Updated Guidance Clarifies Biosimilar Development Requirements
FDA has released an updated draft guidance outlining new and revised recommendations for companies developing biosimilar products, including clarifications on the use of foreign comparator products in clinical studies and requirements for retaining study samples.
The document revises and replaces a 2021 draft guidance titled New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 3) and updates several question-and-answer sections describing the agency’s current thinking on biosimilar development under the Biologics Price Competition and Innovation Act.
The draft guidance revises three previously issued questions and answers and retains another without changes. One of the most significant updates addresses when developers can rely on clinical data comparing a proposed biosimilar to a non-U.S.-licensed version of the reference drug. Under the revision, FDA says such data may be acceptable in certain circumstances if sponsors provide sufficient scientific justification demonstrating that the foreign comparator is relevant to assessing biosimilarity to the U.S.-licensed reference product.
The agency says this may apply when the products are highly purified therapeutic proteins that can be thoroughly characterized using modern analytical techniques, and when the non-U.S. comparator has the same — or only minor differences in — formulation components that would not affect clinical performance.
However, the agency says sponsors must still conduct comparative analytical testing between the proposed biosimilar and the U.S.-licensed reference product. It notes that publicly available information about the foreign product cannot substitute for those analytical comparisons. The guidance also states that developers should consult with the FDA early in development if they plan to rely on clinical studies using non-U.S. comparator products
The guidance also clarifies regulatory requirements when a non-U.S.-licensed comparator product is imported for use in U.S. clinical trials. Sponsors may submit a single investigational new drug application covering both the proposed biosimilar and the foreign comparator product, which is considered an investigational drug in the U.S., it says.
Because sponsors often do not manufacture the foreign comparator, the agency says developers may request a waiver for certain chemistry, manufacturing and controls information that would normally be required in an investigational application.
Another revised section addresses how long developers must retain reserve samples of products used in comparative pharmacokinetic or pharmacodynamic studies. FDA recommends sponsors keep reserve samples for at least five years after approval of a biosimilar application under section 351(k) of the Public Health Service Act, or for five years after completion of the relevant study if the application is not approved.
Meanwhile, in a viewpoint article published 3/9 in JAMA, FDA commissioner Marty Makary and colleagues described new regulatory initiatives aimed at streamlining biosimilar development, including eliminating certain clinical trial expectations and reducing study requirements that can add years and hundreds of millions of dollars to development programs. The authors argued that existing regulatory practices have slowed adoption of biosimilars — lower-cost versions of complex biologic medicines used to treat conditions such as cancer and autoimmune diseases — even though the products can offer the same safety and effectiveness as branded biologics.
“Burdensome regulatory criteria have kept biosimilars from reaching their potential,” the authors wrote, adding that the agency is now taking steps to remove “expensive and unnecessary” requirements while maintaining safety standards.
Under the reforms described in the article, the FDA plans to limit the use of large comparative efficacy trials, which historically have been required to show that a biosimilar performs similarly to the reference biologic in patients. Those trials can significantly extend development timelines, which typically range from five to eight years and cost between $100 million and $300 million.
According to the authors, reducing reliance on such studies could save companies up to $150 million and shorten development by two to four years. Instead, developers may be able to rely primarily on analytical comparisons, pharmacokinetic data and immunogenicity assessments to demonstrate that a biosimilar matches the reference drug.
Early signals indicate stakeholders welcome the new clarifications. Legal analysts at Alston & Bird say the move suggests regulators are increasingly willing to rely on analytical and pharmacokinetic data rather than large clinical trials.Together, they say the changes point to a potential regulatory framework in which a streamlined clinical data package could be sufficient for approval, possibly requiring only a pharmacokinetic comparison between a proposed biosimilar and a non-U.S.-licensed version of the reference drug.