Lead Author Explains ASCO's Statement on Biosimilars in Oncology

Gary H. Lyman, MD, FASCO

ASCO recently released a statement outlining the organization’s commitment to education and guidance regarding the use of biosimilars in the treatment of patients with cancer, which was published in the Journal of Clinical Oncology.

The statement focused on the value of biosimilars in oncology, naming and labeling, safety and efficacy, interchangeability, and prescriber and patient education.

“ASCO's goal is primarily to educate and inform the oncology community, and in turn, the patients that we represent,” said Gary H. Lyman, MD, FASCO, the lead author of this statement. “Also, what questions to ask, and why we feel that the processes that have been put in place by the FDA and professional organizations should ensure the safety and efficacy of these agents if they are used to treat cancer.”

OncLive: Why did ASCO decide to release this statement?

In an interview with OncLive, Lyman, who is the co-director of the Hutchinson Institute for Cancer Outcomes Research at Fred Hutchinson Cancer Research Center, and a member of the ASCO board of directors, discussed these areas of focus in detail, highlighting the clinical implications of biosimilars for oncologists to recognize.Lyman: Biosimilars is a pretty hot topic right now. We are certainly in the biologic revolution in oncology with the introduction of various effective, but often costly, biologic therapies for many forms of cancer. These include monoclonal antibodies and small molecules like tyrosine kinase inhibitors. These are products produced in living systems, so they are not chemically synthesized in the laboratory the same way that conventional drugs have been. While these have produced startling advancements in the treatment of many cancers, they have come at a heavy price tag because they are very costly to develop, get regulatory approval for, and so forth. There is a lot of concern in general about the rising cost of healthcare, particularly drug prices for cancer treatment, and the major drivers of these rising costs are these biologic therapies.

One of the opportunities that is certainly being explored to curtail or bend the cost curve that has been rising for decades is to increase competition. As some of these products have their patents expire, other companies are seeing an opportunity to develop similar biologic therapies and get them approved to compete. Unlike generics, which can be synthesized in the laboratory and are virtually identical to the parent drug, these are products that are produced in living systems that we cannot necessarily replicate exactly. They may have the same amino acid sequence and functional properties, but they will not be identical to the original biologic. Therefore, they are called biosimilars. The FDA formally defines these as a biologic product that is highly similar to a reference biologic product for which there is no clinically meaningful difference in safety, purity, and activity.

We have had supportive care biosimilars in oncology for the myeloid growth factors GCSF, or filgrastim (Neupogen). The FDA recently approved a couple of biosimilar cancer therapies, including the biosimilar versions of trastuzumab (Herceptin) and bevacizumab (Avastin). These are not yet available for a variety of technical and legal reasons, but they soon will be.

Coming down the pike are literally dozens of these exciting agents. There are a number of companies waiting in the wings for these patents to expire to jump in and become part of that market. The good news, for us, is that the Europeans have been doing this for several years and relatively successfully. A number of biosimilars have been approved in the oncology space and no major critical safety issues have emerged.

It remains to be seen whether the US healthcare system will respond in the same way. The hope is that with increased competition, there will be some reduction in pricing, as there has been with generics and more conventional drugs. Over time, that will mean more patients will get access to these biologic therapies and the cost will not be as prohibitive or burdensome to patients and the healthcare system. It is going to be interesting to see how it all plays out over the next several years in the United States.

ASCO just felt, as the largest professional oncology organization in the world—servicing the vast majority of cancer specialists in the country, including oncologists that use these drugs—it was important to make sure that we are all up to speed on this. And, that we [should] better understand what biosimilars are, why they are being made, how they are being made, how they are approved, and basically to educate the oncology workforce so they themselves can better understand and inform their patients on the benefits, harms, and rationale for using these agents.

What is important for oncologists to understand about naming, labeling, and other regulatory considerations?

