The Clinical Utility of Compounded Bioidentical Hormone Therapy A Review of Safety, Effectiveness, and Use (2020) / Chapter Skim
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3 Regulatory Framework for Compounded Preparations
3 Regulatory Framework for Compounded Preparations
Pages 43-74
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. The Federal Food, Drug, and Cosmetic Act (FDCA)
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These trials may also study different populations and different dosages of the drug; in some cases, the drug may 2 Several of the hormones covered in this report can be purchased online and in health stores as dietary supplements, including in doses and combinations similar to those available through compounded formulations. However, dietary supplements fall under a different regulatory structure than compounded drugs, and thus will not be discussed in detail in this chapter.
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is critical because the clinical trials that support approval cannot predict all of a drug's effects until it is used more broadly. Manufacturers of approved drugs are required to submit regular safety updates to FDA, including results of further studies and adverse event reports they receive 5 In addition to NDAs, there are other types of therapeutic drug applications.
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As part of an emerging wellness movement, some pharmacists advertised compounded preparations as all-natural and lower risk alternatives to FDA-approved drug products ( oodoo, 2010)
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11 Federal Food, Drug, and Cosmetic Act.
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in November 2013 to clarify FDA's authority in regulating and overseeing compounded drugs. Drug Quality and Security Act Title I of the DQSA, called the Compounding Quality Act, amended Section 503A to remove the restrictions on soliciting prescriptions, and added the new Section 503B to the FDCA, creating a second category of drug compounding with increased federal regulatory oversight.16 Section 503B established a new category of compounder termed 503B outsourcing facilities that can voluntarily register with FDA to compound without a patient-specific prescription and without restrictions on interstate distribution.17 See Figure 3-1 for a geographic distribution of 503B outsourcing facilities throughout the United States.
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standards in applicable monographs, if a monograph exists.18 Section 503A also prohibits compounding drugs that have been withdrawn as a result of safety or effectiveness concerns, present demonstrable difficulties for compounding, are essentially copies of FDA-approved drugs, or compounded within 18 Other allowable conditions for the use of bulk drug substances in compounded prepara tions are discussed later in this chapter.
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21 The separate restrictions for producing copies of FDA-approved drug products and using bulk drug substances are described later in this chapter. 22 Federal Food, Drug, and Cosmetic Act.
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are components of FDAapproved drug products if an applicable USP or NF monograph does not exist; or (3) appear on FDA's list of bulk drug substances that can be used in compounding.25 In contrast, the FDCA states that 503B facilities may only use bulk drug substances that: (1)
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The figure does not offer a complete summary of the complex regulatory framework for all drug products or compounded preparations. Compounding preparations can be made from either bulk drug substances or FDA-approved drug products that are subsequently modified.
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. 28 List of Bulk Drug Substances That Can Be Used to Compound Drug Products in A ccordance with Section 503A of the Federal Food, Drug, and Cosmetic Act.
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with FDA.31 The policy serves to facilitate investigations of complaints related to compounded drugs distributed out of the state where it was compounded, and to prevent inordinate interstate distribution of compounded drugs that is characteristic of drug manufacturing.32,33 The law does not restrict interstate distribution of compounded drugs from 503B outsourcing facilities. Regulations Related to Marketing: The Federal Trade Commission and the Consumer Protection Act Compounded drugs have been promoted through major marketing campaigns in physician offices and pharmacies, as well as by online advertisements.
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Recently, Tennessee prevailed in demonstrating that a compounding pharmacy in the state had violated the Tennessee Consumer Protection Act with its cBHT marketing and advertisements. The final ruling concluded 34 Federal Food, Drug, and Cosmetic Act § 505D(c)
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The pharmacy in question was ordered to pay more than $18 million in damages to the consumers who had used its cBHT preparations.35 For consumers to understand the potential risks and benefits of cBHT, it is important that labeling and advertising claims related to compounded drugs be truthful, not misleading, and substantiated with sound evidence. This may be especially true for hormone therapy, since some of the more serious adverse events associated with hormone therapies can take years to 35 Office of Tennessee Attorney General.
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(FTC, 2001b) CURRENT CONCERNS WITH FEDERAL REGULATIONS FOR COMPOUNDED DRUGS Despite the FDAMA's and the DQSA's clarification of compounding's federal regulatory environment, confusion over some aspects of compounding regulation and oversight remain, particularly where both federal and state regulators have overlapping authority.36 These points of unresolved confusion include the registration of outsourcing facilities, prescription requirement, and pharmacy inspections.
