USFDA Guidance on Biosimilar Development and the BPCI Act: Key Regulatory Considerations

The development of biosimilar and interchangeable biological products is an important part of improving access to biological medicines. To support this process, the U.S. Food and Drug Administration (FDA) has issued guidance documents that clarify regulatory expectations under the Biologics Price Competition and Innovation Act (BPCI Act).

Two key FDA guidance documents provide detailed explanations through a question-and-answer format to help sponsors understand the regulatory pathway for biosimilar products.

Guidance: New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 4)

The draft guidance titled “New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 4)” provides additional clarification on several regulatory topics related to biosimilar development. The document updates earlier guidance by revising or introducing new questions and answers for public comment. This draft guidance supports the continued evolution of FDA’s biosimilar regulatory framework and complements the existing final Q&A guidance.

Use of Non-U.S. Licensed Comparator Products

One of the topics addressed in the draft guidance is whether sponsors may use clinical data comparing a proposed biosimilar product with a non-U.S.-licensed comparator product.

FDA explains that such data may be acceptable in certain circumstances if sponsors provide adequate scientific justification demonstrating that the comparator product is relevant for evaluating biosimilarity to the U.S.-licensed reference product. Sponsors must also provide comparative analytical data supporting the relationship between the comparator and the U.S. reference product.

Retention of Reserve Samples

The draft guidance recommends that sponsors retain reserve samples of biological products used in comparative clinical pharmacokinetic or pharmacodynamic studies. These samples should generally be retained for at least five years following licensure of the biosimilar application or completion of the relevant clinical study.

Reserve samples help confirm study results and support investigations if questions arise after the completion of the study.

Demonstrating Strength of Injectable Biosimilars

The draft guidance also provides recommendations on how sponsors can demonstrate that an injectable biosimilar product has the same strength as the reference product. This typically involves demonstrating that both products have the same total content of drug substance and the same concentration of the active substance, where applicable.

Sponsors should use consistent analytical methods and express the strength of the proposed product using the same units of measurement as the reference product.

Use of Non-U.S. Comparator Products in Clinical Investigations

Another topic addressed in the draft guidance relates to the use of non-U.S.-licensed comparator products in clinical studies conducted in the United States.

Such products are considered investigational drugs in the United States and therefore require an Investigational New Drug (IND) application. Sponsors may submit a single IND covering both the proposed biosimilar product and the comparator product used in the clinical investigation. The guidance also explains that sponsors may request waivers for certain chemistry, manufacturing, and controls information if it is not possible to obtain all required data for the comparator product.

Guidance: Questions and Answers on Biosimilar Development and the BPCI Act

The FDA guidance titled “Questions and Answers on Biosimilar Development and the BPCI Act” provides responses to common questions from prospective applicants and other stakeholders regarding the development of biosimilar and interchangeable biological products. The document is designed to support transparency and facilitate product development by explaining FDA’s interpretation of statutory requirements under the BPCI Act.

The guidance is presented in a structured question-and-answer format and reflects FDA’s current thinking on biosimilar regulatory requirements. It also forms part of a broader series of FDA guidance documents intended to support the development and approval of biosimilar products.

Background of the BPCI Act

The Biologics Price Competition and Innovation Act of 2009 established an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product. This pathway was created through section 351(k) of the Public Health Service Act.

Under this framework, a biosimilar applicant must demonstrate that the proposed biological product is highly similar to the reference product, with no clinically meaningful differences in terms of safety, purity, and potency.

Applications submitted under section 351(k) generally include data from analytical studies, toxicity assessments, and clinical studies unless the FDA determines that certain data elements are unnecessary.

Biosimilarity and Interchangeability

The guidance addresses several important questions related to biosimilarity and interchangeability. Sponsors are encouraged to contact FDA for questions related to development programs and may request meetings with the Agency to discuss their biosimilar development strategy.

The guidance further explains that applicants may seek licensure for fewer routes of administration, fewer presentations, or fewer conditions of use than those approved for the reference product, provided the statutory requirements are satisfied.

Pediatric Assessments and Development Considerations

Under the Pediatric Research Equity Act (PREA), certain biosimilar applications may require pediatric assessments unless the requirements are waived, deferred, or considered inapplicable. Sponsors are encouraged to submit an initial pediatric study plan early in development to ensure alignment with regulatory expectations. The guidance also clarifies how pediatric data may be addressed when the reference product labeling already includes adequate pediatric information.

Manufacturing Changes and Regulatory Applications

The guidance provides recommendations for managing post-approval manufacturing changes to licensed biosimilar products. Sponsors should demonstrate comparability between pre-change and post-change products using analytical data and stability information. In addition, the guidance clarifies that a biosimilar application cannot seek approval for a different route of administration, dosage form, strength, or condition of use than those approved for the reference product.

Exclusivity and Orphan Drug Considerations

The guidance also addresses issues related to reference product exclusivity and orphan drug exclusivity. Applicants can request reference product exclusivity in certain biologics license applications, and information on orphan drug exclusivity can be obtained from the FDA’s orphan drug designation database.

Together, these guidance documents support the continued development of biosimilar medicines and help ensure that regulatory pathways remain transparent, scientifically rigorous, and aligned with public health objectives.