In a Flurry of Activity, FDA Releases Compounding Final Guidances Addressing “Essentially Copies” of Commercially Available Drug Products for Both Section 503A and 503B Compounders

As stated in our blogpost discussing FDA’s announcement of 2018 Compounding Policy Priorities (here). FDA also released its Final Guidance on Compounding “essentially copies” of commercially available drugs.  This long-anticipated guidance discusses how FDA intends to determine whether a compounded drug is essentially a copy of a commercially available drug product.  We discuss each Final Guidance separately below.

Essentially Copies Under Section 503A

FDA’s Final Guidance for traditional, Section 503A pharmacy compounders does not read that differently from the draft guidance, which we blogged about here.

The Final Guidance does, however, contain a handy flow chart (similar to the chart FDA included in the 503B draft guidance) that enables the reader easily to review FDA’s criteria for what it considers is essentially a copy and make a determination whether a compounded product meets the guidance’s criteria. FDA states in a footnote that it also considering “the applicability” of the guidance to hospitals and health systems, and will address that issue in a separate guidance or rulemaking, thus telegraphing that the Agency will potentially adopt a different “essentially copies” analysis for compounding for those entities.

The Final Guidance does not change the definition of what it considers a “commercially available drug product” (i.e., considering whether a product is no longer commercially marketed (excluding for reasons of safety or effectiveness) and Section 506E shortage drugs).  It also does not change what it considers “essentially a copy” of a commercially available drug product, using the same test set forth in the draft guidance:

• the compounded drug product has the same active pharmaceutical ingredient (API);
• the APIs have the “same, similar or easily substitutable strength”; and
• the products can be used by the same “route of administration.”

If the compounded formulation meets ALL three of these criteria, then the compounded product is “essentially a copy” of a commercially available product and can only be compounded in small amounts as described in the Final Guidance.  Concerning similar dosage strengths, and despite several comments addressing the issue, FDA left in the Final Guidance its “10% statement:” “FDA generally intends to consider two drugs to have a similar dosage strength if the dosage strength of the compounded drug product is within 10% of the dosage strength of the commercially available drug product.”  And, notably, if the commercially available drug has to be “split” and the tablet is not suitable for splitting, FDA would not consider the compound made to the prescribed dosage strength to be “easily substitutable.”  FDA also maintained its limitations in the Final Guidance concerning compounds that have the same characteristics as two or more commercially available drug products, notwithstanding some industry confusion concerning permissible conduct when compounding multiple ingredients in the same, similar or easily substitutable strength that are also separately commercially available.  The Guidance also again makes clear that price alone is not sufficient to render a product outside the essentially copies prohibition.

The Final Guidance also does not substantively differ from the draft concerning the required “statement of significant difference” when copying commercially available drug products. With respect to whether a compounder is compounding “regularly or in inordinate amounts,” FDA’s final position is also consistent with statements in the draft guidance, including considering permissible compounding “four or fewer” prescriptions of essentially copies in a calendar month.  FDA does not consider any prescription that notes a “significant difference” to be essentially a copy; thus those prescriptions would not be counted in the four-prescription limit.  FDA recommends that pharmacies maintain records documenting statements of significant difference for a period of at least three years.

Essentially Copies Under Section 503B

Notwithstanding dozens of comments from industry, like the Section 503A essentially copies Final Guidance, the Section 503B Final Guidance is not substantially different from the draft guidance that FDA released in 2017, and blogged about here.   FDA adds that it does not intend to take enforcement action against an outsourcing facility for failing to compound in accordance with section 503B(a)(5) if it fills orders for a compounded drug that is essentially a copy of an approved drug that has been discontinued and is no longer marketed.  FDA does not clarify whether these compounds would be limited to those drugs made with substances on FDA’s bulks list 1 (or the bulks list FDA intends to finalize through regulations), however.

FDA is considering the same factors to determine whether the compounded product is identical or nearly identical to the approved drug where ALL of the following are the same:

• active ingredients;
• route of administration;
• dosage form;
• dosage strength; and
• excipients.

Unlike the draft, the Final Guidance adds the following concerning “route of administration:” If the approved drug can be used (regardless of how it is labeled) by the same route of administration prescribed for the compounded drug, FDA intends to treat the “compounded drug as though it has the same route of administration for purposes of this analysis.  For example, if the approved drug is an injectable drug sold in a vial that is labeled for intra-muscular use, but this drug can also be drawn from the vial by a smaller needle for subcutaneous administration, a compounded drug product sold in a similar vial and prescribed for sub-cutaneous use would be considered to have the same route of administration under this analysis.”  In contrast to “essentially copies” under Section 503A (where FDA does not define “identical” or “nearly identical”), if a compounded drug product is “identical” or “nearly identical” to the commercially available drug product, the fact that a prescriber makes a determination of significant or clinical difference is of no matter – such a product may not be compounded under Section 503B unless there is a drug shortage. Like Section 503A, however, FDA does include a footnote that seemingly permits compounding drug products have been discontinued (or never marketed) for reasons other than safety or effectiveness.

Other provisions of the Section 503B “essentially copies” guidance have not changed between the draft and the Final Guidance, other than FDA’s recommendation that a facility keep records demonstrating the clinical difference determination for a period of at least three years. Like in the draft guidance, the Section 503B Appendices setting forth how FDA intends to determine whether a compounded drug product is essentially a copy of a commercially available drug product under Section 503B are attached here.