We do a lot of work at ASCO around clinical practice guidelines. The myeloid growth factor biosimilars have been integrated into those guidelines and, basically, clinicians are advised that they can use the biosimilar or the original biologic product as they should function similarly in patients. Time will tell as other biosimilars come along that are active cancer treatments. And again, time will tell whether they get integrated into guidelines in the same way. My anticipation is that they probably will.We felt that it was important to highlight some things that might be somewhat foreign, that [oncologists] may not have encountered before with more conventional drugs. One of these issues had to do with naming and labeling of biosimilars. The FDA did some tailspins initially when this first started, but has pretty much settled on a system.

The naming is intended to make sure that a biosimilar drug is linked to the original biologic, but is also distinct. For instance, there are 2 components to the naming of the filgrastim biosimilar. The first is the parent molecule, filgrastim, and then hyphenated is “sndz.” Therefore, there is a 4-letter suffix added to the term filgrastim that tells you that this is a biosimilar and which biosimilar it is, because there is probably going to be several of these on the market in the near future. Each will have a unique 4-letter suffix attached to the parent biologic term.

One of the big issues here is monitoring. There are much less clinical data required to get a biosimilar approved than there was for the original biologic. The reason for that is because there is a great deal of preclinical work done so that the biosimilar can be virtually identical in terms of its components, its structure, its behavior in the laboratory with animals, and its behavior in healthy humans. There is less requirement for large phase III clinical trials, because those are the real cost drivers for developing new drugs, including biologics. If we required all of these large phase III trials for biosimilars, there would be no reduction in cost, which defeats one of the goals. The requirement is that you must do all of this preclinical work, and if that shows safety and there is no immunogenicity or antibodies formed, etc, then you don't need to provide that much clinical data in patients. However, because there are less clinical data, there is a lot of interest in doing postmarket surveillance. Any adverse events (AEs) or toxicities that are observed after the biosimilar is on the market must be reported to the FDA.

Sometimes rare or delayed AEs will show up and that could lead to some changes in labeling. An extreme case would be pulling the biosimilar off the market. To do that kind of postmarketing surveillance, you have to know what type of drug the patient got—that is why the naming has to be very specific to the drug and the manufacturer of that drug. The labeling has to do with indications for which the drug is approved. Using the example of filgrastim again, it was originally approved to reduce the risk of infection in patients getting chemotherapy and now has about 10 separate indications. For biosimilar approval, if the data supporting the biosimilar convince the FDA that it works for one indication, the FDA has the prerogative to extrapolate the indications of the biosimilar to the same indications as the original biologic, even without providing additional clinical data.

You mentioned postmarket surveillance. Can you discuss what role oncologists play in the gathering and reporting of safety and efficacy?

In the case of filgrastim-sndz, [the investigators] provided data showing that it reduces the risk of infection in patients getting chemotherapy, so it was approved for that. However, because of the rules that have been put in place, it also got a label for all of the other indications that filgrastim was approved for. This is an effort to save on the cost of development, so that the pricing on these may help bring down healthcare expenditures. The label will clearly indicate what the biosimilar is approved to be used for. For all medications, physicians in general are expected to report severe or unexpected toxicities—AEs that they think are due to the drug that the patient is getting. This is an issue for biosimilars in particular because there are much less clinical data needed to get approval for a biosimilar. It is conceivable, and maybe even likely, that some of these agents will have AEs that only show up months or years later, or are relatively uncommon. It is very important that physicians and patients are aware that with less clinical data available at the time of approval, they have to be diligent and vigilant in recognizing if something shows up. We want to emphasize that they have to report these, so that we can gather a larger experience. You can't mandate it, but we’re asking clinicians to report.

The FDA has developed agreements with organizations that have large, prospective collections of data on patients with cancer. One of these is with ASCO. ASCO has developed a large, integrated data repository called CancerLinQ. The FDA and ASCO are establishing a relationship where the data of patients treated in practices participating in CancerLinQ, including those with biosimilars, will be accessible by the FDA to monitor how well they appear to be working—as well as AEs. By accessing these databases with millions of patients, the FDA can more quickly and definitively capture rare or unexpected severe AEs at the earliest opportunity and make modifications to the label if need be, or in an extreme case, withdraw the drug.

