SILVER SPRING, MD—The Oncologic Drugs Advisory Committee (ODAC) to the U.S. Food and Drug Administration cast a unanimous vote here at its meeting last month recommending that the agency approve EP2006, a proposed “biosimilar” to the biologic drug filgrastim (Neupogen). Neupogen binds to the granulocyte colony-stimulating factor (G-CSF) receptor, and is widely prescribed to treat neutropenia.
The 14-0 ODAC vote is historic because it represents the first time a biologic agent was brought before an FDA advisory committee as a biosimilar drug under a new regulatory pathway. If approved, EP2006 would become the first biosimilar approved in the United States, and would likely pave the way for others. While the FDA does not have to take ODAC's advice, it frequently does.
ODAC members voted to recommend approval of the five indications for which filgrastim is approved:
- Cancer patients receiving myelosuppressive chemotherapy;
- Patients with acute myeloid leukemia (AML) receiving induction or consolidation chemotherapy;
- Cancer patients undergoing bone marrow transplantation;
- Patients undergoing peripheral blood progenitor cell collection and therapy; and
- Patients with severe chronic neutropenia.
A biosimilar drug has no clinically meaningful differences between the biological product and the reference product (in this case Neupogen) in terms of its safety, efficacy, purity, and potency.
“We are just at the beginning of our biosimilars program,” Janet Woodcock, MD, Director of FDA's Center for Drug Evaluation and Research, said in opening remarks at the ODAC meeting. “We think biosimilars will provide benefits to the public. Today is another step along this pathway.”
She predicted that approving biosimilars will improve patient access to needed therapies and reduce costs through competition.
Key to Unanimous Vote
A key to the unanimous ODAC vote is that the biosimilar filgrastim has been marketed by Sandoz Biopharmaceuticals as Zarzio in more than 40 countries outside the United States, generating nearly 7.5 million patient-exposure days of experience.
If approved by the FDA, this biosimilar would be marketed as Zarzio in the United States. Company officials say they believe FDA approval has the potential to lower drug costs and increase patient access to G-CSF therapy.
The robust safety and efficacy data from use in Europe constituted a backdrop that engendered confidence, said ODAC Chair Deborah K. Armstrong, MD, Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins University. This backdrop of patient usage is important, because “these are complicated drugs to make... the biologics have not been around that long,” she remarked to reporters after the meeting.
“This was one of the best clinical packages that I've ever seen for a molecule,” said ODAC temporary voting member Scott Waldman, MD, PhD, the Samuel M.V. Hamilton Professor and Chair of the Department of Pharmacology and Experimental Therapeutics at Sidney Kimmel Medical College of Thomas Jefferson University, also in remarks after the meeting.
“The data were extraordinarily comprehensive; I think this is a pretty high bar to set.” He cited not only the extensive supporting data presented by the drug's sponsor, but also the extensive data presented by FDA staff members.
‘Clinically Meaningful Differences’
ODAC members discussed at length the concept of “clinically meaningful differences” in considering the application for EP2006. “We give so much Neupogen and it's so effective that we need to know that the new drug is really biosimilar,” said ODAC voting member Tito Fojo, MD, PhD, Senior Investigator and Director of the NCI's Medical Fellowship Program.
He wanted to know, for example, if EP2006 was identical to Neupogen under storage conditions. Sandoz staff responded that there is no evidence that stability of the two drugs is different over time. “It's not that there aren't any differences, it's that there aren't any clinically meaningful differences,” stressed Richard Pazdur, MD, Director of FDA's Office of Hematology & Oncology Products in the Office of New Drugs.
Louis Weiner: ‘Comforting Context’
The broad clinical experience with G-CSF was a major factor in the ODAC vote. Not only has G-CSF been widely used around the world for more than 20 years, but there is now a vast worldwide experience with Zarzio, noted Louis M. Weiner, MD, Director of the Lombardi Comprehensive Cancer Center and Chairman of the Department of Oncology at Georgetown University Medical Center, who spoke for the sponsor on behalf of recommending EP2006. “From my perspective, this provides a comforting context for a prescribing physician,” Weiner said, adding: “Proper use of G-CSF benefits patients and reduces costs.”
He noted that G-CSF has “unquestioned clinical value,” and that the introduction of filgrastim biosimilars coincided with more use of G-CSF in Europe. Data from Europe suggest that use of biosimilars has: increased use of clinical practice guidelines; improved clinical outcomes; and reduced drug costs. Weiner said he believes approving EP2006 in the United States is important because it will help to ensure access to U.S. cancer patients who need G-CSF.
“G-CSF is underused and badly used,” he said. He cited a study of Medicare data linking 12,707 courses of chemotherapy for five common cancers and G-CSF use to patients receiving high-risk chemotherapy regimens; G-CSF was given to fewer than 50 percent of the eligible patients receiving a high-dose regimen. The data showed that, depending on tumor type, 4.8 to 22.6 percent of patients receiving a high-risk regimen experienced chemotherapy-induced neutropenic complications requiring hospitalization.
