacy or Federal facility or a licensed physician compounds the drug product using bulk drug substances that: (1) Comply with the standards of an applicable USP or NF monograph,[1] if a Start Printed Page 91073monograph exists, and the USP chapter on pharmacy compounding; (2) if such a monograph does not exist, are drug substances that are components of drugs approved by the Secretary; or (3) if such a monograph does not exist and the drug substance is not a component of a drug approved by the Secretary, that appear on the 503A Bulks List. See section 503A(b)(1)(A)(i) of the FD&C Act. This proposed rule proposes criteria for evaluating substances for inclusion on the 503A Bulks List and identifies six substances the Secretary proposes to place on the list. The Agency considered four other substances and is proposing not to include those substances on the 503A Bulks List. Additional substances are under evaluation, and new substances may be added to the list through subsequent rulemaking.
Section 503A adopts the definition of “bulk drug substance” in FDA's drug establishment registration and listing regulations, which was codified at § 207.3(a)(4) (21 CFR 207.3(a)(4)) at the time section 503A was enacted. See section 503A(b)(1)(A) of the FD&C Act. Under the definition, bulk drug substance means any substance that is represented for use in a drug and that, when used in the manufacturing, processing, or packaging of a drug, becomes an active ingredient or a finished dosage form of the drug, but the term does not include intermediates used in the synthesis of such substances.
On August 31, 2016, FDA published a final rule in the Federal Register to update its registration and listing regulations in part 207 (21 CFR part 207), which included minor changes to the definition of bulk drug substance and moved the definition to § 207.3 (see 81 FR 60170). This definition becomes effective on November 29, 2016. As set forth in § 207.3, “bulk drug substance,” as referenced in section 503A(b)(1)(A) of the FD&C Act, means the same as “active pharmaceutical ingredient” as defined in § 207.1(b). An “active pharmaceutical ingredient” is any substance that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body. Active pharmaceutical ingredient does not include intermediates used in the synthesis of the substance (§ 207.1).
In response to that solicitation, approximately 740 unique substances were nominated. Of those substances, approximately 315 are components of an FDA-approved drug product or the Start Printed Page 91074subject of an applicable USP or NF monograph. Such substances can be used in compounding under section 503A(b)(1)(A)(i)(I) and (II) of the FD&C Act and, therefore, are not eligible for inclusion on the 503A Bulks List.
At least one of the nominated substances is a finished drug product that was nominated by its brand name. Finished drug products are not eligible for the 503A Bulks List because they do not meet the definition of a bulk drug substance in § 207.3(4).
With regard to the substances nominated with sufficient supporting information for FDA to evaluate them, including the 10 nominated substances discussed in this proposed rule, FDA generally does not intend to take regulatory action against a State-licensed pharmacy, Federal facility, or licensed physician for compounding a drug product using a bulk drug substance that is not the subject of an applicable USP or NF monograph or a component of an FDA-approved drug product, provided that the other conditions in section 503A and the FD&C Act are met, until the substance is addressed in a final rule. FDA is not applying this interim policy to a nominated substance however, if the Agency has identified the substance as posing a significant safety risk,[2] or if the substance was nominated without adequate support. For further information on this subject, see the guidance for industry entitled “Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act” (Ref. 1). As described in the guidance, the following categories of bulk drug substances are identified on FDA's Web site at http://www.fda.gov/​downloads/​Drugs/​GuidanceComplianceRegulatoryInformation/​PharmacyCompounding/​UCM467373.pdf: (1) The substances nominated with sufficient supporting information that are under evaluation, (2) the substances nominated with sufficient supporting information but with which FDA has identified significant safety risks relating to the use of these bulk drug substances in compounding, and (3) the substances nominated with insufficient supporting evidence for FDA to evaluate them.
FDA is proposing to add § 216.23 to title 21 of the Code of Federal Regulations (CFR) to set forth criteria to evaluate bulk drug substances for inclusion on the 503A Bulks List. Additionally, after considering 10 bulk drug substances for the 503A Bulks List, Start Printed Page 91075FDA proposes to codify the initial 503A Bulks List to include 6 of the bulk drug substances that were considered and to identify 4 substances that were considered and would not be placed on the list. The criteria and the bulk drug substances considered for inclusion on the list are described in the paragraphs that follow.
