Transparency Vital in the Dawning Age of Biosimilars in Oncology

Gary H. Lyman, MD, FASCO

In an effort to more clearly outline the introduction of biosimilars into the US healthcare system, the FDA published the Biosimilars Action Plan: Balancing Innovation and Competition in July 2018. Though this plan focuses mainly on development and industry standards, there is necessary information for clinicians who will be prescribing these agents.

Following several FDA approvals, oncologists are aware that biosimilars will soon be entering the cancer treatment landscape. There is trepidation though, said Gary H. Lyman, MD, FASCO, as the data regarding the similarity of these agents to the reference products are not in the public domain.

Additionally, the true reduction in cost associated with biosimilars is also unknown, but will likely not be visible until there are multiple biosimilars for a given reference product, according to Lyman. Regardless, the rate at which biosimilars are being produced indicates that they will play a role in the treatment of cancer in the years to come, particularly for patients who cannot currently afford the cost of healthcare.

"This is a part of the puzzle that we are trying to piece together on how to reduce costs and improve access to new cancer therapies,” said Lyman. “It is a high priority item, as far as I am concerned.”

Lyman added that one of the concerns he has once biosimilars are being used in patients with cancer is following postmarketing surveillance. Approvals of biosimilars requires less clinical data compared with a novel biologic, so patients treated with these agents should be observed for delayed toxicities or loss of long-term efficacy.

OncLive: What are your thoughts on the guidance that the FDA has provided to clinicians thus far on biosimilars in oncology?

In a recent interview with OncLive, Lyman, co-director of the Hutchinson Institute for Cancer Outcomes Research at Fred Hutchinson Cancer Research Center, interpreted the available information on biosimilars as it relates to the clinical oncology community.Lyman: There have been many efforts, including by the FDA, to inform clinicians about biosimilars. Their primary goal is to educate and hopefully reassure clinicians of the processes that they have in place, which are focused far more on preclinical data. These data must demonstrate that the molecule is very similar to the reference product, and that it behaves the same way in the laboratory and in animal models, as well as in limited clinical studies with pharmacokinetic and pharmacodynamic studies.

Additionally, there cannot be evidence of immunogenicity or antibodies. They have laid all of this out for clinicians—as to why they may grant an approval to a biosimilar without requiring multiple large clinical trials, like they generally require for an original biologic. The goal of the FDA is to both educate and reassure the clinicians, health systems, and patients, that safety and efficacy is preserved, and that these agents can be used as an alternative to the costlier originator products.

Having said this, it is pretty clear from discussions with colleagues that there remains concern, specifically with the limited clinical data available at the time of approval, and the fact that these are not generics. From the FDA's perspective, those small differences, which are inherent to biologic agents, do not have an impact on safety or efficacy and can therefore be used as an alternative to the reference product. Clinicians remain concerned because they have gotten comfortable with the original agent that was approved, based on the large-scale clinical trial data, and they are a little anxious about jumping to the biosimilar.

The first biosimilars available in the United States are myeloid growth factors that are not cancer treatments themselves but are used to support patients going through cancer treatment. These have been available in Europe for nearly a decade, and now in the United States for a couple years. As far as I can see, they are being utilized and integrated into the clinical practice guidelines of the use of myeloid growth factors.

Where it gets more problematic for some clinicians is how we now have biosimilars for cancer treatment. There is bevacizumab (Avastin) and trastuzumab (Herceptin), which are used as actual treatments for patients with cancer, and are known to have beneficial effects clinically and may even be curative in some settings. Clinicians will be encouraged to use biosimilar versions of these cancer treatments, although there is some hesitancy there.

One other issue is that the data available to the FDA at the time of the biosimilar approval needs to be available to the clinical community. We have had 1 or 2 biosimilars approved recently without public disclosure of the data that was reviewed by the FDA. Usually, an advisory committee, such as the FDA’s Oncologic Drugs Advisory Committee, reviews the data and makes a recommendation to the FDA and all that data are in the public domain.

The FDA has decided now, at least with some of these agents, that they do not need to go through this advisory committee. It turns out that for at least 1 of these agents, the data are not yet in the peer-reviewed literature. The company that produced the biosimilar has the data, the FDA has the data, but the actual clinicians prescribing the biosimilars do not. There is some hesitancy that I have seen in recommending these without having access to the data that the FDA used to grant the approval. The FDA must be aware that just granting approval doesn't mean that it is automatically going to be used by clinicians—they want to see the data and use it based on evidence. That is an issue that still needs to be sorted out. The practicing community and the patients that they care for want transparency.

One final issue is the need for surveillance after marketing. This is something that the practicing community and the FDA agree with. Since they are granted approval and are expected to be used in clinical practice based on more limited data in terms of clinical safety and efficacy, it will be important that the biosimilars are monitored after they are put out in the marketplace. They should be monitored for any signs of delayed toxicities, loss of efficacy, and immunogenicity—anything which may not have been evident in the limited data available at the time approval.

