1. Eastman, Peggy

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Invited speakers explored key concepts and challenges raised by the emerging biosimilars market at a forum in Washington, D.C., sponsored by the Friends of Cancer Research (FOCR) and the Duke Margolis Center for Health Policy (DMCHP). Biosimilar products have the potential to increase patient access to important therapies in oncology and in other illnesses, such as autoimmune diseases, and to decrease costs. The FOCR and the DMCHP released two new white papers on biosimilars at the forum.

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A biosimilar is a biological product that is approved based on the fact that it is "highly similar" to an already approved biological product, referred to as the reference product. In 2012, the FDA issued guidance on an abbreviated regulatory pathway for approval of biosimilars. In 2015, the FDA approved the first biosimilar product, filgrastim-sndz (Zarxio), which is biosimilar to Neupogen. Because biosimilars are far more complex than small-molecule drugs, the regulatory pathway for their approval is much more complicated than that for generic drugs.


Biosimilars have been used in Europe for about 10 years. To date, there are no approved biosimilars for oncology products in the U.S. But last June at the annual meeting of ASCO in Chicago, phase III clinical trial data were presented on a biosimilar for trastuzumab (Herceptin). According to the first FOCR/DMCHP white paper, the trial data showed similar safety, efficacy, and immunogenicity results as the reference biologic, and this trastuzumab biosimilar could become the first approved biosimilar product for cancer. Breast cancer patients treated with the trastuzumab biosimilar had a 69.9 percent objective response rate compared with 64 percent among women receiving the reference product. Other anti-cancer biosimilars being developed include rituximab, bevacizumab, and cetuximab.


Biosimilars & Oncology

The emerging U.S. biosimilars market raises a number of questions relevant to the practice of oncology, including the following issues highlighted by the two FOCR/DMCHP white papers and discussed by speakers at the forum.


* Is it important that there be a distinction between a therapeutic biosimilar agent versus a supportive care biosimilar agent?


* What is the appropriate patient endpoint? Is response rate sufficient?


* A single monoclonal antibody may act through different mechanisms to treat different diseases. Should clinical trials be required for every indication?


* Many therapeutic monoclonal antibodies are given as infusions in hospital settings. How will this affect physician concerns about pharmacy-based substitutions? Should the physician be informed if a substitution is made?


* How likely is it that a patient would be switched multiple times between the reference product and the biosimilar during cancer care? How might this affect the course of treatment?


* Will physicians accept biosimilars, given the history of their initial (and sometimes persisting) concerns about generic drugs? Is the concept of interchangeability for biosimilars realistic?


* How will reimbursement for biosimilars be handled? (As with generic drugs, payers and pharmacy benefit managers will play a key role in influencing the use of biosimilars and price discounts from manufacturers.)


* Will the biosimilar product lead to lower total costs of care without any adverse impact on quality compared to the reference product?


* Will lower out-of-pocket costs linked to biosimilars lead to increased utilization and adherence because of increased patient access?


* Is switching or alternating between biologic therapies safe and effective for all patients?



Approval Process

There is no one pivotal study for approval of a biosimilar; rather, the FDA has outlined a stepwise approach to analyzing data in support of biosimilars, said Leah Christl, PhD, Associate Director for Therapeutic Biologics in the Office of New Drugs, FDA Center for Drug Evaluation and Research, where she leads the Biologics and Biosimilars Staff. "It is a different concept," she said.


The stepwise approach includes analytical studies of the proposed biosimilar and reference product to assess physical, chemical, and functional similarity; nonclinical studies to assess toxicities; comparative clinical studies to evaluate the pharmacokinetic and pharmacodynamic profiles of the proposed biosimilar and reference product and to compare clinical immunogenicity; and potentially additional clinical studies if residual uncertainty remains. "Sufficient scientific justification for extrapolating data is's not a given," explained Christl.


An Emerging Market

Several speakers hailed the promise of biosimilars in increasing patient access to therapies in the U.S. "We're right now on the cusp of having biosimilars become a significant part" of the U.S. market, said Mark McClellan, MD, PhD, Director of the Duke Margolis Center for Health Policy at Duke University, former Commissioner of the FDA and former administrator of the Centers for Medicare & Medicaid Services. He said biosimilars represent a new strategy for trying to address the rising costs of health care, including specialty drugs.


