FDA’s (Re) (Re) (Re) Evaluation of Bulk Drug Substances for Outsourcing Facilities Under 503B: Is the Third Time a Charm, or Three Strikes, You’re Out?

After President Obama signed into law Title I of the Drug Quality and Security Act (the Compounding Quality Act), which created a new breed of drug compounders (deemed “outsourcing facilities”), FDA also came up with a plan to evaluate bulk substances outsourcing facilities could use in compounding pursuant to the statutory mandate set forth in FDCA Section 503B. That draft guidance, rolled out in December 2013, led to industry’s nomination of thousands of bulk substances (here).  After FDA reviewed those nominations, FDA asked for a “do over” of the process (here). About a year after that process concluded, and after receipt of hundreds of bulk substance nominations, FDA published its draft and final “Interim Policies” on compounding using bulk substances by Section 503B facilities (here). The policy included three lists, including “Bulks List I”, which are those nominated substances where FDA made a determination of “clinical need.” Until FDA publishes a final rule concerning the substances, FDA also stated outsourcing facilities were permitted to compound using those List I bulk substances. FDA updated the list on several occasions based on additional industry nominations that met FDA’s published clinical need criteria, and FDA opened a new docket to accept nominations in October 2015 (here). Even as recently as January 2017, FDA publicly announced its revision of its interim policy on bulk substances for 503B outsourcing facilities, and welcomed nominations via a newly established docket (here). True to its word, until July 2017, FDA also regularly updated its interim bulks list based on nominations received and encouraged outsourcing facilities to nominate substances for the lists.

What happened next? One can speculate that a lawsuit filed against the Agency rooted in the Administrative Procedure Act and FDA’s promulgation of the bulks lists as “interim policy” and not a final rule promulgated by notice-and-comment rulemaking (among other claims) is at least part (if not all…) of the issue. See the Complaint filed by Endo International against FDA and blogged about (here), and Press Release by Endo announcing a stay of that litigation in January 2018 based on FDA’s promise to promulgate new guidance by the end of March 2018 concerning compounding from bulk substances by outsourcing facilities pursuant to FDCA Section 503B (here).

Commissioner Gottlieb announced FDA’s latest efforts at creating a bulks list for outsourcing facilities on March 23, 2018. The Commissioner also announced the new draft guidance; (Federal Register Notice here), which is substantially different than the prior interim bulks policy, and which industry has been working with (and relying on) for the last several years in formulating meaningful bulk substance nominations based on FDA’s (now) well-established criteria.

After spending pages describing what bulk substances are and the prior nomination process, FDA states in its latest draft that it intends to maintain a current list of all bulk substances it has evaluated on its website, including separate lists for those substances that it has placed on the list and those that it as determined to not place on the list. Does this mean the current List I will stay in place for at least a while?

FDA also states that it will consider nominations on a rolling basis, and will only include a substance on the list where it has made a determination of “clinical need” for outsourcing facilities to compound the product using bulk substances (which, of course, sounds much like FDA’s statements concerning determinations both the Agency and its Pharmacy Compounding Advisory Committee have been making over the course of the past three years).

The draft guidance details how FDA will now interpret “clinical need” as that term is used in Section 503B(a)(2), including “certain additional procedures” FDA will use in its review of nominations. On the last page of the draft guidance, FDA provides a flow chart of the analysis it intends to engage when making the clinical need determination for bulk substances that that are a component of an FDA-approved drug product, and those that are not. The chart is a helpful summary that boils down to a single page FDA’s multi-page analysis.

Concerning FDA’s “clinical need” determination, FDA points out that it does not consider supply issues or cost to be within the meaning of clinical need.

FDA further states that clinical need determinations may be limited to specific strengths, routes of administration or dosage forms for a particular substance and thus FDA may limit that determination to such uses for particular substances.

Overview of FDA’s Proposed Two-Part Bulk Substance Analysis

FDA intends to use a two-part analysis in its new clinical need determination. Each step is set forth briefly below: Refer to the guidance for FDA’s in-depth description of each part. Note that FDA’s analysis here is substantially different than FDA’s previous nomination process, especially given its new, threshold focus on whether the substance is a component of an FDA-approved drug product.

(1) Determination of whether the bulk substance is a component of an FDA-approved drug

FDA will consider the following questions:

(a) Is there a basis to conclude, for each FDA-approved product that includes the nominated bulk drug substance, that (i) an attribute of the FDA-approved drug product makes it medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation, and (ii) the drug product proposed to be compounded is intended to address that attribute?

(b) Is there a basis to conclude that the drug product proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product?

FDA states that if it answers “no” to either of these threshold questions, then it does not intend to include that substance on a bulks list. If it answers yes to both questions, then it will proceed to the second part of its analysis,

(2) FDA’s “balancing test” of factors when considering bulks substances that are components of approved drugs (and “yes” to the questions above) and when evaluating bulk substances that are not components of approved drug products.

FDA will use these factors in the context of information provided in the nominations and about proposed uses of the compounded products (as well as other information provided through comments, upon request, or by FDA), as follows:

(a) The physical and chemical characterization of the substance;

(b) Any safety issues raised by the use of the substance in compounding;

(c) The available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists; and

(d) Current and historical use of the substance in compounded drug products, including information about the medical condition(s) that the substance has been used to treat and any references in peer-reviewed medical literature.

FDA then spends several pages detailing what it will consider in making the threshold determination concerning the attributes of the nominated substances that are components of FDA-approved products, and now the bulk substance proposed to be compounded will address these issues. For example, FDA states that unless an FDA-approved drug is “medically unsuitable for certain patients” and a compound intends to address the attribute that makes it medically unsuitable, then there is no clinical need to compound using that bulk substance. FDA will focus on the rationale set forth in the nomination, or a rationale that FDA identifies for use of the bulk substance in compounding. FDA states that broad statements without sufficient evidence supporting will not be adequate to demonstrate that an attribute of an approved drug makes it unsuitable for certain patients.

If the substance is not a component of an approved drug, FDA will proceed to Part 2 of its evaluation where it will also evaluate each of the four factors listed above (and described in the draft starting at page 13 of the draft guidance). Thus, the process does not appear to be that different from FDA’s prior nomination process with respect to bulk substances that are not components of FDA-approved drugs.

Notwithstanding, the draft guidance likely renders the nomination process not only more complicating (especially for substances that are components of FDA-approved drugs), but also one that is fraught with questions concerning what an “appropriate” nomination looks like, especially given the DQSA simply does not differentiate between “clinical need” for an FDA-approved bulk substance (which arguably was established during the FDA drug approval process) and a substance is not FDA-approved. The draft guidance also leaves outsourcing facilities (given there are only around 65 facilities at any given time), which FDA has touted since enactment of the DQSA as the safer alternative for compounding, grappling whether to return to more traditional compounding roles or engage in the rigorous nomination process. The next 90 days will be fascinating to watch as outsourcing facilities comment on FDA’s proposed process, which comments are due on May 25, 2018 (Docket No. FDA-2018-D-1067).