The Patient Protection and Affordable Care Act, signed into law in 2010, did more than make it possible for millions of Americans to afford health care; it also established an abbreviated approval pathway for biologic products that are “biosimilar” to, or shown to be “interchangeable” with, a U.S. Food and Drug Administration (FDA)-approved biologic agent. Known as the Biologics Price Competition and Innovation (BPCI) Act, the provision defines biosimilarity to mean that “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product.”
Available in the European Union since 2006, biosimilar agents are slowly making their way to the U.S. market. In March 2015, the FDA approved its first biosimilar product— filgrastim-sndz (Zarxio)—a biosimilar version of filgrastim (Neupogen), for the prevention of infection during chemotherapy. And biosimilar versions of several biologics in the active treatment of cancer, including bevacizumab (Avastin), rituximab (Rituxan), cetuximab (Erbitux), and trastuzumab (Herceptin), may be available in the United States over the next 2 to 3 years as patents for these agents expire.
The development and approval of biosimilars in the United States promise to have a major impact in cancer treatment and supportive care management, potentially driving cost savings in health care—biosimilars are estimated to cost between $100 and $200 million to develop vs $800 million and higher for the originator drug1,2—and broadening access to their use. However, questions remain about how enthusiastically cancer biosimilars will be embraced and integrated into clinical practice; how to regulate, monitor, and track their safety and effectiveness in patients; and how biosimilars will be covered and reimbursed by payers.
In a roundtable discussion with The ASCO Post, four experts weigh in on the impact biosimilars may have on oncology care over the next decade. They include Gary H. Lyman, MD, MPH, FASCO, Co-Director of the Hutchinson Institute for Cancer Outcomes Research, a full member of the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center, and a member of the National Comprehensive Cancer Network (NCCN) Biosimilars White Paper3; Andrew D. Zelenetz, MD, PhD, Vice Chair for Medical Informatics, Department of Medicine, Attending Physician Lymphoma Service at Memorial Sloan Kettering Cancer Center, and former Chair of the NCCN Biosimilars Work Group; Leah Christl, PhD, Associate Director for Therapeutic Biologics, Office of New Drugs Therapeutic Biologics and Biosimilars Staff, Center for Drug Evaluation and Research (CDER) at the FDA; and Steven Lemery, MD, MHS, Lead Medical Officer, Office of Hematology and Oncology Products, CDER at the FDA.
Ensuring Efficacy and Safety
Biologics are complex products produced by living systems. How “similar” are they to the original drug, and how are their safety and effectiveness ensured?
Dr. Lyman: Biosimilars, like the original biologic agent, start with a human gene being introduced into a bacterial or mammalian cell; the gene codes for protein, which is subsequently isolated, and it goes through various processes, ending up formulated as a biosimilar. This is a complicated living process, the results of which, hopefully, are going to be very close to, but not identical to, the original compound.
In terms of comfort level for clinicians and patients, it is a considerable leap to go from a biosimilar supportive care therapy like filgrastim-sndz to biosimilar cancer therapies such as rituximab or trastuzumab.— Gary H. Lyman, MD, MPH, FASCO
Are biosimilars as effective as the original agent? This is the question we need answered. The goal is to make the behavior of biosimilars in patients the same as that of the original drug. The FDA does require that there be evidence that the chemical structure is similar, the pharmacokinetics in the body are similar, and that the biosimilar has some of the same biologic effects as the original compound. However, under current rules, the FDA does not require an exhaustive compilation of clinical studies similar to those required of the original molecule. If the FDA required that same level of evidence—often the results from several randomized controlled clinical trials—then you defeat the purpose of trying to drive down the cost of drug development.
Regulations necessary to ensure safety are now presumably in place. The main question is whether clinicians and patients will embrace biosimilars and how quickly as well as how confident clinicians will be with limited data on the efficacy and safety of biosimilars compared with the original biologics they have gotten used to over a decade of clinical practice. And that is currently unknown in the United States.
Dr. Zelenetz: In addition, all biologic molecules drift over time. For example, if you take a batch of rituximab that was produced in 1997 and compared it with a batch produced today, you will find some minor differences in the molecules. You can’t have an absolutely identical molecule. A product that is biologically manufactured is subject to any number of minor changes such as post-translation modifications or the presence of aggregate, resulting from slight differences in the conditions during manufacture or purification. However, if you ask me whether a biosimilar can be produced so it is highly similar without meaningful differences from the originator product, my answer is yes.
