Is the 505(b)2 Pathway Viable for Biosimilars?

With regulators focused on streamlining the 351(k) biosimilar development, it makes sense to wonder if the 505(b)2 pathway is valid for biosimilar approval.

Can discussions about streamlining biosimilar development reach into abbreviated approval pathways for small molecules? Based on a Stat News webinar I attended yesterday, they already have. What exactly are the differences between the 351(k) pathway for biosimilar candidates and the 505(b)2 pathway for small molecules?

Biosimilar-Type Products Already Approved Through the 505(b)2 Pathway

The 505(b)2 pathway was used for some products that are considered by most as biosimilars today. For example, Basaglar, the first copy of insulin glargine, was approved in 2015 through this pathway; it was before insulins transferred to the biosimilar pathway for approval in 2020. Admelog was the first insulin lispro copy, approved in 2017 through the 505(b)2 pathway as well. However, Granix, the first filgrastim molecule launched that was not Epogen or Procrit, utilized the 351(a) pathway, meant for innovator biologics; it predated the implementation of the 351(k) route to approval.

With streamlining of biosimilar development—a major focus of regulators today—it makes sense to wonder if the 505(b)2 pathway is a valid goal for biosimilar manufacturers.

Infographic comparing 505(b)(2) drug approval and 351(k) biosimilar pathways

The 505(b)2 application pathway was implemented through the Hatch–Waxman Amendments of 1984. It was not meant as an abbreviated pathway for generics, but rather a streamlined way to bring new forms of existing innovative medications to market. These are commonly referred to as “follow-on” products. The basis for its use is that the innovator product on which the follow-on molecule is based has a truckload of patient experience proving its safety and efficacy. The manufacturer would simply have to show that its product was very much like the innovator. Its application could range from new formulations, strengths, to other modifications that wouldn’t be expected to affect the structure or anticipated effectiveness.

According to Drug Patent Watch, development cost of a 505(b)2 product might be anywhere from $8 million to $20 million, and the timeline to reach the market (not counting patent litigation) could be as short as 3 years. The 505(b)2 pathway allows a manufacturer to utilize the innovator product’s preclinical and clinical data, requiring little more than comparability studies and bridging pharmacokinetic studies to reach the FDA application stage. The FDA may still require a phase 3 trial, which would change the costs dramatically, but it appears attractive in any case.

Of course, biosimilars require a bit more consideration, as they are far more complex than small molecules, for which the 505(b)2 pathway was intended. With the push to streamline biosimilar development, including waiving the phase 3 trial mandate, eliminate separate testing for interchangeability (and eliminate the designation itself), and drop the need for bridging studies, it is not difficult to visualize movement in this direction.

The Difference With Insulin as a Biosimilar

Yet, insulin is a relatively simple biologic molecule. It has decades of use and clinical experience supporting its safety and efficacy. When the 505(b)2 pathway was used to approve Basaglar and Admelog, few considered this a big risk (it may have helped that the first biosimilars were already approved and in clinical use).

Biosimilars are not follow-on products, unlike typical 505(b)2 agents. Rather, biosimilar manufacturers strive to make their candidates as close a copy as possible to the innovator (but realizing an exact match is impossible). Logically, it might seem that the biosimilar approval process should be at the same level of proof as the 505(b)2 pathway. No, that can never be the case—the structure of biosimilars will always be a little different than the innovator agent. And the structure will always change a bit over time (as will the innovator biologic).

It is better, instead, that the 351(k) pathway is modified to reflect the real-life experience of the biosimilars approved to date by the FDA and the EMA, and that does provide ample opportunity for lowering the bar, and costs, of development.

This article was written by our Director of Content, Stanton Mehr. Stan has been writing commentary and reporting news about the biosimilar industry since the submission of the first biosimilar 351(k) application to the FDA 13 years ago. Since that time, BR&R has been tracking the US biosimilar marketplace, with the industry’s original, comprehensive and updated database of biosimilar filings with the FDA.

Biosimilar Bytes This Week

The Institute for Clinical and Economic Review (ICER) released a report this week that highlighted seven pharmaceuticals with “substantial price increases on top of already high current spending.” According to ICER, these seven agents accounted for billions in unnecessary expense in 2017 and 2018. AbbVie’s Humira^® and Genentech’s Rituxan^® topped the list, with Neulasta^® coming in at number 5. The first two are not that surprising, because relatively high price increases (even net rebates or other considerations) are common reactions of pharma companies to imminent new competition. This has been typical for small molecule brands facing patent expiration and generic challenges. In 2017 and 2018, AbbVie may have been more concerned that it could not reach a settlement with the several biosimilar manufacturers working on adalimumab agents. Genentech also faced similar conditions with Rituxan. On the other hand, Amgen was already facing strong competition from Zarxio® and Granix®.

ICER specified, “Net price increases for the seven drugs unsupported by new evidence were responsible for increasing total US drug spending by more than $5.1 billion from 2017 to 2018. The drug whose price increases accounted for the greatest single impact on spending was Humira. Humira’s average US price increased 15.9% over this period.” I emphasize, this was net price not list price increases.

In a presentation at the Drug Information Association (DIA) annual meeting, Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research, stated that 83 biosimilar development programs were now ongoing, for a total of 38 different biologics. This implies that biosimilar interest in several new classes of biologics remains strong from established and prospective manufacturers.

Tanvex BioPharma announced in late September that its TX-01 filgrastim biosimilar candidate was not approved by the FDA. According to Tanvex, the FDA’s complete response letter did not cite any data deficiencies that might require additional studies. This leads one to suspect that production facilities problems may be the issue. The soonest Tanvex can expect a new FDA decision is 6 months from its new application submission date. As a result, Zarxio^® and Nevistym^® remain the only two biosimilar filgrastim agents (plus the follow-on product Granix^®) to compete with Amgen’s Neupogen.

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.

Much 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.