FDA Challenges USP Standards for Biologics

A provision in a Senate health reform bill has reignited debate over the whether biological products should have to meet product quality standards established by the U.S. Pharmacopeia. FDA officials contend that efforts by the USP to publish product-specific monographs for biological products could hinder the development of innovative products, including competitive biosimilars. USP officials, with support from pharmacists and some patient and health care groups, maintain that monograph standards are important for ensuring the safety and quality of all drugs and biotech therapies.

The debate has intensified as the March 2020 date nears for a cadre of therapies, including insulin, will shift to falling under the rules applying to drugs to those governing biologics. This change is expected to facilitate the development of biosimilar versions of insulin products and other therapies in this group that have complied with USP monographs for years.

The new policy sought by FDA is contained in bipartisan legislation recently issued by the Senate Health, Education, Labor and Pensions (HELP) committee, which presents multiple provisions designed to improve national health care programs and access to medicines. These include items to revise patent policy, generic drug testing, and biosimilar oversight as part of efforts to reduce the cost of drugs and biologics.

The disputed language (section 207 of S. 1895) excludes all biological products regulated by the Public Health Service Act from meeting USP compendial standards, as is the case for conventional drugs. In a recent posting on the FDA website, Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), and Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), note the recent approval of the 20^th biosimilar as a sign of FDA’s success in smoothing the pathway for bringing competitive biotech therapies to U.S. patients. But they also warn that continued innovation in this area could be blocked by “inflexible standards that can’t evolve quickly enough to keep up with technological development,” as might occur if product-specific USP standards are applied to biologics. FDA already has standards in place to ensure the safety, purity and potency of biological products, Woodcock and Marks observe, and the need to comply with additional standards could extend reviews and delay approvals.

Similarly, Steven Kozlowski, director of CDER’s Office of Biotechnology Products, explains in another commentary that most widely used biological products do not have USP monographs, and that efforts to establish mandatory standards for these inherently complex and variable products could “impede technological progress or innovation.” Kozlowski raises the possibility that the manufacturer of an older innovator therapy could ask USP to write a monograph for its product citing patented characteristics that would produce “unnecessary barriers to innovation and progress.”  Unlike small molecule drugs, which are chemically synthesized to achieve “sameness” with the innovator drug, biological products are highly complex proteins produced from living cells and aim to be “highly similar,” but not the same, as the reference product. 

Kozlowski maintains that adhering to USP standards would not necessarily prevent products from experiencing quality or safety problems and could make it difficult for a subsequent manufacturer to implement changes, such as a more efficient manufacturing process. While FDA supports USP monograph standards for conventional drugs, it prefers optional standards for biological products that align with the agency’s flexible approach for inherently complex biological products.

USP fights back

A coalition of pharmacists, public health and patient organizations supports efforts by USP to convince the authors of the Senate HELP bill to drop the curb on compendial standards for biologics. The group maintains that the proposed policy change would weaken assurances that medicines are safe and of high quality, without doing anything to lower drug costs. USP officials note that mandatory drug quality standards developed by the European Pharmacopeia and the World Health Organization have supported drug development and approval, including biosimilars, in Europe and other regions.  

The 21^st Century Cures legislation of 2016 initially included a similar exemption for biologics from USP standards, but the final legislation dropped that provision. More recently, the administration’s budget proposal for 2020 includes a proposal to end the requirement that biologic products comply with USP quality standards. USP and its supporters maintain that public specifications for product purity and potency provide assurances for patient safety and foster competition in the market for biologics, particularly for insulin. FDA’s high-profile response reflects an escalation in the debate over whether the regulatory agency has to accept USP quality standards for all drugs and biologics, or if more flexibility would provide important benefits for the development of new therapies.