Due to the inherent complexity of biologic products and their manufacturing process, there will be batch-to-batch variability of any given biologic product.— Leah Christl, PhD
Dr. Christl: As noted, due to the inherent complexity of biologic products and their manufacturing process, there will be batch-to-batch variability of any given biologic product. Thus, two biologic products are highly unlikely to be identical, although they can be determined to be highly similar, both structurally and functionally, based on a comprehensive comparative assessment. In general, biosimilar products contain the same amino-acid sequence as the originator (reference) biologic product. However, for example, the exact composition of glycosylation may differ between the biosimilar and the reference product. Also, differences in the reference product may also exist from batch to batch due to the inherent complexity of biologic products. Ultimately, it is up to the biosimilar sponsor to provide adequate data and information to demonstrate that the proposed product and the reference product are highly similar and that there are no clinically meaningful differences to meet requirements for approval.
How are biosimilars regulated? What is the standard for their approval in the treatment of cancer? How are they tested in clinical studies for efficacy, safety, and new indications?
Dr. Christl: The legal standard for approval of a biosimilar product is that the biosimilar is “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product.” Ultimately, the FDA uses a totality-of-the-evidence approach when reviewing a biosimilar application. The approach will consider all available data, such as analytical, animal toxicity if appropriate, human pharmacokinetics and pharmacodynamics, and clinical data (including clinical immunogenicity data).
To demonstrate that the products are highly similar, a sponsor will generally need to conduct an extensive comparative analytical program. The FDA encourages sponsors to discuss the comparative analytical data with the FDA prior to conducting clinical studies. The nature and scope of clinical studies will depend on the extent of residual uncertainty about the biosimilar product after conducting structural and functional characterization and, where relevant, animal studies.
Sponsors may also need to conduct a comparative clinical study to further assess whether there are clinically meaningful differences between the proposed biosimilar and the reference product. This pathway, however, does not require that a sponsor independently establish the safety and efficacy of the proposed biosimilar for each intended indication. As such, the comparative clinical study may use endpoints, such as response rate or some other pharmacodynamic endpoint or populations to compare the proposed biosimilar and the reference product, that differ from what were used to independently establish the safety and efficacy of the reference product.
Dr. Lemery: An important component of the biosimilar pathway is that with adequate scientific justification, the pathway may allow for the extrapolation of clinical data demonstrating no clinically meaningful differences in one indication to other approved indications of the reference product and for which the biosimilar is seeking licensure.
Integration Into Cancer Care
In general, practitioners are going to be less concerned about the supportive care biosimilars than they are about the biosimilar therapeutics, and I think there will be some pushback.— Andrew D. Zelenetz, MD, PhD
Biosimilar cancer therapeutics may be on the market over the next few years. How do you envision them being integrated into cancer care?
Dr. Lyman: Although biosimilar cancer therapies are not available in the United States now, they are coming. In terms of comfort level for clinicians and patients, it is a considerable leap to go from a biosimilar supportive care therapy like filgrastim-sndz to biosimilar cancer therapies such as rituximab or trastuzumab. Clearly, if the biosimilar is not as effective in killing cancer cells as the original agent or has additional major toxicities, it may be considered a bigger issue than a supportive care biosimilar for preventing neutropenia. The anxiety level for providers and patients is likely to be raised.
When such biosimilars hit the marketplace over the next several years, they are going to become extremely prevalent and will have to be watched closely in post-approval surveillance to see how safe and effective they are and whether patients are living as long and their cancers are remaining in control as long as with the original biologic.
Dr. Zelenetz: I agree with Dr. Lyman. In general, practitioners are going to be less concerned about the supportive care biosimilars than they are about the biosimilar therapeutics, and I think there will be some pushback. I have limited concerns. Certainly, the evidence in the supportive care area is that there is no issue. There has not been any safety issue from the biosimilar filgrastims that are available in Europe. A biosimilar for rituximab has been approved in India, and the data I’ve seen show it is perfectly fine.
The advantage often cited of using biosimilars is the cost saving. How much less expensive are biosimilars?
Dr. Lyman: We are expecting biosimilars to be marketed at reductions of 20% to 30% in price compared with the original products, which is what we are seeing in Europe. Of course, the hope is that competition may drive down the price on the original agents as well. Whether this will ultimately drive down overall health-care costs is yet unknown, however. Realistically, it may blunt or bend the cost curve that we have seen going up for cancer drugs and other medical expenditures for cancer care over the past 2 to 3 decades. Hopefully, biosimilars will limit the increase in health-care spending going forward. Nevertheless, we are going to have to wait until we get some actual cancer treatment biosimilars in the U.S. marketplace to see how much of an impact on health-care costs they have.