Then there is a focus on interchangeability, switching, and substitution. What is ASCO saying here in the statement?

There is one additional complexity to the biologics, including the biosimilars, which is because these are produced in living systems they are not exactly the same. With minor changing in manufacturing or packaging, changes in the product may occur over time. For example, a company opens a new plant, and even though they are following the same procedures as they did initially, minor changes in the biologic product may occur. This is what we call “drift.” Over time, there may be small changes in these biologic products, both the originator and the biosimilar. Every time there is a change in manufacturing, or a change in the materials that are used for manufacturing, the FDA has to come in and reinspect and make sure the marketed product has not meaningfully changed. This is very important for clinicians and patients to understand as we rapidly enter into this new world of biologic therapies and biosimilars. Another set of new terms that oncologists and care providers would not be very familiar with is interchangeability, switching, or substitution. The idea here is that if a biosimilar is approved, there are going to be circumstances where, for instance, a patient from New York who has been getting the original compound filgrastim moves to Florida and continues treatment at a practice that uses the biosimilar filgrastim-sndz. At the moment, there is no clear understanding if you can change from one to the other in the midst of treatment. The FDA has established criteria by which a biosimilar, once approved, can go one more level of approval to be considered interchangeable. This requires additional data and clinical trial studies. No drug has been given or requested the status of interchangeable. Presumably, if a biomarker achieved interchangeable status, that would be a marked advantage. That would mean oncologists could switch back and forth between the biosimilar and the original biologic without worry of changes in benefit or harm.

Lastly, the statement covers prescriber and patient education. Where can prescribers gain a better understanding of biosimilars, and what should they be telling their patients?

This is concerning to some oncologists because in its extreme, patients could get switched without the doctor or patient even knowing—particularly if they were treated in a new institution or practice that uses a different version. Several states have now put in place laws that prohibit switching or substitution without notifying the physician. In these states, if a doctor orders filgrastim, the patient cannot get a biosimilar version without the physician being informed. It is a part of transparency. This is something that we go to some lengths within the statement to try to define, and explain to oncologists and patients why these processes are needed and how they are regulated. Hopefully, by being informed and better understanding what to look for, physicians will be able to provide better care and ask the right questions to get the right answers. This is an ongoing challenge because we have so little time to spend with our patients these days. Of course, we focus on their clinical situation, but to get into the nuances of biosimilars is a time-consuming education process. ASCO, in addition to this statement, provides online tools for clinicians at ASCO.org, and Cancer.net for patients. The FDA has educational materials online. We published a special issue of the Journal of Oncology Practice that was totally devoted to biosimilars with a focus on their use in practice. We are having sessions at every major medical meeting to educate attendees about biosimilars.

I do not know that we have done as much as we can or should do, but we are trying to do as much as we can think of, either through online or print education to define these terms, the processes, safety, and efficacy. At the moment, we just need to keep doing this; there may be other tools that come along that we can garner.

Talking to colleagues around the country, the concern was relatively muted around the supportive care products like filgrastim. However, as direct cancer treatments have come online this year, it is going to be increasingly important that physicians and patients understand how these work. We need to be absolutely sure that these products are safe and effective. I am very confident that the processes that have been put in place, and the experience that the Europeans have had for almost a decade all suggest that this is an appropriate way to go and should not lead to anyone being compromised. That means we need to do a lot of education so everyone understands how this is done, and why we are doing it this way.

Again, our hope is that biosimilars will have a net benefit of reining in the cost of care through greater competition. This means that patients might not have to refuse treatment, or stop treatment early due to financial distress. We are hoping that the effect across the board will be a very positive one, and improve the quality and access to patient care, as well as reduce the financial burden of cancer care in this country.

Lyman GH, Balaban E, Diaz M, et al. American Society of Clinical Oncology statement: biosimilars in oncology. J Clin Oncol. 2018;36(12):1260-1265. doi: 10.1200/JCO.2017.77.4893.