Biologic drugs are incredibly versatile. Made by living cells and typically a protein, a single biologic can work in many different ways on a wide variety of diseases.
One such drug is Remicade (infliximab), first approved for Crohn’s disease in 1998, and now used for seven additional indications, including rheumatoid and psoriatic arthritis, ulcerative colitis and ankylosing spondylitis.
The way Remicade works for each indication – that is, its mechanism of action – originally appeared to be the same because the indications are inflammatory diseases triggered by the immune system. Now, we know there are differences in mechanisms, especially between the arthritis-related conditions and the inflammatory bowel diseases (IBD) Crohn’s and colitis.
The differences have not raised clinical concerns regarding the use of Remicade for any of its approved conditions. Experience and rigorous clinical studies to support approval of each indication have affirmed safety and efficacy.
The FDA is now on the verge of approving a biosimilar to Remicade, expected to be called Inflectra in the United States (Remsima outside the U.S.), for which there are no clinical studies in IBD patients, as permitted under the new biosimilar approval process. In mid-February, the agency consulted with its Arthritis Advisory Committee and, by the drug’s April “BsUFA” date, FDA could approve Inflectra. The Committee voted 21-3 and recommended FDA approve the biosimilar candidate for all requested indications.
Last year, when the FDA approved Zarxio (filgrastim-sndz), the biosimilar for Neupogen (filgrastim), not every indication had a clinical study. Still, every indication had the same mechanism of action, which analytical studies confirmed as highly similar between Zarxio and Neupogen. This permitted extrapolation of the clinical results only available for some indications to the remainder.
Not so for Inflectra, where the mechanisms of action for the IBD and arthritis indications differ. In addition, when analytical studies compared the IBD mechanisms, the mechanism reproduced in Inflectra varied enough for Canada to exclude IBD from its approval of Inflectra, as the biosimilar is named there. On the other hand, European Medicines Agency did approve the IBD indication in the absence of clinical trials for those populations.
Because it is impossible for a biosimilar to be an exact copy of its reference product, it is difficult to develop a biosimilar that meets the regulatory test of being highly similar to the reference drug while ensuring that any allowable differences have no significant clinical impact. Deciding whether a biosimilar clears that bar can be an uncertain business in the absence of clinical studies, especially when extrapolating between different mechanisms of action.
As we have seen, Canadian and European regulators, looking at the same analytical evidence, decided differently. The vote on Feb. 9 by the panel broke the “tie” and may be critically important to the successful future of biosimilars in the U.S.
FDA has the ultimate choice of whether or not to base their overall decision off of the committee’s recommendation. Will the FDA approve IBD indications for Inflectra with or without clinical studies and, with its decision, essentially set extrapolation policy for future biosimilars?
As hoped, during the committee’s deliberation the experience of Irish IBD patients was highlighted. Last year, Mercy University Hospital in Cork, Ireland released data from a small study it conducted on an infliximab biosimilar. The study found that 80% of the biosimilar-treated group required hospital readmission, compared to 5% in a historical, matched control group of Remicade patients.(1) Although the study included only a small number of patients, these results are striking enough at least to support the need for caution before approving any indication based on extrapolation. Simply because the reference drug has proven effective in multiple disease states does not guarantee that the biosimilar product will have the same effect or efficacy.
Additionally, in a study published and presented by DT Rubin at the Congress of European Crohn's and Colitis Organization in 2015, patients who were subjected to non-medical switching from one anti-TNF infusion (Remicade) to another biosimilar for infliximab (Remsima/Inflectra) worse outcomes were observed. These patients had RA, AS, PsA, CD, UC and Ps. These patients were compared with a matched group of patients who continued with Remicade. The group of patients who were switched to Remsima required more follow up visits in each of three periods measured: within 30 days of switching, within 90 days of switching, and within 1 year of follow up. The patients who were switched also had more inpatient hospital days and more ED visits. Disease activity scores for patients who were switched and those who had their medications discontinued for non-medical reasons were much worse than those patients who were continued on therapy also.(2)
Nevertheless, biosimilars hold great promise for my patients and those of other biologic prescribers because they can expand choices and lower costs. However, biosimilars can succeed only with the confidence of prescribers and patients. To build that confidence, FDA must require robust analytical and clinical data, including clinical data on each indication prior to approval. The agency must make the scientific findings and clinical data specific to each biosimilar easily available to prescribers as part of the drug’s label and prescribing information. Each biologic, including every biosimilar, must bear a unique and distinguishable name so every prescriber and patient can easily know and remember the exact drug used. Substitution decisions must be made by prescribers, not by payers. And, finally, FDA must monitor the post-market performance of these products with a strong pharmacovigilance system.
The FDA decision is not yet formalized. We hope that the full FDA will decide to limit the indications to the conditions presented in the pivotal trials. To do otherwise would imply interchangeability which is a standard that has not been met by this product.
Each of these confidence-building steps recognizes the inevitable differences between biosimilar and generic drugs. The incredible versatility that makes biologic therapies so valuable is the very reason that we should proceed with caution. For a bright biosimilar future, we must let the data drive the decision making.
Gregory Schimizzi is a practicing rheumatologist, treasurer of the Coalition of State Rheumatology Organizations and co-convener of the Biologics Prescribers Collaborative. He also provided his insight to this FDA Arthritis Advisory Committee.
C. Murphy, K. Sugrue, G. Mohamad, J. McCarthy, M. Buckley. (2015). P505 Biosimilar but not the same. Poster presentations: Clinical: Therapy & observation.