Feb 23, 2016
By Gary H. Lyman, MD, MPH, FRCP, FACP, FASCO
Fred Hutchinson Cancer Research Center and the University of Washington
Over the past two decades, the United States has experienced a dramatic and unsustainable rise in health care costs. The increase in the cost of cancer care has exceeded that of other health care expenditures, with the cost of cancer drugs far exceeding most other categories of therapeutics. In fact, eight of the top 10 most expensive drugs are cancer drugs, notably the novel biologic agents arising out of the recent revolution in our understanding of the genetic and molecular basis of malignancy. As the protective patents on new biologic therapies reach expiration, the race to develop similar agents (biosimilars) has begun, hopefully increasing competition and reducing costs.
While the U.S. Food and Drug Administration has only recently developed regulations for the development and approval of biosimilars and approved the country’s first biosimilar, such agents have now been available for a decade in Europe. Nevertheless, it remains uncertain how rapid and broad the entry of biosimilars will be in the United States, including those drugs intended for the care of patients with cancer. The reasons for such uncertainty are multiple, but fundamentally relate to the biologic nature of these agents: These drugs, unlike generic pharmaceuticals, are large complex molecules derived from biologic processes that are similar but not identical to the original agent and thus subject to immunogenicity and drift over time. The demonstration of comparable efficacy and safety to the originator is a challenge for both regulators and companies, necessitating careful pharmacovigilance following approval.
Nevertheless, the opportunity to bend the rapidly rising cost curve of cancer drugs downward is one we cannot forego. Moving forward, it is essential that oncologists as well as patients have an accurate and informed understanding of both the challenges and the opportunities that biosimilar cancer treatments represent. In the commentary that follows, Dr. Robert Rifkin and Dr. Huub Schellekens provide an excellent discussion of the opportunities presented by these agents and several of the misconceptions or myths that have arisen around their development and use in oncology practice.
Five Myths About Biosimilars: What Every Oncologist Should Know
By Robert M. Rifkin, MD, FACP
Rocky Mountain Cancer Centers
“Biosimilar” is a regulatory term that describes a biologic agent that is highly similar, but not identical, to an approved “reference” biologic agent. Due to the size and complexity of biologic agents, as well as the fact that they are produced in living organisms, it is impossible to replicate them exactly. In this respect, biosimilars differ from chemically synthesized generics of small-molecule drugs.1 Differences in cell lines, culture conditions, and purification procedures can result in variations in protein folding, or posttranslational modifications such as glycosylation, even between batches of a reference biologic.1
Most “originator” biologic agents are approved in the United States under the Public Health Sector Act (PHSA), which requires filing of a Biologics License Application (351[a] or “Originator” pathway).2 In 2009, the Biologics Price Competition and Innovation Act (BPCIA) created an abbreviated route for regulatory approval of biosimilars (351[k] pathway), which requires extensive preclinical and clinical testing to demonstrate analytic, functional, and pharmacologic biosimilarity, as well as equivalent efficacy, safety, and immunogenicity profiles, compared with the original reference biologic.3-5 A third regulatory category is the non-innovator biologic, which is also designed to be a copy of a reference biologic, but is developed through the 351(a) pathway and must undergo the same level of intensive clinical trial investigation as an originator biologic for each unique indication; tbo-filgrastim is an example in this category and is designated as a fully branded drug under the name Granix®.
Biosimilars are already a growing presence globally—the first biosimilar was approved in Europe in 2006, and there are currently 19 such products approved for use, with approximately 400 million patient-days of clinical experience.6 Biosimilars have also been approved in other regions such as Japan, Australia, and Latin America. In March 2015, filgrastim-sndz became the first biosimilar to be approved by the U.S. Food and Drug Administration (FDA),7 although litigation over patent issues has delayed the availability of this agent. With patent expirations imminent in coming years for a number of biologics widely used in oncology, biosimilars are likely to become increasingly prominent in the U.S. health care system.
Thus, it is important for oncologists to have an accurate understanding of these agents. However, in a 2011 survey conducted by the National Comprehensive Cancer Network, over one-half of responding oncologists indicated they were not at all familiar or only slightly familiar with biosimilars, and clinician awareness is not perceived to have changed substantially in the intervening years.8,9 Even in Europe, where biosimilars have been in the marketplace for a decade, 24% of prescribers have either never heard of, or cannot define, these agents, according to a survey of 470 clinicians published by the Alliance for Safe Biologic Medicines in 2013.10
In the following commentary, I will discuss five misconceptions that have gained considerable traction in the community.
