In 2016 the US Food and Drug administration approved two biosimilar products which will be used in the treatment of inflammatory bowel disease in the near future. The FDA has approved Inflectra, a biosimilar to Janssen’s Remicade (infliximab) and Amjevita, a biosimilar to Abbvie’s Humira (adalimumab).
What is a biosimilar?
The FDA defines a biosimilar as biological product that is highly similar to a reference (originator) product, aside from minor differences in clinically inactive components. There should be no clinically meaningful differences in terms of safety, purity and efficacy. An “interchangeable” designation of a biosimilar may allow for free exchange with originator biologics with no greater risk of adverse effects or diminished efficacy, according to the US Biologics Price Competition and Innovation Act of 2009.
Per FDA guidance, Biosimilars go through an abbreviated approval pathway. Clinical trials are not required, but at least one comparative, randomized controlled trial (RCT) in a select sensitive patient population is expected. Dose ranging studies are not required and “indication extrapolation” is possible with scientific justification.
What does an “interchangeable” designation mean?
According to an article published in December, 2016 in Gastroenterology & Hepatology titled, The Role of Biosimilars in Inflammatory Bowel Disease, by David Rubin, MD, professor of medicine at the Inflammatory Bowel Disease Center at the University of Chicago Medical Center in Chicago, Illinois, and colleagues:
To be designated as interchangeable requires a higher standard than simply being biosimilar, and implies that free exchange with the originator biologic agent can occur with no greater risk of adverse effects or diminished efficacy. An interchangeable product must produce the same clinical result as the originator product in a specific patient. In addition, in order to receive the designation of being interchangeable, the biosimilar must have similar effectiveness and safety when switched multiple times with the originator product, and such switches must not cause more risk than remaining on the originator product for the same amount of time.
What is the approval process for biosimilars?
The regulatory process for biosimilars is far more rigorous than for traditional generic medications. Biosimilar products do not need to re-establish efficacy and safety; instead, they need to prove biosimilarity with the originator product, or lack of clinically meaningful difference. Clinical trials are done after demonstration of structural and functional biosimilarity to the originator product; thus, no clinically meaningful difference in outcomes would be expected to exist.1
Have biosimilars been studied in IBD patients?
There have been no biosimilar trials in IBD patients to date. After proving biosimilarity, proposed biosimilars are then required to complete adequately powered, comparative, randomized, controlled trials (RCTs) in a select sensitive patient population. The purpose of these trials is to establish equivalence and detect clinically meaningful differences in efficacy, safety, and immunogenicity between the biosimilar and the originator product. 1
What is “indication extrapolation”?
Indication extrapolation means that clinical studies of biosimilars can be performed in one disease state or sensitive population group (such as in rheumatoid arthritis, RA) and then inferred to work in other disease settings or indications (like ulcerative colitis or Crohn’s disease) for which the reference biologic is approved and licensed.
Extrapolation is dependent on sufficient scientific justification, including (but not limited to) mechanism of action. As such, there is no requirement to independently perform trials in each of the originator biologic indications in order to obtain approval of the biosimilar across all of the same indications. Rather, such approval can be granted based on the principle of clinical experience with the originator biologic and presumed identical mechanism of action due to the totality of evidence of biosimilarity. 1
What does indication extrapolation mean to IBD patients?
The anti-TNFα biosimilars currently utilized for IBD across the world were approved without independent trials in IBD patients. Instead, results from trials in other disease states, i.e., RA, were accepted as effective for IBD patients. Some IBD clinicians and researchers have argued that differences between IBD and other conditions in terms of immunogenicity and other factors mean that equivalence studies may not translate across conditions and that comparative, non-inferiority RCTs should be conducted specifically in IBD patients. In contrast, others, including biosimilar manufacturers, argue that the principle of extrapolation is already in place for changes in manufacturing protocols for originator biologic agents, and that the requirements for biosimilars are more stringent in that they require clinical trials. 1
What are the advantages and disadvantages of using biosimilars in IBD?
The primary rationale for using a biosimilar is the potential cost savings, as increased competition will lead to decreased cost and increased availability. As a result, patients will potentially have greater access to biologic therapies. Although biosimilars are predicted to be less expensive and to drive down costs, it is unclear to what degree these savings will affect patients in terms of decreased insurance costs or improved biologic accessibility. 1
Potential disadvantages include the possibility of inferior clinical outcomes in the absence of a sufficient clinical evidence base prior to approval and concerns regarding nonmedical switching by insurance providers or governmental funding sources for health economic reasons. In turn, there is a theoretical concern that switching may result in the potential for increased immunogenicity and development of antidrug antibodies. It is also important to acknowledge that biosimilars should not be considered an additional or new therapeutic strategy and are unlikely to be effective in circumstances in which the originator biologic product failed or antidrug antibodies have developed. 1
Is there any data on interchangeability, or switching patients from an originator biologic to a biosimilar?
