Based on the information presented by the Food and Drug Administration (FDA) and the nominators of the substances:
- PCAC voted for the inclusion of glutathione on the final 503A Bulks List.
- Glutathione was evaluated for use in the treatment of a number of conditions, including but not limited to, skin lightening, cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic lung disease, oxidative stress, and the reduction of the side effects of chemotherapy.
- PCAC voted against the inclusion of ammonium tetrathiomolybdate, enclomiphene citrate, and ferric subsulfate on the final 503A Bulks List.
- Ammonium tetrathiomolybdate was evaluated for use in the treatment of Wilson’s disease and for use as copper chelation therapy for the treatment of breast cancer, kidney cancer, prostate cancer, colorectal cancer, esophageal cancer, and malignant pleural mesothelioma.
- Enclomiphene citrate was evaluated for use to increase serum testosterone, luteinizing hormone, and follicle-stimulating hormone to normal levels in the treatment of secondary hypogonadism.
- Ferric subsulfate was evaluated for use as an astringent and hemostatic agent during minor surgical procedures.
PCAC also discussed and voted for the inclusion of lorcaserin hydrochloride on the Withdrawn or Removed List under sections 503A and 503B of the FDCA.
How does PCAC’s vote impact these substances?
Although PCAC’s vote is a recommendation and not binding on the FDA, it significantly influences FDA’s decision on these substances, especially for substances voted against for inclusion on the final 503A Bulks List.
The FDA consistently evaluates bulk drug substances nominated for inclusion on the 503A Bulks Lists. During this interim period, while the 503A Bulks List is being formally developed (described below), FDA operates according to its 2017 interim policy. This policy enables the FDA to place reviewed substances in three categories (Category 1, Category 2, and Category 3) that the FDA publishes in an interim 503A Bulks List that set out conditions under which the FDA does not intend to take action against compounding pharmacies that compound drug products from substances that cannot otherwise be used in compounding under section 503A. Hence, PCAC’s vote on these substances may influence the FDA to publish a revised interim 503A Bulks List, as last published on November 2, 2021.
By way of background on the formal process, section 503A of the FDCA describes the conditions that must be satisfied for compounding of human drug products to be exempt from the following three sections of the FDCA: section 505 (concerning the approval of drugs under new drug applications or abbreviated new drug applications); section 502(f)(1) (concerning the labeling of drugs with adequate directions for use); and section 501(a)(2)(B) (concerning current good manufacturing practice requirements).
One of the conditions that must be met for a compounded drug product to qualify for these exemptions is that a licensed pharmacist or licensed physician compounds the drug product using bulk drug substances that:
- Comply with the standards of an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph, if a monograph exists, and the USP chapter on pharmacy compounding;
- If such a monograph does not exist, are drug substances that are components of drugs approved by the Secretary of the Department of Health and Human Services; or
- If such a monograph does not exist and the drug substance is not a component of a drug approved by the Secretary, appears on a list developed by the Secretary through regulations issued by the Secretary under subsection (c) of section 503A.
Under section 503A(c)(1), before developing the final 503A Bulks List through regulation, the FDA must thoroughly review the nominations and consult PCAC, unless the FDA determines that the issuance of such regulation before consultation with PCAC is necessary to protect the public health. In evaluating substances nominated for the 503A Bulks List, the FDA reviews the information provided in support of the nomination and other available information according to the following four criteria:
- The physical and chemical characterization of the substance.
- Any safety issues raised by the use of the substance in compounded drug products.
- Historical use of the substance in compounded drug products, including information about the medical condition(s) the substance has been used to treat and any references in peer-reviewed medical literature.
- The available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists.
Once the evaluation of nominated substances is complete, the FDA presents the results of its review to the PCAC to obtain its advice on whether to include the substances on the list. Then the FDA, in consultation with USP, must publish a notice of proposed rulemaking (NPRM) that identifies the substances it proposes for inclusion and not inclusion on the 503A Bulks List. After the publication of the NPRM, the public has an opportunity to comment on the proposed rule. After considering the comments submitted to the docket, the FDA publishes a final rule that establishes the 503A Bulks List.
After a final rule is published, drug products compounded using a bulk drug substance on the 503A Bulks List are eligible for the section 503A exemptions noted above, provided the drug products are compounded in compliance with the other conditions of section 503A.
What’s next?
The FDA may proceed with first re-publishing the interim 503A Bulks List, as noted above, with ammonium tetrathiomolybdate, enclomiphene citrate, and ferric subsulfate removed from Category 1. Alternatively, the FDA may proceed with publishing a NPRM identifying the bulk drug substances it proposes for inclusion and not inclusion on the final 503A Bulks List. The FDA has been very actively engaged in the rule-making process, as evidenced in its regulatory agenda of March 2023, estimating the publication of a final rule to amend the current final 503A Bulks List. Hence, we encourage industry stakeholders to keep a close eye on the FDA’s next steps.
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