This is the second part of coverage of the 18th Annual International Generic Pharmaceutical Alliance (IGPA) Meeting held in Toronto, Canada on September 16-18, 2015. For additional coverage, see Part One here.
The following day features a panel of chief executive officers from a variety of pharmaceutical companies of different sizes and focus areas. Common themes included ongoing industry consolidation and increasing concern about the supply chain and its impact on product quality. In the U.S., CEOs expressed disappointment with initial returns from GDUFA, which in part occurred because of an underestimation of how large an overhaul FDA’s operational systems required. While ICH and other internationally-oriented bodies have made progress with innovator products, the CEOs observed that there has been little harmonization around bioequivalence standards. As a result, generic companies are forced to develop multiple bioequivalence approaches for products, requiring duplicative but somewhat different biostudies, at a cost to development and largely unnecessary biostudies. Regarding biosimilars, there appeared to be consensus that FDA’s proposed non-proprietary naming model to include the same core name with a four-letter nonsense code to differentiate reference and biosimilar products would create more barriers for acceptance of biosimilars. For the biosimilars industry to succeed, there needs to be more market uptake, e.g., infliximab in Canada only has sales around $7,000 – clearly not a workable model.
Next, an IGPA panelprovided an overview how IGPA has been working to address trade barriers and promote foreign market access for generic and biosimilar medicines. Keon explained that until recently, the generic industry has gotten to the trade negotiations table late, resulting in imbalances in patent linkage systems and intellectual property rights that favored innovator products. IGPA has assembled a team dedicated to addressing trade relations in a more coordinated manner, Keon said, which it hopes can not only benefit small molecule generics but a developing biosimilar industry make inroads for increased market acceptance and product development. IGPA is also involved in the Trans Pacific Partnership (TPP), which represents 40% worldwide trade, and is a living agreement where more countries can join in such discussions as patent linkage and market protection, e.g., exclusivities. Adrian van den Hoven, Director General, EGA, then described how IGPA and its members have been getting involved in the Transatlantic Trade and Investment Partnership (TTIP) and how it may translate into better access to generic, value-added, and biosimilar products, which are EGA’s focus areas.
The final main panel included a regulatory discussion of biosimilars from Dr. Sue Lim, Senior Staff Fellow, Therapeutic Biologics and Biosimilars Team, FDA, Dr. Elena Wolff-Holz, Paul Ehrlich Institute, Member of the EMA Biosimilar Medicinal Products Working Group, and Dr. Ivana Knezevic, Scientist, Group Leader, Norms and Standards for Biologicals, Department of Essential Medicines and Health Products, WHO. Lim explained FDA’s general plan for reviewing biosimilars. Interestingly, Lim noted that the only approved biosimilar, Zarxio® no longer had identical indications to its reference product, because a new indication had been added to the referenced product since approval, which would require a supplement to add the new indication. Lim said that FDA plans to issue guidance for interchangeability, labeling, and statistical approaches. Lim also described the goal behind the recent nonproprietary naming proposal, which FDA believed would prevent inadvertent substitution and facilitate pharmacovigilance by encouraging routine use of designated suffixes while avoid potential inaccurate perceptions of safety and effectiveness differences of biological products based on the licensure pathway. When asked about FDA’s proposed naming policy and whether NDC codes were suggested as a possible suffix, Lim said that it was considered, but FDA did not think it was adequate and could not comment further on it. Lim said that in the U.S., FDA heard that non–proprietary naming was used more than brand names, which is why FDA believes it is more critical for pharmacovigilance.
Lim suggested that biosimilar sponsors come to FDA with a plan to address product differences in advance–“don’t just hope for the best.” Lim also suggested that sponsor be transparent and share feedback from each regulatory authority, as questions to seek clarity and note program differences. Lim said that while sponsors may request parallel scientific advice for biosimilar development, while regulators from different countries may strive for alignment on scientific concepts, she cautioned that they may not be able to harmonize advice and will note similarities and differences.
Wolff-Holz picked up on Lim’s comment that while there has been U.S. and EU convergence on the step-wise process and totality of circumstances, there are still regulatory differences. In the EMA, for example, there is alignment with FDA that there is no regulatory requirement for biosimilarity after granting authorization, e.g., like with Zarxio®, indications added to the reference product after approval of the biosimilar are not automatically added to the biosimilar product, even though there may be that option with extrapolation in a supplemental application. The EMA appears to have a different plan for pharmacovigilance tied to the brand name and batch number, whereas FDA appears to be looking to nonproprietary naming, which goes against EMA policy to avoid proliferation of local drug substance nomenclature. And the various regions also differ on what is considered a biosimilar product, e.g., enoxaparin is regulated as a drug by FDA but as a biologic in the EMA and by Health Canada.
When asked about the difference in extrapolating indications for infliximab in the EMA and Health Canada, Wolff-Holz noted that while both agencies agree in the concept of extrapolation, there were different scientific viewpoints on a single test for a possible mechanism of action for irritable bowel disease result that showed perhaps a 20% difference. The EMA and other countries where this product is approved thought that in the totality of the data, this difference was not clinically meaningful, but Health Canada differed. Wolff-Holz added that Health Canada may ultimately reach the same conclusion once Celltrion provides additional data, which has been requested.
Knezevic explained how the WHO gets involved in biosimilars and biological reference materials and standardization of assays and quality control tests to help standardize biological products worldwide. From her viewpoint, one of the dangers has been that in some countries, biological products are called “biosimilar” when there is no reference biological product in that country, calling this a “fake biosimilar,” where the term “biosimilar” should not be used. Regarding the extrapolation issue for infliximab, Knezevic agreed that each regulatory authority has right to make its own determinations but thought it is still useful to share information.
In the concluding remarks, IGPA appointed its new Chair and President, Vivian Frittelli, CEO, National Association of Pharmaceutical Manufacturers (South Africa) and venue for next year, Orasac-Dubrovnik, Croatia, held jointly with the EGA’s Annual Meeting, from June 8-10, 2016.