FDA reviewed the substances addressed in this proposed rule in the context of adequately supported nominated uses. In certain circumstances, FDA also reviewed substances in the context of unnominated or inadequately supported uses because, for example, such uses appear to be widespread, are intended to treat serious conditions, or pose serious risks to patients. The Start Printed Page 91076information that FDA assessed to evaluate the substances addressed in this proposed rule under each of the proposed evaluation criteria was obtained from publicly available sources, including peer-reviewed medical literature. Some of this information was referenced in the nominations, and the remainder FDA gathered through independent searches of medical and pharmaceutical databases. FDA did not review raw data. The nature, quantity, and quality of the information FDA assessed varied considerably from substance to substance. In some cases, there were very little data. For other substances, reports in the literature were more plentiful and sometimes comprised hundreds or thousands of articles. In those cases, generally the Agency limited its review to a sample of the best literature sources available (e.g., review articles in widely known, peer-reviewed journals; meta-analyses; reports of randomized controlled trials).
The following bulk drug substances are being proposed for the 503A Bulks List, to appear in § 216.23(a) of Title 21 of the CFR:
Brilliant Blue G, also known as Coomassie Brilliant Blue G-250,[3] was evaluated for use as a dye used in staining for visualization during ophthalmic procedures. It is well characterized physically and chemically. There are potential mutagenic and carcinogenic concerns associated with Brilliant Blue G; however, those concerns are mitigated in clinical use because the dye is immediately washed out of the eye after administration, and tissue that is stained with the dye is removed as part of the surgical procedure. Published clinical trials provide some evidence for efficacy of Brilliant Blue G in staining the internal limiting membrane. Brilliant Blue has had relatively widespread use for staining the internal limiting membrane during retinal surgery for approximately 10 years. There is one product that is FDA-approved for staining the internal limiting membrane and the anterior capsule.
Cantharidin, which is obtained from various species of blister beetle, was Start Printed Page 91077evaluated for topical use [4] in the treatment of warts and molluscum contagiosum. It is well characterized physically and chemically. Cantharidin is extremely toxic, due to its potential for severe irritation. However, clinical data accumulated since 1958 indicate that, with careful use under physician direction, toxicities observed with cantharidin, are no worse than and sometimes less severe than those seen with other destructive modalities in the treatment of molluscum contagiosum and warts. Evidence of some efficacy of cantharidin in the treatment of warts and molluscum contagiosum has been reported in the literature. It appears to have been widely used to treat molluscum contagiosum and warts since the 1950s. There are no approved prescription or OTC monograph products for molluscum contagiosum. For warts, there are no prescription drug products approved for use outside of the genital area. A variety of OTC monograph products containing salicylic acid are available.
FDA is proposing that four of the bulk drug substances that it has evaluated not be included on the 503A Bulks List. Bulk drug substances that are considered for the 503A Bulks list but not placed on the list cannot be used to compound drug products that would qualify for the exemptions in section 503A. If a prescribing practitioner nevertheless believes that a patient should be treated with a drug product compounded from such a bulk drug substance, it may be possible to obtain Start Printed Page 91078the drug under an IND. For information about the requirements for proceeding under an IND, visit FDA's Web site at http://www.fda.gov/​Drugs/​DevelopmentApprovalProcess/​HowDrugsareDevelopedandApproved/​ApprovalApplications/​InvestigationalNewDrugINDApplication/​default.htm.
Silver protein mild, also known as mild silver protein, was evaluated for use as an anti-infective agent for ophthalmic use. Silver protein mild is not well characterized because the term “silver protein mild” is used to refer to a variety of different drug products. There are also safety concerns associated with the use of silver protein mild. It can cause argyria, which is a permanent ashen-gray discoloration of the skin, conjunctiva, and internal organs. Regarding effectiveness, silver protein mild has been found to be inferior to another treatment in clinical trials. A number of FDA-approved anti-infective agents for ophthalmic use are available and have been shown to be both safe and effective. While it has a long history of use, dating back to the early 1900s, the use of silver protein mild declined dramatically after the introduction of FDA-approved ocular anti-infectives.
On balance, the physiochemical characteristics, safety issues, questionable effectiveness, and historical use of silver protein mild weigh against inclusion of this substance on the 503A Bulks List. In particular, the Agency's proposal is based on the facts that silver protein mild is not well characterized, that in clinical trials it has been found to be inferior to another treatment and Start Printed Page 91079numerically inferior to no treatment at all, and that chronic use may result in permanent discoloration of the conjunctiva, cornea, and/or lens. FDA proposed to the PCAC that this substance not be included on the 503A Bulks List (Ref. 8). At its meeting on February 23, 2015, the PCAC voted not to include silver protein mild on the list (Ref. 2). The proposed rule would not place silver protein mild on the 503A Bulks List.