MYTH 1: Cheaper = potentially less safe
Biosimilars are expected to be priced approximately 20% to 30% lower than their reference biologic, which has the potential to translate into substantial cost savings to the health care system.9 However, the reduced cost of these agents does not automatically imply a reduction in safety standards.
In fact, the rigorousness of the evidence required for regulatory approval of a new biosimilar agent underscores the paramount concern with ensuring the safety and effectiveness of these agents. Results from well-designed preclinical and clinical studies must demonstrate that the biosimilar exhibits similar or equivalent pharmacologic properties, efficacy, safety, and immunogenicity compared with the reference biologic, a substantially higher bar than required for the approval of small-molecule generics.4,5 Cost savings derive from the ability of the biosimilar to build on the expensive early discovery and development trials whereby the reference biologic established initial therapeutic value in indicated disease states.
MYTH 2: Confirmatory trials are too small to detect clinically meaningful differences
A properly powered clinical trial to determine absolute equivalence between a biosimilar and its reference biologic would require thousands or even tens of thousands of patients, substantially larger than the size of the confirmatory trials required by the FDA for approval of a biosimilar. However, such trials are not necessary to establish that a biosimilar product meets the criteria established by the BPCIA, which requires a biosimilar agent to be “highly similar to the reference product notwithstanding minor differences in clinically inactive components” with “no clinically meaningful differences” in “safety, purity, and potency.”3
Rather, according to recommendations from the FDA, it is the totality of evidence gathered for a proposed biosimilar that provides sufficient proof for the similarity and absence of clinically meaningful differences.5 This evidence includes extensive preclinical analytic structural and functional assays coupled with clinical pharmacokinetic, pharmacodynamic, and immunogenicity studies. The evidence also includes carrying out a confirmatory trial in the patient population and determining the therapeutic indication expected to be most sensitive to detection of a clinically meaningful difference, if such a difference exists, between the biosimilar undergoing evaluation and the reference biologic.5
MYTH 3: Common J-codes will lead to an inability to track safety
J-codes are medical billing codes issued by the Centers for Medicare and Medicaid Services (CMS) that establish reimbursement rates for products or services sharing a particular code. The proposed Physician Fee Schedule for calendar year 2016 issued by the CMS on July 8, 2015, suggests an intention to issue the same J-code for all biosimilars for a given reference biologic, rather than individual codes, regardless of individual average shared prices (ASPs); this proposal has generated substantial concern within the medical community.11 However, while this plan would certainly have economic implications, it would have little or no impact on the ongoing ability to monitor and track adverse events (AEs) related to individual biosimilar agents. In fact, there are many methods for tracking medical products, including brand name, manufacturer, lot number, and unique national drug code, none of which are impacted by shared J-codes.
MYTH 4: Extrapolation is dangerous without clinical trials for each indication
Some clinicians have expressed concern that because the mechanisms of action of most biologic agents are not fully understood, and may differ between therapeutic settings, independent confirmatory trials should be conducted with a proposed biosimilar in each disease state where the reference biologic has an indication. However, if a confirmatory trial is conducted in the most sensitive or representative patient population, and solid comprehensive evidence from structural and functional assays is provided demonstrating a high degree of similarity between the biosimilar and reference biologic, it is very unlikely that clinically meaningful differences would be detected in subsequent trials to confirm additional indications of the reference agent.5 Such trials would waste valuable resources, and thus extrapolation should be the default choice unless there are sound scientific reasons to believe the biosimilar may behave differently in an alternate disease setting.
