Keeping Up with ….. FDA’s Drug Compounding Lists: Todays PCAC Meeting

By James E. Valentine & Karla L. Palmer – 

There are a number of lists that are central to FDA’s regulatory framework for the regulation of pharmacy compounding under sections 503A and 503B of the Federal Food, Drug, and Cosmetics Act (FD&C Act). In recent posts, we’ve discussed additions to one such list: the list of drugs that may not be compounded under 503A and 503B (see posts here and here).

FDA’s Pharmacy Compounding Advisory Committee (PCAC) is meeting to consider substances nominated for inclusion on two other lists:

1. Bulk Drug Substances That Can Be Used By Compounders under Section 503A (also known as the “503A Bulks List”)
2. Drug Products That Present Demonstrable Difficulties for Compounding (also known as the “Difficult to Compound List”)

We thought this post would be a good opportunity to discuss what exactly the PCAC is considering when it advises the Agency on whether or not to include a drug on either of these lists.

Substances Nominated for Inclusion on the 503A Bulks List

One of the conditions that must be met for a compounded drug product to qualify for the exemptions in section 503A is that a licensed pharmacist or licensed physician compounds the drug product using bulk substances that meet one of the following criteria:  

1. comply with the standards of an applicable United States Pharmacopoeia [(USP)] or National Formulary [(NF)] monograph, if a monograph 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 [FDA]; or
3. if such a monograph does not exist and the drug substance is not a component of [an approved drug], that appear on a list developed by [FDA] through regulations issued by [FDA] under subsection (c) [of section 503A (the 503A Bulks List)]

See FD&C Act § 503A(b)(1)(A)(i)).  (FDA defines bulk drug substances as “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” (21 C.F.R. 207.3(a)(4)).

Before developing the 503A Bulks List, FDA must convene and consult an advisory committee on compound unless it determines that the issuance of such regulation before consultation with an advisory committee is necessary to protect the public health (see FD&C Act § 503A(c)(1)).  FDA is doing just that at the November 3^rd PCAC meeting.  The full nomination process is discussed in FDA’s Interim Policy that was published in June.

As discussed at the February 2015 PCAC meeting, in the July 2014 Federal Register notice (79 Fed. Reg. 37,747, 37,748) soliciting (re)nominations for the section 503A Bulks List, FDA proposed the following criteria to evaluate the nominated substances: 

1. the physical and chemical characterization of the substance;
2. any safety issues raised by the use of the substance in compounded drug products;
3. 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; and
4. the available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists.

In evaluating candidates for the 503A Bulks List, FDA is using a balancing test. No single one of these criteria is dispositive; rather, the agency is considering each criterion in the context of the others and balancing them, on a substance-by-substance basis, in deciding whether a particular substance is appropriate for inclusion on the list.

Today, FDA is presenting to the PCAC results of its review of some of the nominated substances to obtain the Committee’s advice on whether to include the substances on the list. Specifically, the substances being discussed at this meeting are:

Whether to Include Products or Categories of Drug Products on the Difficult to Compound List

Both sections 503A and 503B also prohibit compounding of drugs that are on FDA’s Difficult to Compound List. One of the conditions for the exemptions under section 503A is that the compounded drug product is not a drug product that “presents demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product” (see FD&C Act § 503A(b)(3)).

Similarly, one of the conditions for the exemptions under section 503B is that the compounded drug product “is not identified (directly or as part of a category of drugs) on a list published by the Secretary . . . of drugs or categories of drugs that present demonstrable difficulties for compounding that are reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug or category of drugs, taking into account the risks and benefits to patients,” or “is compounded in accordance with all applicable conditions identified…as conditions that are necessary to prevent the drug or category of drugs from presenting [such] demonstrable difficulties” (see FD&C Act § 503B(a)(6)).

FDA solicited nominations for the Difficult to Compound List in its December 2013 Federal Register notice (78 Fed. Reg. 72,840). For today’s PCAC meeting, FDA considered a drug product that was nominated for the list, and is proposing the following to the advisory committee:

If you are interested in tuning in to see how the PCAC considers products nominated for these two lists, the public comments concerning the same, and the Committee deliberations (and vote), you can find the webcast information here.