NCHR Comments on FDA’s Bioequivalency for Generic Drug Formulations Draft Guidance

July 18, 2023

We are pleased to have the opportunity to share our views with the Food and Drug Administration (FDA) on the Product-Specific Guidance: Draft and Revised Draft Guidance for Industry.

The National Center for Health Research (NCHR) is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.

NCHR agrees with the efforts of the FDA to streamline public access to information, research, and ultimately lower-cost generic medications. However, safety and effectiveness must remain paramount throughout bioequivalence (BE) guidelines. Patient safety must be safeguarded and the standards for generic products must be as rigorous as those required for a new compound submitted by an innovator company.

For generic versions of drugs to be safe and effective they should be tested across a range of people with variability in drug absorption and metabolism. That is, FDA guidelines should recommend that BE studies are conducted among people who are representative of the patient population in terms of sex, ethnicity, age, and health status for both innovator drugs and generic products. A drug can only be determined to be safe and effective if that drug has indeed been studied with sufficient numbers of patients in its target patient population. Thus, when generic drugs are subject to BE testing they should be required to demonstrate safety and effectiveness across all patient demographics in whom the drug will be administered (across sex, ethnicity, age, and health statuses). This expands FDA’s bioequivalence study guidelines that require all drug products intended for the use in both sexes be studied in both sexes.

Generic versions of innovator drugs also need to remain safe and efficacious across biochemical compound variability. This is especially true for drugs in the form of suspensions and emulsions, as these compounds are complex and highly variable. Because of this concern, we recommend that the BE of generic products are not solely tested in laboratory settings but are tested in-vivo whenever possible. This will help assure that standards are not lowered when BE testing is performed for generic drugs and that BE testing will yield safer, more effective generic drugs.

One area of specific concern that we will highlight as an example is the FDA’s proposed BE guidelines for the innovator drug, Sirolimus. Sirolimus is an immunosuppressant commonly used after an abdominal organ transplant to avoid rejection of the new organ. The BE study design proposed by the FDA recommends that testing be performed in healthy male and female populations. Yet, Sirolimus is often administered to patients who are chronically ill and have underlying conditions that disrupt drug absorption and metabolism.

Given that Sirolimus has a narrow therapeutic index, it is of the upmost importance that the BE of generic formulations be accurate and precise to avoid harm. Testing the BE of a drug in a healthy population may result in an inaccurate therapeutic dosage that will be harmful when administered to patients who are chronically ill and have disrupted drug absorption and metabolism patterns. This study design potentially undermines the standards for safety and effectiveness set by the FDA, and is an important example of why we strongly recommend greater diversity (across sex, ethnicity, age, and health status) in BE testing standards.

In closing, we appreciate the opportunity to support the efforts of the FDA to streamline access to publicly available information and research on BE, which ultimately has the potential to expedite the availability of lower-cost generic drugs. We strongly recommend that FDA ensure that streamlining does not result in lowered standards or permitting research designs that ultimately undermine the FDA’s own requirements for safety and effectiveness.