Phase 3 Studies in Biosimilars: Do They Tell Us Enough to Be Useful?

The argument for the elimination of the need for phase 3 studies in biosimilars is pretty simple: They cost a great deal but what do they add to our knowledge about the safety and efficacy of biosimilars? One of the primary tasks of the Food and Drug Administration (FDA), in educating health care professionals, media, the public, academia, and manufacturers, was to deemphasize the importance of the clinical trial in the totality of evidence approach they use to evaluate biosimilars.

Do we need phase 3 studies in biosimilars?The health care professional community, academia, and patient advocates may take another view: They are complex biochemical medicines and we cannot be sure of their safety and efficacy without carefully controlled studies in large populations. We have been ingrained for 40 years with the need for randomized, phase 3 clinical investigations that it may be very uncomfortable indeed to approve a drug without them.

Phase 3 Studies in Biosimilars: Statistically Speaking

At least one pharmaceutical company (Adello) is seeking FDA approval without phase 3 trials that study large groups of patients with the disease indication. In biosimilars, FDA is willing to extrapolate approvals without any clinical studies in other indications, and indeed, payers and providers are willing to accept this.

Furthermore, the FDA has taken many steps to speed access of biosimilars to approval. Other than altering the intellectual property and exclusivity timelines, what action can save more time in the process (much less money for the biosimilar developer) than the elimination of phase 3 studies in biosimilars?

In a phase 3 clinical trial of the originator biologic vs. a biosimilar, what do we expect to see? Since the expectation is that the physiochemical characteristics of the two molecules are exceedingly similar, and phase 1 trials should have proven equivalent pharmacodynamics, we don’t expect big differences in outcomes by phase 3. If phase 2 studies have been performed successfully, we believe this more emphatically.

At worst, we expect to see clinical effects that are on the edges of anticipated norms for the originator drug but within the range expected. One French investigator wrote this month in BioDrugs that typical phase 3 studies with 600 to 1000 patients are not statistically powered to detect more than major differences in safety. What is the real implications of 2 versus 5 drug withdrawals in patients taking medications that are much more alike than they are different? This author believes that well-designed phase 1 trials in volunteers can sufficiently detect the formation of antidrug antibodies and other immunogenicity differences between biosimilars and their originator drugs. This may be particularly true in patients with autoimmune disorders. When patients are routinely given methotrexate (another immunosuppressant) concomitantly with the biologic therapy, reliable evaluations of immunogenicity of the study medications are very difficult. Finding that hidden safety signal may not be possible.

More Pressure on Postmarketing Surveillance

In other words, it is easier to determine whether a biosimilar drug is “noninferior” to a reference product in clinical testing. The range of expected values is small (and there is little or no expectation that a biosimilar will demonstrate superiority). I’m no statistician, but I’d expect that to detect clinically significant differences among outcomes in this type of comparison, one would need study populations far exceeding that of the typical phase 3 study in biosimilars. Unlike in a clinical trial of a study drug versus a placebo or other standard therapy, large differences may be seen, and population sizes may be less important (hence, phase 2 trials of 100 patients may reveal red flags or lack of effectiveness).

Without the use of phase 3 trials in biosimilars to attain comfort and security, the post-marketing surveillance machinery becomes that much more important. The observation of safety issues based on real-world prescribing and utilization will be a front-line defense, not a backstop, to identify unintended pharmaceutical outcomes. This means that more of the onus will fall on the conduct of registry trials, FDA’s Sentinel program, and notably the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC), which is in the process of preparing for its first comparative-effectiveness studies in long-acting insulins (Q4 2018) and granulocyte colony-stimulating factors (i.e., filgrastim, pegfilgrastim).

This would still be a significant leap of faith, based on the approvals and limited use of biosimilars today, but I can envision other companies gambling, with FDA’s consultation, on skipping this traditional step to drug approval. I wouldn’t bet against it.

Restating the Record on Biosimilar Safety and Efficacy

At this point in time, it may be a bit more difficult to find professionals who are convinced that approved biosimilars are not as safe and effective as the originator agents. The call of those manufacturers defending their long-time marketshare is being drowned out by (1) informational sites published by major pharmaceutical manufacturers and marketers, and (2) the facts presented by the governmental agency with the most experience approving and regulating biosimilars—the European Medicines Agency (EMA).

