The Food and Drug Administration has started laying the groundwork for approving so-called biosimilar products. As part of the Affordable Care Act, Congress created an abbreviated licensure pathway for biologic products that can be shown to be "highly similar" to an already approved biologic drug. The Biologics Price Competition and Innovation Act, which lawmakers had been working on for years, was passed in 2010 as part of the ACA. It will make it possible for biosimilar manufacturers to bring their products to market with less clinical testing than is required of originator biopharmaceuticals and therefore at a significantly lower cost to consumers.
Dr. Jonathan Kay
Under the new pathway, biosimilars must be shown to be highly similar to an already approved product. The biosimilar may have minor differences in clinically inactive components, but there must be no clinically meaningful differences between the original and the biosimilar in terms of safety, purity, and potency, according to the FDA. The Agency is moving forward with the process and, in February, issued draft guidance on biosimilar product development.
While several companies are developing biosimilar products, it’s unclear when the first biosimilar will hit the market in the United States. Dr. Jonathan Kay, a rheumatologist who has written extensively about biosimilar development and the new approval process, shared his thoughts on how the products will be received by clinicians and patients.
Question: How does the FDA draft guidance balance safety concerns within the abbreviated approval pathway?
Dr. Kay: The designation of "biosimilar" allows a biopharmaceutical to follow an abbreviated pathway for approval. Because the therapeutically effective dose of the originator biopharmaceutical already has been determined, the biosimilar can skip phase II testing, which is usually conducted to ascertain the optimal therapeutic dose of a novel drug. However, the biosimilar has to undergo a number of analytic studies to prove that it is chemically and mechanistically very similar to the originator biopharmaceutical before it can be tested in human subjects. Once these analytic studies have been completed and are successful, phase I studies of the biosimilar are then conducted in human subjects, usually in patients with the disease of interest but sometimes in normal human volunteers. In these studies, the pharmacodynamic and pharmacokinetic properties of the biosimilar are compared to those of the originator biopharmaceutical. The biosimilar must be shown to be similar, but neither more nor less effective within a prespecified range (usually 80%-125%), than the originator biopharmaceutical. The FDA’s draft guidance requires at least that at least one clinical trial be conducted in patients with the disease that is most sensitive to assess the efficacy of the drug. Although one clinical trial of 3- to 6-months’ duration may satisfy the regulatory requirements, additional trials may be needed. There is also the expectation that post-approval pharmacovigilance surveillance will be conducted for several years to monitor safety of the biosimilar. However, given all of the analytic, pharmacodynamic, pharmacokinetic, and clinical studies that are required to show similarity, as well as the years of clinical experience with the originator biopharmaceutical, it’s unlikely that new safety issues will arise with a biosimilar.
Question: Are physicians likely to trust these medicines and prescribe them routinely?
Dr. Kay: Physicians most likely will be skeptical about the safety and efficacy of biosimilars, when they are first introduced, because of their unfamiliarity. However, having reviewed the various regulatory pathways that have been proposed to evaluate these drugs, I’m quite comfortable that, if approved, there will not be a significantly increased risk of toxicity or of inadequate efficacy. Personally, I will be comfortable using biosimilars that have been approved according the FDA’s abbreviated licensure pathway. Physicians should remember that, when a patient is started on an originator biopharmaceutical, it is impossible to know whether the patient will respond to that biopharmaceutical. Until the patient has taken the biologic agent for several months, there is a chance that she or he may be a nonresponder. With a biosimilar, the same risk holds true. Just because the drug is a biosimilar, there is not a greater likelihood that any given patient will not respond to the biosimilar than to another innovator biopharmaceutical.
Question: What about patients? Will they be comfortable using biosimilars?
Dr. Kay: The degree of comfort that a patient will have using a biosimilar will depend upon how much information is available regarding comparability of the biosimilar with the originator biopharmaceutical. Patients are very concerned about the out-of-pocket costs that they face with expensive medications. I’ve encountered patients who require biologic agents to treat their rheumatoid arthritis who could not afford high monthly copayments of nearly $500. If a lower-priced drug with similar efficacy and similar safety were available, patients in that situation would probably opt to try the less-expensive medication for financial reasons. The regulatory pathway requires that these medications be studied adequately. Thus, there should not be the expectation that patients would be receiving a less effective medication. The FDA will have subjected biosimilars to rigorous analytical and clinical testing before approval.