By Manfred Weiler and Angel Uriol
In early January 2017, the U.S. FDA finally released the long-awaited draft guidance for interchangeability: “Considerations in Demonstrating Interchangeability With a Reference Product.” Since the introduction of the Biologics Price Competition and Innovation Act (BPCI Act)[1], signed into law on March 23, 2010, interchangeability has been considered the Holy Grail in biosimilar development.
In several states in the U.S., interchangeability will allow pharmacists to substitute a biologic therapy with a biosimilar one. In most states, the pharmacist has to notify the prescriber within a given time frame, but this differs state by state, from one day (North Dakota) up to ten days (Indiana). Of course, interchangeability is seen as a key prerequisite for rapid biosimilar market penetration of biosimilars.
The biggest uncertainty in demonstrating interchangeability has been the requirement that the “biosimilar must be expected to produce the same clinical result in any given patient, and that switching a patient back and forth between the reference product and the proposed interchangeable product does not present a risk to the patient in terms of safety or diminished efficacy when compared to treating them with the reference product continuously.” By nature, demonstrating the same clinical result in any given patient is difficult to prove and there has been much speculation as to how to properly address this concern.
In our recent experience with the FDA, we had already seen the request for a single switch from the originator to the biosimilar. While this addresses the concern of increased immunogenicity after switching from the originator to the biosimilar, it is not sufficient to demonstrate interchangeability.
The new draft biosimilar guidance provides better clarity on how to assess interchangeability. With clinical efficacy endpoints in most cases not being sensitive enough, the agency recommends assessing clinical pharmacokinetics (PK) and pharmacodynamics (PD) as primary endpoints. There is also a request for at least two separate exposure periods to each of the two products, which makes it at least three switches.
PK considerations (inter-subject variability in AUCtau or Cmax) will drive sample size calculation for these studies. While many of the Phase I PK studies for biosimilars have been conducted in healthy volunteers, this might be difficult given the repeated exposure to the study drugs in an interchangeability study design. The exact nature of a biosimilar interchangeability study will depend on the specific biologic, the indication and targeted patient population, treatment intervals and mechanism of action. Both options are possible.
Conducting two separate studies:
- Demonstration of no clinically meaningful differences between the reference product and the proposed biosimilar; and
- Evaluation of the impact of switching or alternating for interchangeability, or combining them into one two-part study design.
For sure, addressing interchangeability will create more complexity in clinical trial design and will require thorough planning and consideration of all the requirements.
The Syneos Health Biosimilar Focus Group is comprised of clinical development and regulatory experts who focus on this ever-changing environment to support our biosimilar customers. We have supported several customers in the generation of full clinical development plans and we have the expertise to address this new chapter in the biosimilar regulatory landscape.
To learn about our experience in biosimilar clinical trials, click here.
[1] https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/ucm215089.htm
About the Authors
Manfred Weiler, Senior Vice President, Europe & Asia Pacific Business and Alliance Development
Manfred Weiler is a member of the CSO office, focusing on the establishment of cross-therapeutic platforms providing scientific and medical support for our customers. He has established and leads the Syneos Health Biosimilar Consortium, a team of experts from all Syneos Health™ departments actively engaged in the development of biosimilars from regulatory consulting, market access consulting, clinical operations, therapeutic business units, and Real World Evidence.
Manfred has held leading roles in the CRO industry in Business Development and Alliance Management for the last ten years. Before, he was responsible for strategy and marketing for Research and Development and QC testing services for pharmaceuticals/biopharmaceuticals. Overall, Manfred has worked in the Life Sciences industry for over 20 years in strategy, sales and marketing. He holds a PhD in molecular biology from the University of Bonn, Germany.
Angel Uriol, Vice President, Clinical Development, Oncology
Angel Uriol has 21 years of clinical research experience and has played several roles in clinical trial management and operations leadership experience in pharmaceutical companies and top tier contract research organizations (CROs). Angel has focused primarily in leading large global/multi-national Oncology studies and is the subject matter expert for Oncology Biosimilar Studies in Syneos Health Biosimilars Consortium Group. Angel is a registered pharmacist and has a master’s in international relationships.