Once biosimilars are in the marketplace, to what extent do you believe clinicians will be able to make prescribing decisions?

The FDA, as well as ASCO and other organizations are deeply engaged in discussions on how to better monitor these agents after their approval. We know that adverse events are supposed to be reported by clinicians, and they do a good job of that, but it is certainly not perfect and quite onerous on clinicians who are very busy. We are looking more at the use of big data through things such as ASCO's CancerLinQ, where we can monitor the use of the biosimilars after they are available in the marketplace, and capture information on expected or unexpected side effects. This extends to the effect on a patient's disease course, and ultimately longevity and survival.It’s complicated. Ultimately, the clinician has to order the drug. Most clinicians are going to be convinced or have some level of confidence that what they are ordering is in the best interest of the patient; it is safe and effective. However, the reality is that most of us practice in large hospitals and health systems which exert some control over that. Then there are the payers and healthcare plans. These “middle men” may somewhat restrict which agents are used, and they can make it much more convenient or favorable to use a less expensive biosimilar than a reference product that a clinician may be more comfortable with. There are pressures that can be brought to bear on the clinician through their health system or insurance carriers.

The other element is the pressure on the patient, namely the copay. Copays are a huge issue, especially for patients with cancer who are on so many treatments and are getting multiple tests. Insurance companies are increasingly putting much of the cost of treatment on the patient. In other words, the cost of coverage is falling more on the patients—premiums and copays are going up. We are faced with a dilemma that could potentially come along where a patient would have to choose between a higher copay for a long-established drug or a lower to no copay for a biosimilar.

One other permutation of this is the question of whether the ultimate goal here of maintaining quality of care and bringing down pricing and healthcare costs will be a reality. It has occurred in Europe with some of the biosimilars, but not as dramatic as the introduction of generics, where we saw a 70% to 80% decrease in prices. For biosimilars, it is probably more modest—15% to 25% at most.

In the United States, it is far more complicated and nuanced situation that is less regulated than Western Europe or Canada. What we have seen in Europe is that the introduction of a single biosimilar as a competitor to a reference product has seemed to only have a limited impact on prices. It has not been until there were several biosimilars competing with the reference product that prices were driven down. It will be interesting to see if this happens in the United States.

In what way can physicians contribute to the FDA’s refinement of their approach to biosimilars?

My projection in the United States is that the uptake on the use will be a little bit slower, the impact on pricing and healthcare costs will be more gradual, and it will not be until we have an array of biosimilars for each class of these drugs where we may see meaningful reductions in pricing. This is all in the context of a continuing rise of healthcare costs across the board. It is not just the price of the drugs—it is imaging tests, hospitalizations, and emergency room visits—these are all rising in terms of cost, and the impact of the drug prices is important and needs to be reined in. The impact of healthcare costs on patients drive some into bankruptcy, and some must refuse or stop treatment because they don't want to leave their family in financial distress.They need to be vocal. Patients place their care in the physician’s hands; they are not trained to understand the complexities and nuances of the regulatory process of drug development and approvals. The patients are very much reliant on the clinicians to be fully educated and engaged. Professional organizations, such as ASCO, ASH, and AACR, are all doing educational programs around this because it is so important that physicians—and the patients under their care—are fully knowledgeable about these processes, and that they ask the right questions.

Clinicians, as well as health systems, often rely on these guidelines, because not everyone can be an expert on everything. They turn to these guideline panels that have reviewed all the data and have experts around the table to make informed, evidence-based recommendation. The clinician can then go to these guidelines or pathways. What we have seen is that those pathway panels and clinicians who try to be informed on this, want to ensure that the evidence supporting the approval of these agents is available to them.

That links back to transparency, making all the preclinical and clinical data available for critique. When that is not the case, they are going to push back and say, “How can we make a recommendation or prescribe one of these agents for our patients when we haven't seen the data or evidence?" Clinicians are going to want that transparency upfront, and should expect, if not demand—that surveillance after marketing of these agents be followed.

There is this additional complexity of the naming, which is a little obtuse. Thus far, they have been adding a random 4-letter suffix to the original name of the biologic. When there are multiple biosimilars on the market with multiple 4-letter suffixes, we are going to have to get familiar with these odd names when it comes time to selecting treatment.

Clinicians will have their challenges, and it will be important to know exactly what biosimilar or biologic a patient receives, and if they switch from one to another. That must be clearly evident in the data reported. Everybody understands that now, but there are going to be some challenges in tracking and monitoring. We still need to encourage clinicians and patients to report anything unusual, including any unexpected adverse events. We are still in a learning phase here, and we need to continue to keep our eyes open to monitor and protect the patients under our care.

US Food & Drug Administration. Biosimilars Action Plan: Balancing Innovation and Competition. https://bit.ly/2BD2Zui. Published July 2018. Accessed August 22, 2018.