"If we do this well, biosimilars will be with us in full force about l0 years from now" in a way that provides increased patient access in the developed world and also in the developing world," said Elaine Daniels, MD, PhD, Vice President for Biosimilars Clinical Development at Pfizer Essential Health and a co-author of one of the new white papers. She noted there are patients in the U.S. who today do not have access to the life-saving drugs they need. "It is the combination of stakeholders that's going to make this work. It's very true that not every drug is going to work for every patient; this is going to have to be a collaboration," Daniels emphasized.


This is the beginning of a new industry," said Lisa Bell, PhD, Senior Vice President for Regulatory Affairs at Coherus Biosciences and a co-author of one of the white papers. "It's very exciting. We're looking for value, safety, and reliability," she added. "I want these [biosimilars] out there; I'm happy about this," stressed Kimberly Wright, a Susan G. Komen Advocate Scholar, breast cancer survivor and co-author of one of the white papers.


ASCO has no position on biosimilars, said Richard Schilsky, MD, ASCO Senior Vice President and Chief Medical Officer and a co-author of one of the white papers. "We're watching this area with great interest," he told Oncology Times. He said the semantics of the field are confusing because some of the words used have both a common meaning and a regulatory meaning-and physicians and patients use the common meaning. "It's not the least bit clear to me what the definition of 'similar' is," he said, adding that the word "biosimilar" would likely not be used in clinical practice.


Complexities of Biosimilars

Schilsky said ASCO has an obligation to educate its members as the biosimilars market develops, and the way these drugs are used will depend on the level of confidence of physicians and patients. "Establishing that confidence and satisfaction in physicians and patients is going to be important," he said. He noted that trastuzumab, for example, now has 25 years of data behind it. "Would I be comfortable prescribing to my patient a trastuzumab biosimilar based on a limited dataset?" he asked.


Schilsky also raised the issue of how much control physicians will have in deciding which drug is available to which patient, given the role of payors and pharmacy benefit managers. For some physicians, FDA approval will be sufficient to prescribe a biosimilar; they may be too busy to delve into the data enough to know what the evidence base for approval was.


"There is no cancer drug that is effective for all patients," he stressed. With biosimilars it will be much more difficult to determine efficacy, and there may be some patients who do better on the reference product than on the biosimilar. "Sorting that out is going to be very difficult," he said. Schilsky added that oncology is different from inflammatory diseases, and there is likely to be variability among cancer patients.


Schilsky said that when he was a practicing oncologist on the south side of Chicago, he saw a very diverse patient population, and noted that there are complex management issues in oncology, such as what to do when drug resistance develops. "Switching and sequencing are very complicated," he said. Schilsky noted that if he were the patient he would probably prefer to start on the original reference product that has a long track record, and then if his disease were under control he might consider switching to the biosimilar product.


For physician-owned oncology practices, biosimilars are going to get even more complicated, predicted Schilsky, because the oncologists have to allocate money up front to buy the biologic products in advance. Will they have to buy biosimilars as well as reference products? "It's very complicated as it is, and it's going to get more complicated," warned Schilsky. Also, he said, documentation will become more difficult, because it will be important to determine and note whether the reference product or a biosimilar was used in the patient's record. "The challenge is how to integrate all these datasets," he said, noting that a biosimilars registry may need to be developed to track patients.


Andrea Ferris, President and Chairman of LUNGevity, a lung cancer advocacy and research organization, and a co-author on one of the white papers, agreed that tracking patients is going to become more difficult as biosimilars enter the marketplace. "How are we going to track biosimilars?" she asked. "How will we track safety? I think there are still a lot of unanswered questions." She stressed the importance of transparency in prescribing and clinical decision-making, and cautioned that "we go down a dangerous path when we have reimbursement driving decisions."


Ferris added it would be irresponsible to put the burden on the cancer patient of understanding immunogenicity and other technical issues relating to biosimilar products. Ultimately, she said, the patients must depend on the confidence of physicians who prescribe the biosimilars


Peggy Eastman is a contributing writer.


Next Steps for Biosimilars


* Further FDA guidance regarding issues such as interchangeability or patient switching that will have an impact on price negotiation and use


* Ongoing stakeholder education efforts to increase confidence in the use of biosimilars


* Continuing to build the infrastructure for the capture of high-priority postmarket data and methods for using these data to develop more extensive evidence on biosimilar comparative effectiveness and impacts on the costs of care


* Development of evidence on pharmacy benefit management and payment reform strategies that will impact drug choice and switching