Alternative versions of biologic agents, ie, “biosimilars,” will presumably be getting the green light by the FDA, giving oncologists more choices for treatments that come at lower costs to patients and society.
The FDA plans to issue its guidance on biosimilars by the end of this year, paving the way for drug development. The National Comprehensive Cancer Network (NCCN) recently published a white paper written by a panel of stakeholders who identified key issues relevant to oncology.1 NCCN Guidelines panels will be evaluating data and, when appropriate, will incorporate biosimilars into guidelines.
The ASCO Post asked Gary Lyman, MD, MPH, who served on the NCCN white paper panel and recently coauthored an article on the topic,2 to describe the emerging landscape. Dr. Lyman is Director of Comparative Effectiveness and Outcomes Research at Duke University School of Medicine and Senior Fellow at the Duke Center for Clinical Health Policy Research.
Biosimilars vs Generics: The Hurdles
Biosimilars are not generics. Whereas generic agents duplicate the original product and can be produced with some consistency, it is technically unfeasible to make an exact copy of a biologic agent. Their production process is also proprietary; therefore, a company manufacturing a biosimilar must develop its own process. This can result in inadvertent chemical modifications that may not produce clinically meaningful differences but could alter immunogenicity or other attributes, Dr. Lyman noted.
“Whether companies will be required to show comparability or true interchangeability remains to be seen,” Dr. Lyman said. Pharmacokinetic equivalence does not ensure comparability, and interchangeability is an even more stringent requirement, mandating that the new agent provide the same clinical result in any given patient. “Clearly,” he noted, “this is a high bar.”
It is believed that large phase III trials may be mandated, probably powered for noninferiority with the original product. This would mean an enormous investment for interested companies, “especially if the goal is to bring down the cost of drugs,” Dr. Lyman added.
Mark Pegram, MD, Professor of Medicine and Associate Director for Clinical Research, Sylvester Comprehensive Cancer Center at the University of Miami (Florida) Health System, suggested that the cost of conducting clinical trials would be offset by the potential for enormous profit.
“Some recombinant protein drugs are a multibillion dollar global market. If it costs a few hundred million to do a phase III noninferiority trial and tap into this market, of course it could be worth it to industry. Even if the margins are thin, there is still a huge upside for the right investment,” Dr. Pegram maintained.
When to Expect Biosimilars
Biosimilars will enter the marketplace as patents for agents near expiration. First among these are the hematopoietic growth factors and erythropoiesis-stimulating agents, for which biosimilars have already been approved in Europe. The European Union in 2004 introduced a new regulatory path for biosimilars and approved the first biosimilar in 2006.
Active treatment agents will follow, with rituximab the first monoclonal antibody biosimilar expected to be approved in Europe. Teva Pharmaceuticals announced it has an agent set to begin clinical trials in anticipation of the Rituxan patent expiration in 2013.
“In the United States, we are still waiting for final FDA rules on what will be required for approval,” Dr. Lyman said.
The FDA is struggling to reconcile the science of biosimilar development with the new regulatory framework required by the Biologics Price Competition and Innovation (BPCI) Act of 2009. The BPCI authorized the FDA to oversee an “abbreviated pathway” for approval of these agents. The many challenges were recently described in a New England Journal of Medicine article.3
“The FDA process for biosimilarity must consider the product’s complexity, its formulation, its stability, and the usefulness of biochemical and functional characterizations and incorporate these factors into a risk-based approach,” the authors noted.
“This is new territory for the FDA,” Dr. Lyman noted. “They may pull in external or expert consultants to help figure this all out.” The agency is expected to finalize regulations by the end of this year, which means some biosimilars could emerge on the market early next year, unless new clinical trials are mandated.
A number of companies are gearing up. Hospira, a leader in generic injectable drugs, recently announced the start of a U.S. phase I clinical trial of its biosimilar erythropoietin in patients with renal dysfunction, comparing Amgen’s epoetin alfa (Epogen) and Hospira’s erythropoietin. Hospira already sells biosimilar versions of erythropoietin and filgrastim in Europe.
To what extent providers will embrace biosimilars is unclear. Oncologists’ comfort and experience with the older agent may influence decisions in clinical practice, Dr. Lyman maintained. “A large-scale move to biosimilars is not a foregone conclusion,” he said.
Dr. Pegram agreed. “Oncologists will be concerned about the safety of biosimilars. They will want to ensure that the chemistry, manufacturing, and composition are on par with the labeled product,” he noted.
“I am sure the FDA, clinicians and patients themselves will be in tune with the safety issue and will be relying on very high quality controls,” he continued. “And I suspect the FDA will require noninferiority trials to assure not only safety but evidence-based efficacy.”
History supports their concern. “In Canada, a modification in a single amino acid chain of erythropoietin caused deaths from pure red cell aplasia. We can’t afford to repeat this catastrophe,” he said. ■
Disclosure: Dr. Lyman is principal investigator on a research grant to Duke University from Amgen. Dr. Pegram reported no potential conflicts of interest.
1. Zelenetz AD, Ahmed I, Braud EL, et al: NCCN Biosimilars White Paper: Regulatory, Scientific, and Patient Safety Perspectives. J Natl Compr Canc Netw 9 Suppl 4:S1-S22, 2011.
2. Hirsch BR, Lyman GH: Biosimilars: Are they ready for prime time in the United States? J Natl Compr Canc Netw 9:934-943, 2011.
3. Kozlowski S, Woodcock J, Midthun K, et al: Developing the nation’s biosimilars program. N Engl J Med 365:385-388, 2011.