Animal Drug Compounding from Bulk Substances and FDA’s Release of GFI # 256: Is or Is Not the Third Time a Charm?

On April 13, 2022, FDA released its long-anticipated final Guidance for Industry # 256 – Compounding Animal Drugs from Bulk Drug Substances (GFI).  As readers of this blog likely remember, the animal drug compounding GFI has had a relatively long and tortured history, blogged about here, and here and here.

In its communication released with the GFI, FDA stated that it received many comments on its previous 2019 draft guidance.  A review of the docket reveals that FDA received in fact well over 2,000 comments on its last attempt.  FDA noted that it made “significant changes” to the final GFI to provide “recommendations for veterinarians seeking to access  animal drugs compounded from bulk drug substances for those animals that need them.”  (FDA Press Release at 4).  But, FDA recommends that compounds from bulk substances only be used after the prescribing veterinarian considers whether the FDA-approved treatment options can be used. FDA is clear in its communications accompanying the GFI’s release that compounding  from bulk substances for animals is not permissible federally unless compounding pursuant to the limited conditions set forth in the Guidance.  Thus, for FDA to deem compounding appropriate, there must be a circumstance where no FDA-approved or indexed drug (including the extralabel use of an FDA-approved animal or human drug) can be used to treat the animal’s particular medical condition.

FDA’s GFI addresses in particular:

• The types of drugs compounded from bulk substances that present the greatest risk, in FDA’s determination, and thus are prioritized for enforcement action
• The circumstances under which FDA does not intend to take enforcement action (i.e., it will exercise enforcement discretion), for violation of the FDCA’s approval, adequate directions for use and cGMP requirements – separately considering non-food producing; office stock for non-food producing; and food producing animals.

FDA also strongly urges reporting of adverse events by veterinarians, pharmacists and owners on FDA’s Form 1932a.  Later in the GFI, FDA makes such reporting within 15 days a requirement of  compounding (from non-food producing animals) as a condition of FDA’s enforcement discretion.

The Guidance contains a fair amount of detail about what FDA will consider concerning documentation of reasons necessitating compounding in lieu of an FDA- approved product. To compound for individually identified non-food producing animals, pages 10-15 of the GFI list the necessary conditions, and accompanying documentation (and note that documentation of reasons seems critically important for FDA’s exercise of enforcement discretion).  Concerning controversial animal drug office use compounding (pages 15-16, and Appendix at 19-22), FDA retains (from the earlier draft) its nomination and “list” concept (adopted from FDA’s “bulks list” approach for human drugs).  The Appendix sets forth what nominators must include in their nominations.  Importantly,

• There is no marketed FDA-approved, conditionally approved, or indexed animal drug(s) that can be used to treat the condition, and demonstrates;
• There is no marketed FDA approved, conditionally approved, or indexed animal or human drug(s) with the same active ingredient(s) that could be used in an extralabel manner to treat the condition; and
• FDA has not identified a significant safety concerning specific to use of the drug substance in animals;

AND in addition,

• Urgent treatment with the compounded drug is necessary to avoid animal suffering or death, or to protect public safety.

The Appendix provides docket information and a description of the information that should be submitted with the bulk substance nomination.  We have seen these “bulks lists” before.  Importantly, unlike this animal compounding GFI, FDA’s “bulks list” for human drugs is dictated by the statutory command for FDA to create the lists, set forth in Section 503A (individually identified patients) and Section 503B (outsourcing facility/office use).  This blogger wonders where FDA’s authority derives to regulate through a guidance document animal drug compounding in the first instance.  This has been debated for decades and blogged about over a decade ago, right here, and here, where the Agency lost that argument at the federal district court in Florida.  Given the FDA’s recent and widely publicized troubles in its implementation of the human drug compounding MOU, blogged about here,  it is surprising FDA would again take the GFI “leap” when it may lack statutory authority to do so.