According to the draft guidance, a drug will be considered “commercially available” if it is a marketed drug product and neither has been discontinued nor appears on the FDA drug shortage list under Section 506E of the Federal Food, Drug, and Cosmetic Act.

When Congress enacted the Drug Quality and Security Act in 2013, it provided that state-licensed pharmacies engaging in drug compounding under Section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA) could not “compound regularly or in inordinate amounts (as defined by the Secretary) any drug products that are essentially copies of a commercially available drug product” and that registered outsourcing facilities, compounding under Section 503B of the FDCA, could not compound any drug that is “essentially a copy of one or more approved drugs.” Drugs compounded in violation of these provisions lose their eligibility for exemptions to certain provisions of the FDCA for compounding conducted in accordance with Sections 503A or 503B.[1]

On July 7, 2016, the U.S. Food and Drug Administration (FDA) released two new draft guidance documents setting out FDA’s proposed approach to the provisions governing compounded drugs that are essentially copies of commercially available drug products (Section 503A) or approved drug products (Section 503B). These documents are:

  • Draft Guidance on Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry[2]
  • Draft Guidance on Compounded Drug Products That Are Essentially Copies of Approved Drug Products Under Section 503B of the Federal Food, Drug, and Cosmetic Act Guidance for Industry[3]

The draft guidances set forth FDA’s proposed current interpretation of the statutory provisions mentioned above and provide insight into how FDA intends to enforce them.

Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A

In its new draft guidance related to 503A compounding, FDA announces that it plans to enforce this provision of the FDCA by determining first whether a compounded drug is essentially a copy of a commercially available drug and, second, whether the drug is compounded regularly or in inordinate amounts.

According to the draft guidance, a drug will be considered “commercially available” if it is a marketed drug product and neither has been discontinued nor appears on the FDA drug shortage list under Section 506E of the FDCA. If a pharmacy compounds a drug on the drug shortage list, it must make a notation on the prescription of the date the list was checked.

FDA will consider a compounded drug to be “essentially a copy” of a commercially available drug if:

  1. It contains the same active pharmaceutical ingredient(s) (API);
  2. Its dosage strength is within 10 percent of that of the commercially available drug or is easily substitutable (e.g., it is a multiple of the dosage strength of one dose of the commercially available drug); and
  3. The prescribed route of administration for the compounded drug is the same as that for the commercially available drug (e.g., both are administered in pill form).

Nonetheless, a compounded drug that meets the above criteria will not be considered “essentially a copy” if the prescriber determines that a particular change will produce a “significant difference for the patient for whom it is prescribed.” The patient-specific prescription must include a physician’s notation of the change and the “significant difference” produced by that change. FDA notes that it generally does not intend to question a prescriber’s determination but will investigate whether the compounder has sufficient documentation of such a determination when it asserts that a drug is not essentially a copy.

The draft guidance also explains how FDA intends to determine whether drugs that are essentially copies of commercially available drugs are compounded regularly or in inordinate amounts. FDA interprets “regularly” to mean “at regular times or intervals, usually, or very often.” FDA provides several, non-exclusive factors that speak to whether a drug is compounded regularly or in inordinate amounts, including the number of prescriptions for such drugs or their percentage of all compounded products prepared or prescribed; whether the compounder routinely substitutes compounded drugs that are essentially copies of commercially available drugs; and if the drug product is compounded on a regular schedule instead of on an as-needed basis. FDA further suggests it will take enforcement action where a pharmacy compounds within a single month more than four prescriptions for a particular drug that is essentially a copy of a particular commercially available drug and for which there has not been a determination by the prescriber that a change will produce a significant difference for the patient.

Compounded Drug Products That Are Essentially Copies of Approved Drug Products Under Section 503B

In its new draft guidance related to 503B compounding, FDA declares that “drugs compounded by outsourcing facilities should only be distributed to health care facilities or dispensed to patients to fulfill the needs of patients whose medical needs cannot be met by an FDA-approved drug.” FDA explains that an “approved drug” is an FDA-approved drug for which an application was submitted under Section 505 of the FDCA; notably, this does not include over-the-counter drugs.

Under Section 503B of the FDCA, a drug is “essentially a copy” if it is “identical or nearly identical to an approved drug.” FDA will consider a compounded drug to be “identical or nearly identical” to the FDA-approved drug, and thus “essentially a copy,” if the two products share the same:

  1. Active ingredient(s);
  2. Route of administration;
  3. Dosage form;
  4. Dosage strength; and
  5. Excipients (except where such information is not publically available).

A compounded drug product that meets all of these criteria will not be deemed “essentially a copy” if the FDA-approved drug appears on the FDA drug shortage list at the time the drug product is compounded, distributed and dispensed. Recognizing that the duration of a drug shortage may be unpredictable, FDA states that it will not take regulatory action against an outsourcing facility where the order for a compounded drug was received while the approved drug was on the shortage list, provided that such drug was still on the list within 60 days of the distribution or dispensing of the compounded drug. FDA takes the position in this draft guidance that identical or nearly identical drugs cannot be compounded even where a change will produce a clinical difference for a patient.

If a compounded drug does not qualify as identical or nearly identical to the approved drug, FDA will still consider it to be “essentially a copy” if the compounded drug contains the same bulk drug substance as the approved drug unless the compounding involves a change to the drug that produces a clinical difference for the patient to whom it will be given. Here, the drug need not be compounded for a specific, identified patient, but the prescription or order must still contain a notation of the change and the clinical difference it will produce for the patient to whom it ultimately will be administered. As with the 503A-related draft guidance, FDA generally does not intend to question a prescriber’s determination of clinical difference, but will investigate whether the outsourcing facility has sufficient documentation of such a determination when it asserts that a drug is not essentially a copy.

Finally, Section 503B does not permit the compounding of drugs that are essentially copies of over-the-counter (OTC) drugs because these drugs are not approved through an application submitted under Section 505 of the FDCA. FDA explains, however, that if the bulk drug substance at issue is a component of both an approved drug and an OTC drug, FDA will evaluate it as being a component of the approved drug.

Conclusion

FDA is accepting public comments on the two draft guidance documents through October 11, 2016.[4] Comments may be submitted electronically at http://www.regulations.gov or in writing to the FDA Division of Dockets Management. Further details on the procedure for submitting comments on the respective draft guidance documents are provided in the Federal Register as part of FDA’s notice for each document.Stakeholders with concerns about FDA’s newly asserted positions should consider submitting comments.