New Biosimilar Guidances From the FDA Announced by Commissioner Gottlieb

On December 11, the Commissioner of the Food and Drug Administration (FDA), Scott Gottlieb, MD, issued a far-ranging statement on actions to be taken by the federal government to improve access to biosimilars and to begin the transition of insulins, growth hormones, and other selected drugs to biologic status, under section 351 of the Public Health Service Act.

“Today, we’re taking additional actions to advance this framework,” stated Dr. Gottlieb. “Among them, we’re issuing four new draft guidance documents today. The first two guidance documents provide greater clarity on scientific and regulatory considerations for the development of biosimilar and interchangeable products. We intend to update these new guidance documents regularly, to address development issues as they evolve.”

FDA Commissioner Scott Gottlieb

These actions were first signaled by the announcement of the Biosimilars Action Plan earlier this year.

Hiding Behind REMS to Deter Access to Samples

These guidance documents, created in question-and-answer format, address specific issues, some of which get to the heart of biosimilar development and access. For example, one section speaks to abuse of limited distribution systems requirements, in connection with Risk Evaluation and Mitigation Strategy (REMS) programs. These programs have been used as a way to “delay or derail access to reference product samples that biosimilar sponsors need for testing to support their applications for a biosimilar product.” Dr. Gottlieb said, “While the limited distribution programs can have a role in promoting patient safety, too many branded products are still misusing these programs as rhetorical smokescreens to hide anti-competitive behavior.”

Dr. Gottlieb said that FDA will, upon request only, “review study protocols submitted by biosimilar applicants to assess whether their protocols contain comparable safety protections to those in the REMS for the reference product they’re trying to reference.” The FDA will be willing to state in a letter to the reference manufacturer “that comparable protections exist, and that the FDA won’t consider it to be a violation of the branded drug company’s REMS to provide the biosimilar sponsor with a sufficient quantity of the reference product to perform testing necessary to support its biosimilar application.”

He also reiterated that it may be possible for biosimilar developers to obtain EU-licensed samples for use in comparative studies. Dr. Gottlieb indicated that the FDA was still evaluating this option.

New Routes of Administration for Biosimilars not Allowed

Another Q&A would put to rest the notion that a biosimilar maker can produce a new formulation or route of administration for an approved biosimilar product under the 351(k) pathway. The guidance states, “An applicant may not seek approval, in a 351(k) application or a supplement to an approved 351(k) application, for a route of administration, a dosage form, or a strength that is not the same as that of the reference product.” This would mean development of a subcutaneous form of infliximab, for example, would not be possible under the biosimilar regulatory pathway, because Remicade® is only available as an intravenous infusion.

On the Road Toward Interchangeable Insulins

One of the key provisions of the BPCIA is that insulins, growth hormones, and other agents for which reference products were not available under the FD&C Act, will be transitioned to the biologic regulatory pathway (under the Public Health Services Act) by 2020. The FDA has begun to consider just how this will occur.

Transition drugs

Starting in March 2020, this transition will take place. “Today, we’re laying out our policy on how these products will transition from the drug pathway to the biologics pathway, and in so doing, how we intend to use this new framework to promote competition,” said Dr. Gottlieb.

Under the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009,” the final guidance from the FDA specifies that these newly deemed biologics will be subject to the same regulations as today’s biosimilars. “Anti-evergreening provisions under the biosimilars legislation—meant to prevent sponsors from being able to game the exclusivity provisions to forestall biosimilar entry—will apply to these newly deemed products, including insulin.”

Furthermore, these agents will not gain any additional exclusivities because of the transition (they will not get any additional exclusivity). It is assumed that once they are transitioned, and if their patents have expired, biosimilar competition can begin at once. This could mean far greater pricing pressure on insulin products (not simply glargine), and potentially even interchangeable designations that can be automatically substituted at the pharmacy.

As part of this transition, Dr. Gottlieb explained, biological products that have been approved under section 505 of the FD&C Act will be removed from the FDA’s Orange Book on March 23, 2020, based on the agency’s position that these products are no longer ‘listed drugs.’ That means that a follow-on applicant won’t be able to rely upon these NDAs for approval. They have to go down the biosimilars path after the transition.”

FDA’s Gottlieb Wants to Make It Easier to Obtain and Study Biologic Samples

Over the next couple of weeks, I’ll be further analyzing some details of the Food and Drug Administration’s (FDA’s) new Biosimilars Action Plan.

 

biosimilar developmentMuch has been made of the difficulties biosimilar manufacturers have been having in obtaining reference product samples. These are used for the most basic biosimilar development tasks: (1) the reverse engineering of the molecule, (2) physiochemical comparison of the originator and the new biosimilar, and (3) clinical testing in humans to compare the effects of the new product with the originator.

Manufacturers of the originator biologics have not made it easy. A couple of strategies used to protect access to the samples include exorbitant pricing and withholding products based on Risk Evaluation and Mitigation Strategies (REMS) mandates. These and other creative methods can delay the supply of samples to biosimilar manufacturers, and thus access to competitive products.

Legislative attempts to bypass these tactics include the CREATES Act, which is making its way through the Senate. However, at the rollout webinar of the Biosimilars Action Plan on July 18, FDA Commissioner Scott Gottlieb suggested a sensible solution: allowing the prospective biosimilar developer to purchase samples of the originator product outside the US.

He noted, “The FDA is seeking to strengthen its partnerships with regulatory authorities in Europe, Japan and Canada. Such partnerships can enable greater efficiency in developing safe and effective biosimilars.” Dr. Gottlieb continued, “For example, we’re actively exploring whether data sharing agreements could give us better insights into biosimilars’ real-world safety and efficacy and, in some circumstances, facilitate the increased use of non-US-licensed comparator products in certain studies to support an application under Section 351(k).”

Within the framework of the biosimilar approval pathway, biosimilar manufacturers had been permitted to use “bridging studies.” These allow drug trials using the EU-licensed version of a biologic after comparator studies have demonstrated the similarity of the EU- and US-licensed samples. The idea, in simplest terms, is that an EU-approved version of Remicade® is not exactly the same as the US-approved version. In biologic manufacturing, lot-to-lot differences in some structural elements are common, but they do not seem to affect the clinical outcomes of the product. Dr. Gottlieb has allowed that the differences between the two versions may be insignificant, and this could spur biosimilar development.

“We know that when those developing biosimilars use biologics sourced ex-US as their comparator product, it can lower the cost of clinical studies since many of these products can be procured more easily, and cheaply, in European and Asian markets,” Dr. Gottlieb said.

Furthermore, the Biosimilars Action Plan states that FDA will also explore “ways to reduce the number of lots of the reference product required for testing.” Overall, this can make the initial steps in biosimilar development less expensive.