The FDA has released a draft guidance for industry outlining criteria for demonstrating that a biosimilar is interchangeable with a reference product under section 351 (k) of the Public Health Service Act.
An interchangeable product is a biosimilar that may be substituted for a reference product without the intervention of the prescribing health care provider. “Pharmacy-level substitution,” as it is called, is subject to state regulations in the U.S., and currently varies from state to state.
The guidance includes information on the type and quantity of evidence needed to demonstrate interchangeability of a proposed therapeutic protein product; how switching studies or other studies to support interchangeability should be designed; how reference products should be used in switching studies; and how to develop presentations for proposed interchangeable products.
“To support a demonstration of interchangeability, the data and information submitted to FDA must show that a proposed interchangeable product is biosimilar to the reference product and that it can be expected to produce the same clinical results as the reference product in any given patient,” Leah Christl, PhD, associate director for therapeutic biologics and lead of the therapeutic biologics and biosimilars staff in the Office of New Drugs in the FDA’s Center for Drug Evaluation and Research, wrote in an FDA perspective article.
Interchangeability, like biosimilarity, will be determined on “a case-by-case basis” due to the complex nature of biologics, and may be affected by factors like the product’s complexity, the indications for the reference product and the potential for complications with the immune system, according to the draft guidance.
The FDA will consider data previously generated to support a product’s biosimilarity, which applicants can then build upon using the same “step-wise” approach to address any “residual uncertainty” about interchangeability.
Biosimilarity is typically supported by structural and functional data, animal studies, comparative pharmacokinetic studies, pharmacodynamic studies if necessary, clinical immunogenicity studies and possibly clinical safety and effectiveness studies. In addition to these data, interchangeability criteria will require data showing the product is expected to deliver the same clinical result as the reference product in any given patient, and in all the indications for which the reference product is licensed.
“Also, for products that will be administered more than once, the data and information must show that switching a patient back and forth between the reference product and the proposed interchangeable product presents no greater risk to the patient in terms of safety or diminished efficacy when compared to treating them with the reference product continuously,” Christl wrote.
These data can be generated by a switching study or studies in at least one appropriate indication evaluating the risk for reduced safety and efficacy resulting from alternation or switching of products. Results can also be extrapolated to other indications if scientifically justified by the applicant, according to the guidance.
The FDA noted that it will “generally” not consider post-marketing surveillance studies of already licensed biosimilars to support interchangeability, “without corresponding data derived from an appropriately designed, prospective, controlled switching study or studies.”
The Agency may also require evidence showing that patients or caregivers can administer the interchangeable product without additional training.
“Although the data requirements for approval of originator, biosimilar, and interchangeable products vary, all biological product applications are reviewed based on the data and information provided by the applicant, and approved only after they meet FDA’s rigorous approval standards,” Christl wrote. “The approval standards that apply to each category of product ensure that a product is safe and effective. Patients can be assured that an FDA-approved interchangeable biological product has been thoroughly tested.”
Gastroenterology, rheumatology implications
It is important to recognize that this is a guidance for industry, “not a statement that says ‘all biosimilars are interchangeable with reference products,” David T. Rubin, MD, professor of medicine at University of Chicago Medicine, told Healio Gastroenterology.
David T. Rubin
A key consideration in the draft guidance, especially for gastroenterologists and their patients, is the requirement to demonstrate the immunogenicity risk of an interchangeable product in different patient populations, Rubin noted.
“This is important because we think that Crohn’s disease, and probably ulcerative colitis, are more immunogenic than psoriasis or ankylosing spondylitis, and maybe similar to rheumatoid arthritis in this regard,” he said, adding that the FDA recognized that different reference products may be more immunogenic than others and may require more rigorous studies to demonstrate interchangeability. “They acknowledge that glycosylation or other post-translational structural changes may impact on this.”
Additionally, a press release from the American College of Rheumatology described the draft guidance as “strik[ing] a good balance between ensuring safety and efficacy while also getting biosimilar products to market as efficiently as possible.”
Over the next 60 days, the FDA is seeking comments on the draft guidance, as well as on general questions on interchangeability posed in the notice of availability, regulation of these products throughout their lifecycle, and on questions regarding post-approval manufacturing changes.
“The availability of biosimilar and interchangeable products in the U.S. marketplace will provide more treatment options, which will hopefully drive down costs to give more patients access to treatment,” Christl wrote. – by Adam Leitenberger
FDA. Considerations in Demonstrating Interchangeability With a Reference Product: Guidance for Industry. Accessed January 17, 2017. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf
FDA. From our perspective: Interchangeable biological products. Accessed January 17, 2017. http://www.fda.gov/Drugs/NewsEvents/ucm536528.htm
Disclosure: Christl employed by the FDA. Rubin reports serving on the CCFA Board of Directors and the advisory board for Cornerstones Health Inc., reports consulting for AbbVie Pharmaceuticals, Amgen, Emmi, Janssen, Pfizer, Prometheus Laboratories, Takeda Pharmaceuticals and UCB Pharma, reports receiving research grants from AbbVie, Given Imaging, Janssen, Pfizer, Prometheus Laboratories and UCB, and receives royalties from Slack Publications.