WHITE OAK, Maryland — As the US Food and Drug Administration (FDA) prepares to shift to regulating insulin products as biosimilars, the agency held an open meeting that focused in large part on how biosimilar insulin manufacturers should be required to demonstrate that their products are interchangeable with reference products at the pharmacy level.
The issue is key to the likelihood that incoming “biosimilar” insulins will bring down costs. Whereas pharmacies can routinely substitute generic drugs for prescribed brand name products, this is not the case for biosimilars. The two currently marketed biosimilar insulins Basaglar (glargine, Lilly) and Admelog (lispro, Sanofi) are not “interchangeable,” meaning pharmacies can’t automatically substitute them for brand name Lantus and Humalog, respectively, without a physician writing a new prescription.
With the Biologics Price Competition and Innovation Act of 2009, regulated under the Public Health Service (PHS) Act, Congress created a pathway for approval of new biosimilar and interchangeable products. “What this means is that biologics are now open to competition, providing more treatment options to patients at potentially lower prices,” acting FDA commissioner Norman E. “Ned” Sharpless, MD, said in opening remarks at the meeting held May 13 at FDA headquarters.
The FDA has already approved 19 biosimilar products, with more on the way. On May 10, the agency issued final guidance on interchangeability of biosimilars, describing the regulatory path whereby these products can be substituted for branded biologics by pharmacies and payers without the involvement of the prescriber. “This is important and is a key step toward controlling the prices of biologic drugs in general,” Sharpless said.
Starting March 23, 2020, certain applications for biologic products currently approved under the Food Drug and Cosmetic Act (FD&C), including insulin, will be transferred to regulation under the PHS Act. This allows for new follow-on insulin products to become available and open to competition, Sharpless explained.
But the PHS law stipulates that, in addition to demonstrating biosimilarity, an “interchangeable” product must meet additional requirements based on further testing to show that it will produce the same clinical result as the reference product in a given patient. And for products such as insulin that are taken more than once, manufacturers will be required to provide data evaluating the risks in terms of safety and efficacy of switching between the products.
Should “Interchangeability” Requirements Be Less Stringent For Insulins?
At the meeting, during which the FDA sought input on a variety of issues related to the agency’s review of new applications for insulin biosimilars, stakeholders expressed a range of viewpoints regarding the optimal nature of the “interchangeability” requirements for biosimilar insulins specifically.
Abhijit Barve, MD, PhD, head of global clinical research at biosimilar manufacturer Mylan, pointed out that insulin and insulin analogs have already been extensively characterized, including their immunogenic potential, and that they are far smaller and simpler molecules than the much larger biologic products used in rheumatology and cancer.
“No unique scientific considerations are justified beyond [delivery device] compatibility testing…Scientifically, biosimilar insulin approved as interchangeable should have the same pharmacokinetics, pharmacodynamics, safety, efficacy, and immunogenicity as the reference products and should be allowed for substitution at a pharmacy level without prescriber intervention.”
Moreover, Barve noted, “Patients, physicians, and pharmacists are already exposed to switching between insulin and insulin analog brands based on insurance coverage and pharmacy preferences.”
A representative from another insulin biosimilar manufacturer, Biocon, made similar points.
But Sherry Martin, MD, vice president of Diabetes Global Medical Affairs for Lilly, said that “robust showing of biosimilarity is a necessary first step,” and that Lilly recommends “case-by-case assessment for interchangeability requirements based on strength of the biosimilarity data package…Analytical characterization of the molecule can reduce uncertainty.”
In particular, Martin emphasized the need for switching studies to show “no meaningful increase in immunogenicity from switching or alternating between the insulin biosimilar and the insulin reference product,” as well as the need to assess interchangeability specifically for the context of “connected diabetes ecosystems,” including digital health technologies, mobile apps, and closed-loop insulin delivery systems.
“How the insulin product functions within the ecosystem will be relevant to whether a biosimilar may be substituted for the reference product safely and effectively without the involvement of the prescriber,” she said.
The other two major insulin manufacturers — Novo Nordisk and Sanofi — did not participate in the meeting.
Jing Luo, MD, MPH, pointed out that the development of anti-insulin antibodies, typically mentioned as a concern, “often have no clinical significance” and that “rare clinical events may be impossible to identify in pre-approval studies.” Luo is an instructor of medicine at Harvard Medical School and a faculty member, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts.
Luo noted that if an individual patient experiences an adverse event with a biosimilar insulin, the physician can always write “dispense as written” for the patient to receive the branded product.
Mariana P. Socal, MD, PhD, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, said she and one of her colleagues viewed the 2009 PHS Act “with concern” because the interchangeability requirements could actually worsen the access and affordability of insulins in the United States.
“To encourage the production of high-quality affordable insulins, we propose that an exception should be made such that proof of biosimilarity should be considered grounds for interchangeability in the case of insulins,” said Socal, who emphasized that she was not speaking on behalf of Hopkins in general.
Socal noted there’s no evidence the development of autoantibodies — if they occur at all — are associated with any long-term diabetes complications. “In the case of insulin, we contend there is no justification or credible evidence for requiring additional studies for interchangeability…Concerns are merely theoretical at this point.”
For providers, she said, “adding an artificial divide between biosimilarity and interchangeability for insulins would generate confusion and uncertainty, and has the potential to generate liability concerns…It would also increase the cost to bring new products to market without adding real gains.”
Although the interchangeability criteria may be important for other biologics, “we contend that these criteria should not be blindly applied to older and smaller molecules, like insulin, that happen to be produced through biological pathways. Insulin is not Humira…The FDA can and should consider insulin to be an exceptional product, to which the rules…should be carefully reinterpreted, if applied at all, in order to maximize benefit, affordability, and access for all Americans living with diabetes.”
Robert Ratner, MD, professor of medicine at Georgetown University, Washington, DC, speaking on behalf of the American Diabetes Association, advised FDA that — regardless the specific requirements for interchangeability — all new insulins approved as biosimilars also be approved as interchangeable, rather than allowing biosimilar approval without the interchangeable designation as is the current case with Basaglar and Admelog.
“A biosimilar that is interchangeable at the pharmacy level can bring down costs, direct competition, and you don’t have to worry about what’s on the formulary…The charge to the FDA is make them interchangeable so that we can all write the generic name and the cheapest product can be given to the patient, Ratner told Medscape Medical News in an interview.
Luo has reported being a consultant for Alosa Health. Ratner has reported being a consultant for Novo Nordisk and Sanofi. Socal has reported no relevant financial relationships.