Several manufacturers have excellent resource sites on how biosimilars are manufactured and how they differ from the originator products. These include “minor” players such as Amgen, Merck, Pfizer, among others. Their sites are pretty informative, and do not seem to be developed strictly as a marketing platform for their biosimilar products. As a group of resources, they are contributing to a public educational effort to ease potential concerns with biosimilars.

The immunogenicity and extrapolation issues are historically the greatest points of sensitivity to patients and providers. The EMA issued a report in May 2017 that summarized its findings over 10 years of biosimilar surveillance—there is no evidence of safety problems or efficacy problems with approved biosimilar products since the first licensed product. “Extrapolation is not a new concept but a well-established scientific principle used routinely when biological medicines with several approved indications undergo major changes to their manufacturing process (e.g. to introduce a new formulation). In most of these cases, clinical trials are not repeated for all indications and changes are approved based on quality and in vitro comparability studies,” states the report. Moreover, “Over the last 10 years, the EU monitoring system for safety concerns has not identified any relevant difference in the nature, severity or frequency of adverse effects between biosimilars and their reference medicines.”

Although this is absolutely true for the first-generation of biosimilars, the monoclonal antibody biosimilars have been licensed by the EMA more recently, with the first being infliximab in 2013 and the last being rituximab and etanercept in June 2017. Over time, utilization and evidence will accumulate to support their safety and effectiveness in real-world practice and across multiple indications. Yet, the potential for immunogenicity, which several switching studies have shown is low, will eventually fade as a concern.

The “Eprex Incident” of 1998 remains the sole alarm bell for a true product safety problem related to the manufacture of a biosimilar-type of product (predating by several years the introduction of biosimilars and biosimilar approval regulations, even in Europe).

Obviously, the past does not predict the future. That is one reason why organized surveillance efforts are needed both in the EU and in the US to capture any safety signals. However, it does seem that products making it through the regulatory approval systems are delivering the promised results.


Biosimilar Immunogenicity, Antibodies, and Extrapolation

Based on the clinical studies to date, most clinicians and policy makers would be surprised if a biosimilar did not yield the same patient efficacy outcomes as the originator biologic. We’ve become accustomed to seeing these equivalent results. However, one of the greatest concerns of physicians and patients in biosimilar development has been the potential safety of the biosimilar when it replaces an originator product.

This concern is largely driven by the type of immunogenetic response the biosimilar molecule might elicit. What is the likelihood that it will result in the production of neutralizing antibodies, which would affect the clinical effectiveness of the product? The appearance of antidrug antibodies could theoretically cause serious immunogenic reactions, beyond just injection-site reactions, including anaphylaxis. Years of experience gained in the US and Europe with the first generation of approved biosimilars (filgrastim, epoetin, etc) have demonstrated that these concerns are unfounded. The question is just beginning to be addressed for the first biosimilar monoclonal antibodies approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). Clinical studies of patients who received Inflectra®, Amjevita®, or Erelzi® showed that immunogenicity was not significantly different between these and the originator products. However, their use for other approved autoimmune disorders (i.e., extrapolation) seem to concern those clinicians expressing discomfort with biosimilar prescribing. Usually, studies of the biosimilar do not address ankylosing spondylitis if the principal clinical studies involved rheumatoid arthritis. This is why the FDA weighs so heavily the importance of analyzing the equivalence of a compound’s structure and characterization. Even these characterizations do not necessarily predict the risk of immunogenicity in practice.

According to the FDA, a head-to-head study in treatment-naïve patients is the most sensitive way to detect potential immunogenicity differences. The FDA believes, however, that a single crossover design, in a subgroup of patients, from originator to biosimilar agent, should help quantify the immunogenicity risk. Critical measurements include the formation of antibodies (measurement of their concentrations or titers), how quickly they develop and how long they persist, and their implications for pharmacokinetics and clinical sequelae. Additionally, researchers should monitor for the neutralization by antibodies of the drug’s activity.

An interesting question that could be raised is whether the immunogenicity of the product varies in patients with different autoimmune disorders (e.g., Crohn’s disease vs. rheumatoid arthritis). Although this has not been extensively studied, the use to date of Inflectra®, for instance, in its various indications, has not revealed a significant problem.

The key is that biosimilars in clinical trials and in experience have not elicited immunogenicity responses that are significantly or clinically different than those of the originator. Comprehensive efforts at tracking and surveillance postmarketing will either put these concerns to rest or raise red flags, rather quickly.