Dr. Zelenetz: And we have to remember that this is a big world, and there are some countries where a drug like rituximab is not available because of the cost. If you can get a 30% to 45% reduction in the cost of a drug like rituximab, you will be able to expand its accessibility and treat more patients.
When biosimilar chemotherapeutics are available in the United States, are you ethically bound to discuss their use with your patients?
Dr. Lyman: Yes. There is a sense in the United States that the push to use biosimilars is an economic one, and clinicians and patients are often not happy having cost issues drive their clinical decisions. However, health-care costs are on everyone’s mind, and these discussions are needed. Health-care systems, even my own, are restricting which agents we can use once they have negotiated the best deal with insurance companies and industry; clinicians are asked to use the less expensive drug as opposed to the drug they may have used in the past. If we feel that the original compound is still better or safer, we can push back and appeal to insurance companies, but we usually don’t get very far.
In the United States, patients appear to be more engaged in their care than their European counterparts. They want to play a role in their care and have an open dialogue with their oncologist, so how much and how quickly biosimilars will be accepted here remain to be seen. My projection is that biosimilars will gradually make their way into clinical practice and become a big part of cancer care, but the trajectory is going to be slower than it was in Europe. It will take us 5 to 10 years to get where Europe is today.
Dr. Zelenetz: Until we are sure that biosimilars are truly safe, we have to discuss their use with our patients, particularly those we have treated with the original agent. If a patient was treated with rituximab for his lymphoma and 3 years later the cancer recurs and you have a biosimilar rituximab you would like to prescribe, there is definitely a discussion that needs to take place. We have to explain to our patients what biosimilars are and how the formulation may change, even though we think it has the same efficacy and safety as the original drug.
Coming Soon to the Clinic
What progress do you expect to see in the approval and use of biosimilars in cancer care over the next few years?
Dr. Lyman: I would say that rituximab and trastuzumab are closest to becoming approved biosimilars for cancer treatment because the background clinical development on these drugs is fairly far advanced. They are likely to hit the marketplace over the next 2 to 3 years. We will be monitoring the 5- to 10-year head start that Europe has had with these biosimilars to see whether any safety signals have emerged to provide reassurance in their use.
Dr. Zelenetz: Yes, I agree. A biosimilar trastuzumab is a bit further ahead than rituximab in prospective trials in the United States, demonstrating similar human pharmacokinetics and pharmacodynamics and similar clinical activity as the original drug.
As of January 21, 2016, 59 programs involving the development of biosimilar products to 18 different reference products were in the Biosimilar Product Development program.— Steven Lemery, MD
Dr. Christl: Under federal law, we are prohibited from disclosing the existence of a pending application unless it has been previously publicly disclosed, and we are prohibited from discussing the status of a pending application. Since program inception and as of December 31, 2015, five companies have publicly announced submission of eight 351(k) Biologic License Applications to the FDA for proposed products. One 351(k) Biologic License Application for a biosimilar product, Zarxio, has been approved to date.
Dr. Lemery: The FDA’s CDER is actively engaged with sponsors regarding biosimilar development. This engagement includes holding development-phase meetings and providing written advice for ongoing development programs. CDER continues to meet with sponsors interested in developing biosimilar products. As of January 21, 2016, 59 programs involving the development of biosimilar products to 18 different reference products were in the Biosimilar Product Development program. Publicly available information regarding proposed biosimilar products being developed may be available through clinicaltrials.gov and in public statements by sponsors developing proposed biosimilar products. ■
Disclosure: Drs. Lyman, Zelenetz, Christl, and Lemery reported no potential conflicts of interest.
1. Federal Trade Commission: Follow-on biologic drug competition. Available at www.ftc.gov/os/2009/06/P083901biologicsreport.pdf. Accessed February 17, 2016.
2. DiMasi JA, Hansen RW, Grabowski HG: The price of innovation: New estimates of drug development costs. J. Health Econ 22:151-185, 2003.
3. Zelenetz AD, Ahmed I, Braud EL, et al: NCCN Biosimilars White Paper: Regulatory, Scientific, and Patient Safety Perspectives. Supplement of the Journal of the National Comprehensive Cancer Network, September 2011. Available at http://www.nccn.org/JNCCN/supplements/PDF/2011_Vol9_Suppl_4_Biosimilars.pdf. Accessed February 17, 2016.