Earlier this year, the Food and Drug Administration (FDA) issued three draft guidance documents on biosimilar product development to assist industry in developing such products in the United States.
The Patient Protection and Affordable Care Act (PPACA), signed into law by President Obama on March 23, 2010, amended the Public Health Service Act to create an abbreviated approval pathway — under section 351(k) — for biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product. The Biologics Price Competition and Innovation (BPCI) Act of 2009, created an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological reference product. FDA proposes to use a risk-based, totality-of-the-evidence approach.
Biological products are therapies used to treat diseases and health conditions. They include a wide variety of products including vaccines, blood and blood components, gene therapies, tissues, and proteins. Unlike most prescription drugs made through chemical processes, biological products generally are made from human and/or animal materials.
The FDA defines a biosimilar as “a biological product that is highly similar to an already approved biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency.”
FDA’s comment period on the draft document ended on April 16, 2012. Consequently, a recent article from Genetic Engineering & Biotechnology News analyzed several comments that stakeholders have submitted to FDA on the draft Biosimilar guidance documents. The article noted that comments “show discontent over certain definitions as well as requirements,” and criticisms over the suggested protocols.
Comments on Biosimilar Documents
Two drug developers said that FDA should tighten its proposed biosimilarity standards. Genentech took issue with FDA’s proposed wording that manufacturers “should” thoroughly assess the analytical similarity of their biosimilars to their reference products, and “should” perform in-depth chemical, physical, and bioactivity comparisons with side-by-side analyses of “an appropriate number of lots of the proposed biosimilar product and the reference product.”
The assessment of the analytical similarity of a biosimilar product and the robustness of these methods are fundamental requirements for a biosimilarity assessment, and use of the word “should” implies that it does not necessarily need to be done, Genentech noted. “Please replace ‘should’ with ‘is expected to’ or ‘needs to,’” Genentech stated in a letter transmitted to the agency by Earl Dye, director of technical regulatory policy and strategy.
Novo Nordisk urged FDA to define biosimilars as products that are as similar as scientifically possible to their reference products, at least through sharing the same amino acid sequence, without exception, as their reference products. The company cited FDA’s emphasis on the importance the 3-D structures of proteins play in their biological functions and the ability of post-translational modifications to alter the proteins’ functions.
“FDA should never permit biosimilar applications for products that cannot be adequately characterized,” Novo Nordisk stated in its letter.
Biosimilar producer Biocon counter-suggested that FDA should expect that the expression construct and/or the processing of a proposed product will result in the same primary amino acid sequence as the reference product. Some expression constructs may give a precursor protein that only after modification in the process will yield the same amino acid sequence as that of the reference product, Biocon noted in its letter.
Demonstrating Safety
Novo Nordisk also believes that biosimilar applicants “should always submit the results of comparative animal toxicity studies.” It added, “in the current state of science, some form of comparative safety and effectiveness testing will be necessary for almost all biosimilars.
“All biosimilar applicants should conduct at least one comparative clinical pharmacokinetic study and, where there is a relevant pharmacodynamic marker, at least one comparative clinical PD study,” Novo Nordisk added. “Similarly, a biosimilar applicant should always conduct at least one comparative clinical immunogenicity study.”
Two patient groups also called for FDA to promote greater safety. The Colon Cancer Alliance asked FDA to require “extensive” clinical testing of biosimilars, with a system capable of rigorously tracking and tracing them back to their product of origin. “It is critical to the safety of patients that these drugs be submitted to open and robust clinical studies and are marked with a unique and transparent product labeling system that will facilitate robust pharmacovigilance,” Global Healthy Living Foundation (GHLF) president Seth Ginsberg wrote in GHLF’s letter.
Debating Interchangeability
Ginsberg noted that it is difficult to designate a biosimilar as interchangeable with their innovator products unless there is sufficient data. He expressed concern that decisions on interchangeability could be made by pharmacists or insurers through states’ automatic substitution policies. “We believe that the choice of product should be decided only by patients and physicians, who are ultimately responsible for patient care and have the full spectrum of a patient’s medical history,” Ginsberg added.
Jonathan Mitchell of Aphelion Consultants added that the determination that a product is interchangeable with a reference product raises two potentially significant issues the agency should weigh further. One is the exclusivity period accorded to the first biological product deemed interchangeable with a given reference product. Secondly, Mitchell added, “an important unanswered question is how this federal statutory definition will intersect with state laws governing pharmacy substitution of prescribed drugs.”
Novo Nordisk urged FDA to confirm that it would not designate a new biosimilar delivery device or container closure system as interchangeable with its reference product “where additional training on the new device or system is necessary to guide safe use, or where the proposed delivery device or container closure has inequivalent performance or critical design features.”
Tying Up the Loose Ends
“The keys to success for the biosimilar pathway are informing and educating patients and physicians on the benefits and safety challenges of replicating biologic drugs, providing a unique and distinctive naming and labeling system, and understanding that the FDA’s approval of a biosimilar as a standalone therapy does not mean that it is interchangeable with its biologic counterpart,” the Colon Cancer Alliance stated in its letter to FDA written by CEO Andrew Spiegel.
The alliance urged FDA to adopt a system that uses individual nonproprietary names for biologics and biosimilars, enabling physicians, patients, and regulators to differentiate between products easily—a suggestion also made by Novo Nordisk and the National Association of Chain Drug Stores.
Biocon took issue with FDA’s requirement that sponsors provide “sufficient scientific justification” for extrapolating clinical data to support biosimilarity determinations for each condition of use for which a license is sought. “Once biosimilarity is established, and product is approved for one indication, no additional clinical studies should be expected for obtaining approval for other approved indications,” Biocon stated. “If the route of administration, dosing frequency, and dosage amount of the proposed biosimilar is identical to the reference product for each indication, any additional clinical studies should not be expected.”
Novo Nordisk also urged FDA to publish product-class specific guidance for biosimilar and bioequivalent applications for complex proteins, like the EMA has done. With all the discord that FDA’s draft biosimilar guidance has created, the agency will have to work to balance the interests of innovators, biosimilar developers, and patient groups. The agency will have to ensure that it does not tilt its final guidance toward developers of new drugs by rules that unduly impede biosimilars. Nor should it tilt its requirements toward biosimilar makers seeking less rigorous review. It won’t be easy, but balancing competing interests will ultimately benefit companies, researchers, and especially patients, by finally providing a biosimilar pathway in the U.S.