On November 2nd and 3rd the FDA held a public hearing to address the challenges it will face in the implementation of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). This act established an abbreviated pathway for follow-on biologics (a.k.a. biosimilars) that are either “highly similar” or “interchangeable” with previously approved biologics. Many industry stakeholders were in attendance to voice their opinion on the matter including Pfizer, Roche, Merck, Novo Nordisk, Novartis, Amgen, Shire, and TEVA, amongst others. I tuned into these webcasts to extract the salient areas of debate.
Below are some issues and pertinent questions surrounding the development of a biosimilars pathway that came up frequently over the course of the 2 days:
- What constitutes biosimilarity and at what resolution must we interrogate protein structure to establish it?
2. Clinical Development
- Are analytical characterization techniques and in vitro assays sufficient to establish biosimilarity?
- If not, what is the extent that comparability must be established through animal and human studies?
- What would clinical trial design look like?
- Is it ethical to duplicate animal studies and clinical trials in humans if this data already exists for the reference product?
- Are unique names required for biosimilars?
- How do we prove interchangeability in clinical studies?
- Should this be done in pre-market studies or post-market surveillance studies?
- Will biosimilars and their respective reference products remain interchangeable throughout their lifespan?
5. Access and Affordability
- What measures can the FDA implement to ensure that pricing remains fair and patients receive affordable therapeutics?
- Should we allow for the production of “bio-betters”? Or will this force costs upwards?
6. Exclusivity and Evergreening
- Does the ability to renew exclusivity periods drive innovation or does it prevent new drugs from coming to market?
- In what circumstances should evergreening be allowed/disallowed?
7. Global Harmonization
- How can countries work together to share data and support an abbreviated biosimilars pathway?
In many instances speakers began by emphasizing that a pathway for the development of biosimilars should focus on end-user safety and not economic considerations. The words ‘quality’, ‘safe’, and ‘affordable’ resounded frequently; though it will not be an easy task for the FDA to accommodate the diverse, and sometimes contradicting, demands of stakeholders.
For example, a conundrum was introduced by a physician from the American Academy of Pediatrics who asserted that a new pathway must deliver safe and effective products to children while simultaneously urging that the bar for approval be set high. Of course the higher the bar, the smaller the incentive for industry to chase biosimilars, and the fewer safe and effective products in the pipeline for children. Another example illustrating the difficulty in designing a path forward is the debate over duplicate clinical trials and upholding the integrity of the Declaration of Helsinki. This declaration, first written in 1964 by the World Medical Association, outlines principals which should be followed in medical research involving human subjects. Unnecessary exposure of human subjects to medical studies through duplicate clinical trials is unethical in the eyes of the declaration, and although it does not hold bearing in international law, it is still respected to the extent that it has become ingrained in the development of regulations in the medical world.
Many interesting points came from industry. Rivka Kreitman, VP of Innovative R&D at TEVA, explained that the complexity of biosimilars warrants a balanced approach and a robust pivotal clinical trial will likely be necessary for safety reasons. But like many others, she recognized that duplicate clinical trials are unethical and should be avoided where possible. This sentiment was echoed by Nikhil Mehta, VP of Regulatory Affairs (Biologics) at Merck, who relayed the fact that Merck strongly believes one positive controlled clinical trial should be necessary for approval of a biosimilar. Anshuman Patwardhan, Senior Director in the Biologics Division at Dr. Reddy’s Laboratories, was more progressive with his outlook, outlining that a biosimilars pathway should maximize competition, minimize prices, and push biosimilars to market as fast as possible. Dr. Reddy’s has already launched biosimilars in several markets, including Asia, Latin America, and the Middle East – an example of which is Reditux, a biosimilar of rituximab, which is a chimeric monoclonal antibody used to treat lymphomas, leukemias, and autoimmune disorders.
Mark McCamish provided a testimony on behalf of the Novartis group of companies. In doing so he discussed the need to create ‘goal posts’ as a scientific foundation for establishing biosimilarity. This comparability exercise would ensure that the quality attributes of candidate biosimilars are within range of the reference product. Goal posts could also be used to monitor ‘drift’ between biosimilar and reference product post-approval, as it is inevitable that quality attributes will sway as manufacturing methods change. Setting these parameters will be crucial in maintaining interchangeability between two biological products over the course of their lifetime.
Below are some points to take home from the hearing:
- Although biologicals are structurally complex molecules with myriad modifications and folding patterns, we do possess the analytical tools to characterize them. These tools must be used as the basis for determining biosimilarity.
- Providing the necessary analytical characterization and in vitro assays have been carried out, pre-clinical toxicology testing and certain clinical trials may be foregone providing adequate scientific and clinical justification exists.
- A balanced approach is likely necessary – the complexity of biologicals may require a positive pivotal clinical study, however duplicative clinical trials should be avoided for ethical reasons. The clinical requirements of biosimilar approval should be assessed on a case by case basis.
- Data sharing and “global harmonization” should be a future goal in the development of biosimilars. Not only will this increase the speed of bringing biosimilars to market, it will reduce cost and increase patient access.
- The FDA must work quickly to establish the necessary guidance documents to expedite and encourage the development of biosimilars.
- Rules governing ‘evergreening’, or the continued renewal of 12-year periods of exclusivity through small changes to a biosimilar, should be set in stone such that industry has a clear view of when this is acceptable or unacceptable.
- If interchangeability is established for a biosimilar and given reference product, the ‘drift’ between the two will have to be monitored vigilantly. Batch to batch variation, differences in manufacturing methods, and the use of different cell lines, could lead to a departure from biosimilarity and clinical equivalence.
- Given the advances that have already been made in the biosimilar field in the EU, the FDA should have discussions with the European Medicines Agency and consider adopting aspects of their regulatory path.
The public hearing was an excellent opportunity to gain insight into the minds of various stakeholders. It is clear that the FDA will have much to deliberate over in the coming months as they iron out a path forward for biosimilars in the United States.