Tranilast, an antiallergenic agent, was evaluated for the treatment of allergic disorders, arthritis, dry eye syndrome, keloids, and hypertrophic scars. It is approved in South Korea and Japan for the treatment of asthma, keloids, and hypertrophic scarring, and as an ophthalmic solution for allergic conjunctivitis. It is well characterized physically and chemically. However, there are significant safety concerns associated with its systemic administration. In a well-controlled clinical trial with nearly 12,000 participants (the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) Trial) (Ref. 10), tranilast was associated with significantly elevated liver enzymes (three times the upper limit of normal) in 11 percent of patients within 1 to 3 months of drug initiation, as well as anemia, renal failure, rash, and dysuria.[5] Liver toxicity is of particular concern because many of the conditions for which tranilast was nominated are chronic conditions. While there is some evidence that tranilast may be effective for allergic disorders, evidence of effectiveness for other uses is either not available or inconclusive. For allergy, arthritis, and ophthalmic indications, there are numerous FDA-approved and OTC monograph products. The length of time tranilast has been used in compounding is uncertain, although it has been discussed in scientific journals dating back approximately 40 years.
As was found in the Agency's initial review and presented to the PCAC, there is no persuasive information available regarding the safety or effectiveness of topical tranilast. FDA has identified only two reports in the literature describing the efficacy and safety of tranilast administered topically for the treatment of keloids and hypertrophic scars (Refs. 12 and 13). One of those studies was an open-label trial, and the other was a case series. Between the two studies, only five patients were exposed to topical tranilast.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires us to Start Printed Page 91080prepare a written statement, which includes an assessment of anticipated costs and benefits, before proposing “any rule that includes any Federal mandate that may result in the expenditure by State, local, and tribal governments, in the aggregate, or by the private sector, of $100,000,000 or more (adjusted annually for inflation) in any one year.” The current threshold after adjustment for inflation is $146 million, using the most current (2015) Implicit Price Deflator for the Gross Domestic Product. This proposed rule would not result in an expenditure in any year that meets or exceeds this amount.
Annualized Monetized $ mil/year Not Estimated (N.E.) 7 10
Annualized Monetized $ mil/year N.E 3 10
Annualized Quantified N.E 7
Annualized Quantified N.E 3
Qualitative Not including four bulk drug substances from the 503A Bulks List would limit the use of potentially ineffective or unsafe unapproved drugs
Annualized Monetized $ mil/year N.E 7 10
Annualized Quantified $118 to $235 one-time per firm costs 2014 7
Annualized Quantified $118 to $235 one-time per firm costs 2014 3
Federal Annualized Monetized $ mil/year 7
Federal Annualized Monetized $ mil/year 3
Other Annualized $ mil/year N.E 7
Other Annualized Monetized $ mil/year N.E 3
Start Printed Page 91081
From/To From: Producers of bulk drug substances not proposed for inclusion and compounding pharmacies using these substances To: Producers of alternative treatments, consumers, using these treatments and payers for these treatments
State, Local, and/or Tribal Government: No effect
Small Business: Unknown effect
The Economic Analysis of Impacts of the proposed rule performed in accordance with Executive Order 12866, Executive Order 13563, the Regulatory Flexibility Act, and the Unfunded Mandates Reform Act is available at http://www.regulations.gov under the docket number for this proposed rule (Ref. 14) and at http://www.fda.gov/​AboutFDA/​ReportsManualsForms/​Reports/​EconomicAnalyses/​default.htm. We invite comments on this analysis.
The submission of comments on this proposed rule would be submissions in response to a Federal Register notice, in the form of comments, which are excluded from the definition of “information” under 5 CFR 1320.3(h)(4) of Office of Management and Budget regulations on the Paperwork Reduction Act (i.e., facts or opinions submitted in response to general solicitations of comments from the public, published in the Federal Register or other publications, regardless of the form or format thereof, provided that no person is required to supply specific information pertaining to the commenter, other than that necessary for self-identification, as a condition of the Agency's full consideration of the Start Printed Page 91082comment). The proposed rule contains no other collection of information.
1. FDA, “Guidance for Industry: Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act,” (http://www.fda.gov/​downloads/​Drugs/​GuidanceComplianceRegulatoryInformation/​Guidances/​UCM469120.pdf), 2016.