The FDA has not designated approved biosimilars as interchangeable with originator products.
As far as switching patients from an originator biologic to a biosimilar, results from a recent independent study sponsored by the Norwegian government (NOR-SWITCH), which assessed the efficacy, safety and immunogenicity of switching adult patients to Remsima (biosimilar infliximab, available in Europe) from Remicade have recently been made available.
The Norwegian government-sponsored phase 3, randomized, double-blind, noninferiority trial included 481 patients, 32.4% of whom had Crohn’s disease, 19.5% of whom had ulcerative colitis, and the rest of whom had arthritic diseases or psoriasis. Patients, recruited from 40 sites, were on stable treatment with Remicade for at least 6 months. Between October 2014 and July 2016, Jørgen Jahnsen, MD, PhD, professor of gastroenterology at the University of Oslo, Norway, and colleagues randomly assigned about half of participants to either continue Remicade therapy or switch to the biosimilar, and followed them for 52 weeks. The study found that switching to biosimilar infliximab is not inferior to continued treatment with originator and that cost-savings may improve patient access.
Dr. Rubin provided the following commentary on the NOR-SWITCH study results, to Healio Gastroenterology in October, 2016:
The study results showed that the patients who continued Remicade compared with those who were switched to the biosimilar agent of infliximab did not have any difference in worsening disease at 1 year, which was the primary outcome. There were some subtle differences in the way that they looked at Crohn’s and UC that are worth talking about at a later date, but the bottom line is biosimilars are here in the U.S.
Looking more closely at the IBD data, and particularly at the Crohn’s data from NOR-SWITCH, there may be some cause for concern, as a December, 2016 article in Gastroenterology and Endoscopy News notes:
Patients with Crohn’s disease who switch from infliximab to a biosimilar alternative may not fare as well as those who maintain treatment on the branded medication. The NOR-SWITCH trial found that compared with patients who stayed on infliximab, 15% more of those who switched to a biosimilar experienced worsening of their Crohn’s disease symptoms within the next year. However, the results were not conclusive, leading the investigators to conclude that the biosimilar was “non-inferior” to the original agent.
Still, Gary Lichtenstein, MD, professor of medicine in the Division of Gastroenterology and director of the Center for Inflammatory Bowel Disease at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, called the disparity in worsening of symptoms, “a big difference, and it does suggest that Crohn’s disease patients may do worse after switching to a biosimilar, but we need more research to determine whether that is in fact the case.” 2
In fact, when the data were parsed according to disease type, they showed that 21.2% of Crohn’s disease patients who continued with infliximab experienced disease worsening by the end of the 52-week study, compared with 36.5% of those who switched from the originator to the biosimilar. That difference exceeded the 15% threshold for noninferiority but was not statistically significant, since there were not enough patients in the individual subgroups.
The difference between groups was smaller among those with ulcerative colitis, with 9.1% of originator recipients and 11.9% of biosimilar recipients experiencing worsening disease within one year. The data also suggested switching is safe, with no differences between the originator and biosimilar groups in the rates of development of antidrug antibodies or adverse events. 2
What does all of this mean?
The emergence of biosimilar agents poses unique challenges and opportunities in the care of IBD patients, for whom biologic agents are often the most effective therapies available. There is concern regarding the abbreviated regulatory process and extrapolation of biosimilar formulations and risks involved with nonmedical switching. However, the data currently available are positive in regard to the bioequivalence of these agents in the de novo setting, although interchangeability has not been adequately established. An important new risk for clinicians to understand is the cross-reactivity of biosimilar and originator antidrug antibodies. Ongoing post-marketing studies are essential to clearly define the safety, efficacy, and immunogenicity profiles of biosimilar agents in IBD and inform future regulatory processes. 1
1 The Role of Biosimilars in Inflammatory Bowel Disease Gastroenterology & Hepatology, Volume 12, Issue 12, December 2016 Sudarshan Paramsothy, MD, Noa Krugliak Cleveland, MD, Nada Zmeter, MD, and David T. Rubin, MD
2 Study Raises Questions About Biosimilar Switching for Crohn’s, December 6, 2016, Gastroenterology & Endoscopy News, David Wild
NOR-SWITCH: Switching to Remicade biosimilar safe, noninferior, October 24, 2016, Healio Gastroenterology, Adam Leitenberger