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BOX 3-2 Large-Scale Compounding Operations at 503A Compounding Pharmacies Large-scale compounding operations are acquiring pharmacy licenses in multiple states and operating under 503A exemptions and requirements (see, for example, Compounding Pharmacy of America, 2020a; University Compounding Pharmacy, 2020; Women's International Pharmacy, 2020)
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Section 503A compounding pharmacies, in contrast, require patient-specific prescriptions to dispense compounded drugs.39 However, some state laws, in conflict with federal law, do allow 503A pharmacies to compound "office stock" without a patient-specific prescription (The Pew Charitable Trusts, 2016) .40 Another complicating factor is that in these situations, the compounder and the prescriber of the compounded drugs may be the same individual, setting the stage for a potential conflict of interest not found in the traditional prescription model in which the prescriber and the manufacturer are two different entities.
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USP-NF monographs for bulk drug substances and other ingredi ents used in drugs, both compounded and manufactured, as well as set standards for identity, quality, purity, strength, packaging, and labeling.
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In addition, the inspection found that insanitary equip ment was used in the compounding process. The outsourcing facility was also found to have neglected to investigate failures in batches of compounded drugs or quality failures.
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<1160> Pharmaceutical Calculations in Pharmacy Practice describes how to appropriately perform calculations required for compounding and dispensing medications, including quantities of ingredients, dosages, infusion rates, endotoxin load, stability, and expiration dates. <1163> Quality Assurance in Pharmaceutical Compounding explicates the responsibilities and practices of a robust quality assurance system for compounded preparations.
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See Appendix E for additional estimates for 503A compounding pharmacies and 503B outsourcing facilities.
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Idaho Administrative Code, Section 27.01.05.100.05; Illinois Administrative Code, Section 1330.640; Code of Maryland Regulations, Section 10.34.19.02; Pennsylvania Code, Section 49.27.601. SOURCES: NABP, 2018; The Pew Charitable Trusts and NABP, 2018.
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Even after the DQSA, the majority of compounding pharmacies remain under the oversight of state entities. Outside of high-risk 503A compounding pharmacies and 503B outsourcing facilities, FDA has maintained that its "aim is to leave the oversight of traditional pharmacy to states" (FDA, 2018a)
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Section 503B of the FDCA provides FDA with greater oversight of 503B outsourcing facilities than it has for 503A compounding pharmacies. Questions have arisen regarding how state laws or regulations governing compounded drugs should apply when overlap or conflict exists with expanding FDA oversight.
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While outsourcing facilities are overseen by FDA, 38 states license or register 503B facilities under various categories, including outsourcing facilities, manufacturers, wholesale distributers, or others.47 Additionally, while federal law does not require outsourcing facilities to obtain a pharmacy license, some states do, while others prohibit pharmacy licensure of 503B facilities. Such overlapping regulatory schemes can be challenging for facilities seeking to register as 503B distributors (The Pew Charitable Trusts and NABP, 2018)
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. Navigating conflicts of interest -- particularly financial conflicts -- is a special concern in the context of circumstances involving compounded preparations in which regulatory oversight is limited and variably enforced.
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, originally passed in 2010 as part of the Patient Protection and Affordable Care Act, requires reporting of all payments or gifts of value greater than $10 made to physicians and hospitals by group purchasing organizations and manufacturers of drugs, biologics, and medical devices covered by certain government payers.49 Notably, these financial relationships are also required to be publicly disclosed.50,51 The PPSA, though, does not cover the disclosure of payments and financial relationships between providers and compounding pharmacies or outsourcing facilities. Individuals with financial stakes in clinics and pharmacies that sell cBHT medications and related services have published peer-reviewed articles on the effects of cBHT.
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As stated in Section 503A of the FDCA, the existence of a USP-NF monograph for a bulk drug substance allows compounders to use that bulk drug substance in compounded preparations under 503A.52 Because USP-NF monographs do not directly address the safety or effectiveness of the bulk drug substance, requests to add new monographs without such data could be seen as a way for the sponsor, and 503A compounders generally, to market new compounded formulations by diversifying the APIs available to them. Pharmacists undoubtedly have an important role in patients' use of medications, as supported by the Centers for Medicare & Medicaid Services advocating for pharmacists' ability to prescribe certain drugs in urgent situations (Wachino, 2017)
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2017b. Interim policy on compounding using bulk drug substances under Section 503a of the Federal Food, Drug, and Cosmetic Act: Guidance for industry.
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2019a. Evaluation of bulk drug substances nominated for use in compounding under Section 503b of the Federal Food, Drug, and Cosmetic Act: Guidance for industry.
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2013. Seeing through the murky vial: Does the FDA have the authority to stop compounding pharmacies from pirate manufacturing?
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n.d.-a. Compounded preparations monographs (CPMs)
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