2. FDA, Transcript of the February 23, 2015, Meeting of the Pharmacy Compounding Advisory Committee (Afternoon Session), 2015, (http://www.fda.gov/​downloads/​AdvisoryCommittees/​CommitteesMeetingMaterials/​Drugs/​PharmacyCompoundingAdvisoryCommittee/​UCM444500.pdf).
3. FDA, Transcript of the February 24, 2015, Meeting of the Pharmacy Compounding Advisory Committee, 2015, (http://www.fda.gov/​downloads/​AdvisoryCommittees/​CommitteesMeetingMaterials/​Drugs/​PharmacyCompoundingAdvisoryCommittee/​UCM444501.pdf).
4. Transcript of the June 17, 2015, Meeting of the Pharmacy Compounding Advisory Committee (Afternoon Session), 2015, (http://www.fda.gov/​downloads/​AdvisoryCommittees/​CommitteesMeetingMaterials/​Drugs/​PharmacyCompoundingAdvisoryCommittee/​UCM458513.pdf).
5. Memorandum to File on FDA Consultations with USP, September 26, 2016.
6. Letter from USP to FDA, October 7, 2016.
7. FDA Briefing Document for the June 17-18, 2015, Meeting of the Pharmacy Compounding Advisory Committee, 2015, (http://www.fda.gov/​downloads/​AdvisoryCommittees/​CommitteesMeetingMaterials/​Drugs/​PharmacyCompoundingAdvisoryCommittee/​UCM449535.pdf).
8. FDA Briefing Document for the February 23-24, 2015, Meeting of the Pharmacy Compounding Advisory Committee, 2015, (http://www.fda.gov/​downloads/​AdvisoryCommittees/​CommitteesMeetingMaterials/​Drugs/​PharmacyCompoundingAdvisoryCommittee/​UCM433804.pdf).
9. Obeso, J. A., et al., “Piracetam in the Treatment of Different Types of Myoclonus,” Clinical Neuropharmacology, 11(6): 529-536, 1988.
10. Holmes, D.R., Jr., M. Savage, J.M. LaBlanche, et al., “Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) Trial,” Circulation, 106(10): 1243-1250, 2002.
11. FDA Supplemental Review of Topical Tranilast, April 25, 2016.
12. Shigeki, S., T. Murakami, N. Yata, and Y. Ikuta, “Treatment of Keloid and Hypertrophic Scars by Iontophoretic Transdermal Delivery of Tranilast,” Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery, 31(2): 151-159, 1997.
13. Banov, D., F. Banov, and A.S. Bassani, “Case Series: The Effectiveness of Fatty Acids From Pracaxi Oil in a Topical Silicone Base for Scar and Wound Therapy,” Dermatology and Therapy, 4(2): 259-269, 2014.
14. Economic Analysis of Impacts.
3. Section 216.23 is added to read as follows:
1. FDA has interpreted the statutory language “applicable USP or NF monographs” to refer to official USP or NF drug substance monographs. Therefore, a substance that is the subject of a dietary supplement monograph, but not a USP or NF drug substance monograph, does not satisfy the condition regarding bulk drug substances in section 503A(b)(1)(A)(i)(I) of the Act. Such a substance may only be used as a bulk drug substance under section 503A of the FD&C Act if it is a component of an FDA-approved drug product or is on the 503A Bulks List.
2. This is not a determination regarding whether the substances will be added to the 503A Bulks list. FDA intends to make that determination after notice and comment rulemaking, as set forth in this proposal.
3. While there are other substances referred to by the name “Brilliant Blue,” only Coomassie Brilliant Blue G-250 (CAS RN 6104-58-1, UNII M1ZRX790SI) was evaluated, and the Agency is proposing only that substance for inclusion on the 503A Bulks List. The other substances referred to as “Brilliant Blue” would have to be nominated and separately evaluated for consideration for inclusion on the 503A Bulks List.
4. Except where specified otherwise, “topical use” means for application on the skin only and does not include oral, intravaginal, or ophthalmic use.
5. During the PCAC meeting on June 17, 2015, the PRESTO trial was criticized by one of the tranilast nominators as having insufficiently accounted for the medical history of the subjects, among other things (see Ref. 4). To the contrary, the five-arm trial design appears to have been properly controlled for the patients' various medical conditions, and signals of liver toxicity were consistent across arms (see Ref. 10).
[FR Doc. 2016-30109 Filed 12-15-16; 8:45 am]