In Canada, Mandated Biosimilar Switching Again Shines Spotlight on Need for Education

The Canadian province of British Columbia mandated on May 27 that patients receiving public coverage who are using reference insulin glargine, infliximab, and etanercept therapies must be switched to biosimilars in the next 6 months. This has caused a predictable flaring of tempers, and generated some opposition on my Twitter feed.

The article in the (Vancouver) Globe and Mail announcing the decision quoted the province’s health minister: “Biologic drugs continue to be a growing pressure for public drug plans. If we continue to spend more and more of our finite health dollars on biologics, it restricts our ability to provide coverage for existing drugs … not to mention hindering our ability to list any new drugs.” According to the article, British Columbia will save nearly $100 million through 2022 as a result of the policy. This policy does not affect those individuals who receive their drugs through private insurance or employer-sponsored plans (which can act independently of the government).

Like in the US, Janssen’s Remicade® still accounts for 92% of the infliximab utilization in Canada.

On the morning after the decision was announced, opinion on Twitter was divided. One side acknowledged the limited dollars available in the Canadian system. The other side wondering whether this economic decision will result in deleterious outcomes. Here, I breakdown some of the more notable negative responses:

“Specialists prefer the biologic to the biosimilar”

Any physician treating a patient with stable chronic disease would not want to change the drug regimen without good reason. However, the point of the tweet may have been that specialists actually believe the biosimilar to be inferior. In dozens of interviews with specialists, I’ve not found this to be the case. They accept the biosimilar to be safe and effective, as determined by the Food and Drug Administration (FDA), and that the biosimilar should not provide a greater risk to a treatment-naïve patient compared with the originator product. A new French study found that patients with ulcerative colitis taking Inflectra® actually had fewer serious side effects than those taking Remicade. Does this mean the biosimilar is a better medication? No one would claim this is the case. However, it is certainly no less safe.

“For teens hoping to live for decades, are 2-month to 1-year studies adequate?”

It is true that regulatory groups like the FDA do not require biosimilar agents to be subjected to long-term safety evaluations. The FDA has emphasized that it values the physiochemical and pharmacokinetic comparability to be far more important in biosimilar evaluations. In fact, the argument has been made that phase 3 trials are of very limited use in biosimilar testing.

That said, there are at least 2 areas where longer-term evidence does exist and can be generated: (1) the actual experience in Europe, where biosimilar infliximab has been available for use since 2014, (2) and the ongoing efforts of organizations dedicated to studying and monitoring postmarketing use and outcomes. For the former, see the previously cited French study, involving nearly 5,000 patients with ulcerative colitis. For the latter, consider the Biologics and Biosimilars Collective Intelligence Consortium in the US.

“Biosimilars, well, they’re synthetic, not the same at all”

Without regard to how the writer defines “synthetic,” biosimilars are engineered proteins, just as reference biologic are engineered and produced using live cell lines. Of course, no one is arguing that biosimilars are exact copies of biologics. Even manufacturers of interchangeable biosimilars would never infer this.

It has been pointed out repeatedly that the originator drugs introduced years ago are, by our definitions today, biosimilars of themselves, because of manufacturing changes, production modifications, etc. Therefore, making the statement that biosimilars “are not the same at all” is not really true, particularly if we view the similarities in molecular structure, pharmacodynamics and pharmacokinetics, and patient outcomes.

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.