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 “Among them, we’re issuing four new draft guidance documents today.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.”

What Will Be Considered a Biosimilar in 2020?

Payers, providers, and patients in the US are narrowly focused on a limited set of biosimilar products; we all know them well—the anti-TNFs, the colony-stimulating growth factors, and most recently some antitumor drugs (e.g., trastuzumab, rituximab, and bevacizumab). In 2020, before the first biosimilar to Humira® hits the market, some medications may be reclassified as biosimilar status.

Tucked away in the Biologics Price Competition and Innovation Act of 2009 (BPCIA) is a set of obscure provisions that has the potential to create a good deal of confusion at that time.

“Transition drugs.” If you’re familiar with the term, you’re one of the few. Some medications are “transitioning” in the next couple of years. Specifically, drugs that will be transitioned include the insulins, but also other naturally occurring proteins, such as hyaluronidase, human growth hormones, and menotropins.

The mechanism is actually quite simple. Today, these products are all approvable under the original Food, Drug, and Cosmetics (FD&C) Act of 1962. By 2020, these agents will be approvable as biologics under the BPCIA. That means that they will not only be categorized as a biologic, but they will be subject to biosimilar—not generic—competition. No more new drug applications or abbreviated new drug applications, only biologic license applications of the 351(a) and 351(k) varieties.

In March 2016, the Food and Drug Administration (FDA) issued draft guidance on these transitional producinsulin-pensts. As the Regulatory Affairs Professional Society described it earlier this year, “Put simply: FDA will not approve any pending or tentatively approved application for a biological product under the Federal [FD&C] Act after 23 March 2020.”

This may have the effect of slowing approval of today’s so-called follow-on biologics, which will have to go through the 351(k) application process. For example, Lilly received approval for its insulin glargine product under a 505(b)2 application. This application process allowed Lilly to use clinical data from Sanofi’s originator product Lantus®. Under the letter of the new law, because no insulin glargine product has been approved via the biologic license application route, there are no “reference” or originator insulin products.

This can result in labeling and exclusivity period issues as well, possibly discouraging manufacturers of these products from applying for FDA approval. “Nothing in the [BPCIA] suggests that Congress intended to grant biological products approved under section 505 of the FD&C Act—some of which were approved decades ago—a period of exclusivity upon being deemed to have a license under the PHS Act that would impede biosimilar or interchangeable product competition in several product classes until the year 2032,” FDA said.

A legislative proposal was introduced in 2015 by Representative Michael Burgess (R-TX), which would have asked the Government Accountability Office to review the provisions and their potential impact before the 2020 transition took place. The proposal did not advance in the House.

A search revealed no updates on the legislative or regulatory sides of the fence, so we assume the transition will occur as intended. Currently stated policy by the FDA is that all biologics will receive a new four-character suffix to their nonproprietary names. Will this apply to the older insulins and growth hormones as well? Will coding, descriptors, or nomenclature for Lantus® have to change to reflect a new status as a reference biologic product? Or will this only apply to medications approved after March 2020 (in which case, there could be a confusing dichotomy here).

It could get a bit messy, folks.