When Will Biosimilars Start Making a Serious Difference in Oncology?

We recently some sent three questions about biosimilars to the American Society of Clinical Oncology (ASCO). Gary H. Lyman, M.D., M.P.H., a professor at the Fred Hutchinson Cancer Research Center in Seattle and past chair of the ASCO Biosimilars Work Group, emailed back some answers.

Here they are, edited lightly for clarity and length:

Biosimilars are supposed to bring the cost of healthcare down. Have they made much of a difference in oncology so far?

The short answer is that we have very little evidence related to the impact of biosimilars on healthcare costs in the US.

In Europe, which is about a decade ahead of the US in approving biosimilars, there has been a meaningful decrease in drug prices. However, most of the healthcare systems in the EU are quite different than in the U.S.

There are now 28 FDA approved biosimilars in the U.S., about half of which are relevant to cancer care including the earliest approvals for supportive care and the most recent approvals for actual cancer treatment.

Having said that, FDA approval is just the first step. There are then often patent challenges and disputes (the patent dance) related to the multiple patents on many of these agents and this can delay marketing by years.

Most of the approved biosimilars in the US have only been approved in the last 1-2 years and made it to the market and clinical practice in the last year or so, a period far too short to fully understand the impact on drug pricing.

The experience with generics (e.g., generic versions of Gleevec) suggests that it often requires multiple competitors in a drug class to start to move the price curve down.

In the U.S., the initially marketed biosimilars may be more motivated to share in the very lucrative market of exorbitantly priced biologic therapies rather than compete directly by lowering prices significantly.

Drug prices represent only a piece of the problem we have with steeply rising healthcare costs in the U.S., which also include rising costs of hospitalization, test such as scans, etc. Therefore, we cannot yet draw any firm conclusions about the impact of these agents (biosimilars) on healthcare costs.

We do have some early evidence that the price associated with supportive care biosimilars has begun to decrease with multiple biosimilar competitors.

Many of us hope that the prices of costly biologic agents for cancer treatment will also begin to decrease as it has elsewhere — but perhaps at a slower pace because of the unique U.S. healthcare market.

Lower prices are likely to improve access to these important agents and meaningfully reduce the financial burden or toxicity that patients with cancer experience on a daily basis. Although we remain hopeful that this will be the case, many believe that it will take more fundamental or structural change in healthcare financing in the U.S. for a real reduction in the enormous financial burden that patients with cancer and other serious illnesses face in the U.S.

One issue with biosimilars is, of course, just how similar they are to the reference product and whether the differences are clinically significant. What is your opinion? Are you confident of the similarity? Do you have any reservations are substitution?

I am very confident that the development, review and approval process in place related to biosimilars provides agents that are highly similar and as effective and safe as the originator or reference biologic. In fact, the analytic sophistication now available to companies and the FDA for carefully evaluating these complicated molecules today is far superior to what was utilized a couple of decades ago when the original biologic was developed and approved.

While less clinical data is required to approved biosimilars than for originators, the detailed analytics and early clinical testing of the pharmacokinetic-pharmacodynamic (PKPD) attributes and immunogenicity of a biosimilars has consistently demonstrated that trials will demonstrate highly similar clinical efficacy and safety.

Continuous monitoring of manufacturing and pharmacologic vigilance after approval are essential for both biosimilars and the originators, which should be thought of as biosimilars of the product produced and approved 20 years ago because of changes in manufacturing processes and components.

Both biosimilars and originator biologics are subject to “drift” due to manufacturing changes and need to be closely monitored to be certain that safety and efficacy have not been compromised.

This is not a hypothetical concern. Drift in functionality of biologics has been demonstrated in actual practice but it is applicable to all biologics. While careful monitoring of the multiple attributes considered critical to a biologic, I am perfectly comfortable with using biosimilars in cancer treatment.

Would you draw any distinction between agents for supportive care (for example, Neupogen and its biosimilars) and agents for treatment (Herceptin and its biosimilars)?

Clearly, clinicians are more anxious about cancer treatment biosimilars than supportive care agents due to the potential impact on cancer outcomes and survival. This is understandable. However, there is every indication that with careful monitoring , there should be no reason for greater concern around biosimilar cancer treatment than for the most recent version of their originator counterparts.

In fact, the most concerning apparent example of drift was seen with an originator* and not with the biosimilar cancer treatment, which we only became aware of during the process of biosimilar development and regulatory development. I think this has been a wake-up call that will make all biologic cancer treatments, properly monitored moving forward, as safe and effective as possible for use in patients with cancer.

*In response to a follow-up question about this originator, Lyman sent a study published in the European Journal of Cancer last year that pointed to drift — unplanned changes — in trastuzumab (Herceptin) as an explanation for the finding that a trastuzumab biosimilar, Ontruzant, was safer than trastuzumab with respect to cardiotoxicity. Lyman, who is one of the co-authors of that study, was paid a consulting fee by Samsung Bioepis, the manufacturer of Ontruzant.

Here is a list of the biosimilars for cancer treatment drugs:

And here is a list of the biosimilars for cancer supportive care biologics (i.e., agents that boost white and red blood cell counts):