In fact, said Weiner, data from another study showed that G-CSF compliance reduces the emergency room admission rate from 25.9 to 10.5 percent, resulting in patient-care cost savings.
ODAC voting member James Liebmann, MD, Assistant Professor of Medicine at the University of Massachusetts, pressed the sponsor on whether approval of EP2006 would really bring down U.S. costs.
Yes, costs have indeed come down in Europe because of competition, said Mark McCamish, MD, PhD, Head of Global Biopharmaceutical & Oncology Injectables at Sandoz. But, he noted, “Price is not as easy as one might expect.” He said that if approved, EP2006 would provide cost-savings for U.S. payors, but the agent can't be priced too low because there would then would be less incentive for specialty pharmacies to fill prescriptions for the drug.
“I can't predict what the cost will be,” said Kimberly Blackwell, MD, Professor of Medicine at Duke University Medical Center, who served as a Sandoz consultant. But, she said, “I believe that having options will improve access and make a difference to the patient.”
ODAC temporary voting member and patient representative Randy Hillard, MD, of East Lansing, Michigan, agreed: “I voted yes and I'm willing to bet my life on it,” he said after casting his vote at the meeting.
Regulatory Pathway a Recent Development
The regulatory pathway for FDA's approval of biosimilars is a recent development. The Biologics Price Competition and Innovation (BPCI) Act of 2009 was passed as part of the Affordable Care Act that President Obama signed into law in March 2010, explained Leah Christl, PhD, Associate Director for Therapeutic Biologics in FDA's Office of New Drugs and a member of the agency's Biologics and Biosimilars Team. The BPCI Act creates an abbreviated licensure pathway for biological products shown to be biosimilar or interchangeable with an FDA-licensed reference product—in this case, Neupogen.
The definition of biosimilarity means that the “biological product is highly similar to the reference product notwithstanding minor difference in clinically inactive components,” she said. The FDA has issued draft guidance on biosimilars, which focuses on therapeutic protein products; discusses general scientific principles; outlines a stepwise approach to generating data and the evaluation of residual uncertainty at each step; and introduces the totality of the evidence approach—which takes into account all the evidence available and does not rely on one pivotal study that demonstrates bioavailability.
The goal is not to independently establish safety and efficacy for the proposed biosimilar product, because that was already done for its reference product, but to come up with an overall assessment that a biological product is truly biosimilar to its reference product.
Janet Woodcock: Cognitive Dissonance
Woodcock noted that the approval of biosimilars is a new paradigm that requires a different mind-set. This new paradigm has created what she termed “cognitive dissonance.”
She said that the agency is used to seeing clinical trial data demonstrating safety and efficacy, but with biosimilars FDA staff are looking for something else: a demonstration of biosimilarity. “We are not looking for safety and efficacy—that's already been demonstrated by the reference drug; that's what I mean by cognitive dissonance.”
Woodcock emphasized that approval of a biosimilar will be done without sacrificing the agency's high standards for drug approval, although approval will be done through a different regulatory pathway. “We think it can be done rigorously, but it is different,” she noted of the new approval process for biosimilars.
Remarks at Open Public Hearing
During the open public hearing part of the ODAC meeting, 18 people spoke, most in favor of approving EP2006. Among them was Jim Roach, MD, Chief Medical Officer and Senior Vice President for Development of Momenta Pharmaceuticals, Inc., who stated that “interchangeability is achievable for complex drugs.” He stressed, though, that biosimilars will need to undergo an intensive review, and that both clinicians and patients will require extensive education on their use.
Richard Markus, MD, Executive Medical Director at Amgen, Inc., which manufacturers Neupogen, agreed. He emphasized the necessity of ensuring that the regulatory pathway for biosimilars is sufficiently rigorous.
“This really is a historic meeting,” said Gordon Johnston, representing the Generic Pharmaceutical Association. He said that biologic agents are often the only hope for patients with serious diseases, and thus approval of biosimilars would give these patients more access to life-saving drugs.
Also speaking was Mary Jo Carden, RPh, JD, Senior Director for Regulatory Affairs at the Academy of Managed Care Pharmacy (AMCP), who told OT that the Academy sent comments to ODAC supporting an expedited approval process for biosimilars to encourage the development of new and more affordable treatments for cancer, multiple sclerosis, rheumatoid arthritis, and other serious conditions.
In a news release issued after the meeting, AMCP urged the FDA to determine on a case-by-case basis whether to require additional clinical studies for a biosimilar prior to approval, as well as any post-marketing studies after approval. “The regulatory process must be designed to rigorously examine the safety and efficacy of a biosimilar applicant, but not prove so burdensome in either the length of time required for review or in added costs for the manufacturer seeking the biosimilar license that manufacturers are discouraged from filing for approval,” the organization stated.