MYTH 5: Pharmacovigilance will be poor without different nonproprietary names
Nonproprietary names, (e.g., filgrastim) serve to indicate the active ingredient in a brand name product, and are designed to reduce confusion regarding the therapeutic class to which a drug belongs. There is currently an ongoing debate regarding the nonproprietary naming convention to be applied to biosimilars, with some arguing that biosimilars for a given reference biologic should share the same nonproprietary name as the reference drug, as is the case with generics, while others argue that each biosimilar should be issued a distinct nonproprietary identifier. For example, when Zarxio® was approved in the United States, it was given a “placeholder” nonproprietary name, filgrastim-sndz, with a suffix indicating the manufacturer. The FDA has yet to make a conclusive determination on this issue, although in August 2015, they issued a Draft Guidance, “Nonproprietary Naming of Biological Products: Guidance for Industry.” (The Draft Guidance is currently in the comments period and has not been finalized).12 Whichever way this issue is eventually resolved, it will not impact the ability to monitor the safety of biosimilar agents in the marketplace. As discussed earlier, there are numerous alternative mechanisms for tracking AEs associated with a specific agent, including brand name, manufacturer, lot number, and unique national drug code.
The imminent introduction of biosimilars into the oncology treatment armamentarium has the potential to reduce health care costs and increase patient access to efficacious biologic agents. However, there are still hurdles before the full potential of these agents can be realized. Due to the complexity of the manufacturing process and challenges to market entrance for biosimilars compared with small-molecule generics, fewer competitors are likely to enter the field, reducing competitive pressures on pricing.13 Healthy market competition can be encouraged through 1) a reduction in these barriers through public investment to advance technologies benefitting the development of biologics and their biosimilars, and 2) reformation of the patent dispute resolution process to fairly balance the rights of innovators with biosimilar developers.13
Perhaps the largest hurdle to the integration of biosimilars will be acceptance of these agents by physicians and patient consumers. Toward this end, careful regulatory review during the approval process and rigorous postapproval monitoring of safety and efficacy will be essential in building confidence in the use of these agents.
Acknowledgement: I wish to thank Susan Peck, PhD, at McKesson Specialty Health, Inc., for her outstanding editorial assistance.
2. U.S. Food and Drug Administration. www.fda.gov/RegulatoryInformation/Legislation/ucm148717.htm. Accessed August 10, 2015.
4. U.S. Department of Health and Human Services. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid.... Published April, 2015.
5. U.S. Department of Health and Human Services. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid.... Published April, 2015.
6. Davis J. Biosimilar cost savings in Europe beyond 25% might cull sponsors, EGA warned. Pharma & Medtech Business Intelligence. www.pharmamedtechbi.com/publications/the-pink-sheet-daily/2015/4/7/europes-revised-biosimilars-guidelineallows-noneu-data-in-applications. Published April 7, 2015.
7. U.S. Food and Drug Administration. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm436953.htm. Published March 6, 2015.
10. Alliance for Safe Biologics. safebiologics.org/resources/wp-content/uploads/2015/06/asbm_physician_survey_full_report_v2.pdf. Published November 2013.
11. Federal Register: The Daily Journal of the United States Government. www.federalregister.gov/articles/2015/07/15/2015-16875/medicare-program-.... Published July 2015.
12. U.S. Food and Drug Administration. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guid.... Published August 2015.
A Decade Of Biosimilars In Europe
By Huub Schellekens, MD, PhD
Utrecht University, The Netherlands
The first wave of biosimilars in Europe consisted of growth factors and hormones, which have had an excellent track record in that not a single biosimilar-specific adverse effect has been reported. The evidence argues that the quality of these biosimilars is at least as good as the original biologic products. Uptake of biosimilars in Europe was initially slow, but it is increasing steadily; today, some biosimilars are prescribed in greater numbers than their reference products.
In fact, the Dutch and Finnish regulatory agencies have declared that biosimilars and reference products are completely interchangeable.
A year ago, the first biosimilar monoclonal antibody, infliximab, was introduced in Europe. To extrapolate the indications for infliximab, European regulators used in vitro biologic assays only, confirming the reduced need for clinical trials to convince European regulators about the similarity of biosimilars and reference biologic products. Whereas the cost of the first biosimilars to be introduced in Europe was a modest 20% to 30% less than reference products, infliximab has been offered at more than 70% less than the price of the original. Infliximab was also the first biosimilar in Europe to be produced by a non-Western company. Indeed, Asia is expected to be the main source of many biosimilars in the future.
My view is that in Europe, biosimilars are now treated more and more like generics. I think it is likely that in another 10 years we will wonder, “Why did we think there was a problem with biosimilars?”
The views and opinions expressed in Current Insights in Oncology are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology.
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