This week, the U.S. Food & Drug Administration (FDA) published draft guidance, describing FDA’s policy and process for evaluating bulk drug substances used in compounding by outsourcing facilities that are registered under Section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act).
By way of background, under Section 503B a facility may register as an “outsourcing facility” and qualify for certain exceptions from drug approval and labeling requirements at Sections 502(f)(1), 505 and 582 of the FD&C Act. However, Section 503B also contains provisions that outsourcing facilities must still comply with the other requirements for pharmaceutical manufacturers, including current good manufacturing processes (cGMPs), FDA inspections, adverse event reporting, and others. The FD&C Act provides that outsourcing facilities do not have to (but may) obtain prescriptions for identified individual patients and they can distribute compounded drugs to healthcare practitioners for “office stock,” to hold pending patient need.
In prior Section 503B guidance issued in January 2018, FDA noted that because compounded drugs are subject to a lower regulatory standard, they should only be distributed to health care facilities or dispensed to patients where the medical needs cannot be met by an FDA-approved drug. Further, among its other concerns in this most recent guidance, the FDA cautioned that, unlike approved products, with bulk drug substances the FDA has not assessed quality standards, specifications, and controls and, further, the substances may be manufactured by a facility that is not regulated by FDA. The Agency also stressed that using bulk substances that are components of FDA-approved drugs when there is no clinical need (as with economic reasons) undermines the drug approval process.
503B Bulks List
Section 503B directs FDA to develop a list of bulk substances for which there is a clinical need (503B Bulks List). The process for determining which substances will comprise the 503B Bulks List has been ongoing since at least 2013, when FDA requested nominations for the Agency to consider listing. The Agency published Interim guidance in June 2016.
The draft guidance published last week provides insight into FDA’s policy for determining “clinical need” as well as the factors and process FDA intends to use to evaluate bulk substances for the 503B Bulks List. FDA clarified that, among other considerations, the Agency:
- will not interpret supply issues, such as backorders, as clinical need;
- will not interpret cost considerations to be within the meaning of clinical need;
- may limit clinical need to the production of compounded drugs with certain attributes, such as specific strengths, routes of administration or dosage forms; and
- intends to separately list salts or esters of an active moiety, and will not include within that category other salts or esters, or the base compound, of the same active moiety.
FDA plans to use a two-part analysis, described in greater detail in the draft guidance. In Part 1, FDA will first determine whether the bulk drug substance is a component of an FDA-approved product. Generally, this will be satisfied where the substance is the same as the active pharmaceutical ingredient in the FDA-approved drug (as defined in product labeling). If the bulk substance is a component of an FDA-approved drug, FDA will conduct a threshold review, asking:
- Is there a basis to conclude, for each FDA-approved product that includes the 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?
- Is there a basis to conclude that the compounded drug must be produced from a bulk drug substance rather than from an FDA-approved drug product?
FDA will proceed to Part 2 of the analysis only if it answers “yes” to these two questions or if the bulk drug substance is not a component of an FDA-approved product. Part 2 will involve a balancing test, with the FDA considering factors related to: (i) the physical and chemical characterization of the substance, (ii) safety issues raised by use in compounding, (iii) available evidence of effectiveness, and (iv) current and historical use of the substance in compounding, including medical conditions and peer-reviewed medical literature.
FDA indicated that it may consider information provided by nominators of the bulk substances, as well as public comments, and other information identified by the Agency in its review. The Agency may also ask nominators and others who have submitted docket comments to provide additional information.