Reference-Anchored Equivalence: A Unified Scientific Framework for the Approval of Follow-On Drugs and Biological Products

Follow-on approval processes in the United States are conducted through three distinct legal pathways: abbreviated new drug applications under section 505(j) of the Federal Food, Drug, and Cosmetic Act; applications under section 505(b)(2); and biosimilar applications under section 351(k) of the Public Health Service Act. A determination made under one pathway does not serve as a precedent for another. Nevertheless, these regulatory regimes rest on a shared scientific principle known as reference-anchored equivalence: reliance on a reference product is justified when sufficiently sensitive comparative evidence shows no clinically meaningful differences within a legally permissible comparison, while the successor product’s inherent risks are independently assessed. The FDA’s August 2026 therapeutic equivalence guidance illustrates the agency’s current application of product-level, evidence-based reasoning, particularly when identity cannot be presumed. A comprehensive framework is proposed, including a legal eligibility gate, a reference sampling gate, six evidence domains, pre-established decision criteria, independent assessment of successor-specific risks, and explicit cessation protocols. This framework has been tested against a hypothetical scenario involving a same-serotype, same-cassette adeno-associated virus successor, integrated within an operational pathway based on existing procedural mechanisms. Distinguish scientific unification from legal consolidation: products whose capsid, lipid nanoparticle, or cellular component directly contribute to clinical function may fall outside the statutory definition of biosimilarity and, consequently, require novel reliance authority.