Tag: FDA Commissioner

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.

Analyzing FDA Chief Gottlieb’s Remarks—Part 2: FDA and Marketing Exclusivity

Food and Drug Administration Chief Scott Gottlieb, MD, received a great deal of coverage for his recent remarks on providing better access to biosimilars. He seems intent on finding solutions to the underlying problems in delayed biosimilar launches.

He discussed in the interview with CNBC perhaps the most intractable problem: The US biosimilar industry has been severely affected by the reference drug manufacturers filing multiple patent filings and extending their market exclusivity well past the 12 years provided by law. For example, it was hoped that an adalimumab biosimilar would already be marketed, but it now seems that 2022/2023 may be the earliest in US launch because of this “patent maze.”

Dr. Gottlieb agreed that patents filed to protect “small changes in how you manufacturer the drugs” shouldn’t convey an additional 12 years of market exclusivity, and he thinks we’ll see less of these actions in the biologic space going forward. However, “there’s no silver bullet here in terms of trying to really make this market go gangbusters. I think Food and Drug Administrationthis is going to be a slow build. But we’re going to be coming out with…about a dozen policies that I think incrementally will each move the ball in the direction of trying to create more avenues of biosimilar competition.”

One of the underlying challenges is that market exclusivity is described by two components: (1) regulatory (defined by Congress and FDA) and (2) patent law outlined in the US Constitution (and governed by the courts). The first is typified by the Biologics Price Competition and Innovation Act (BPCIA), which specifies 12 years of market exclusivity for the biologic manufacturer.

Originally, the Obama Administration wanted 7 years of market exclusivity but settled for 12 in order to pass the BPCIA. Based on Dr. Gottlieb’s remarks, it seems to be a question of what the FDA can do on its own to effect change. Perhaps the only leverage the agency has today over biologic manufacturers is at the time of approval. I really can’t envision what power it can wield in this fight; does the agency have the authority to cut deals with manufacturers to limit patent applications in exchange for drug approval? It may be that Dr. Gottlieb will try to work with Congress to circumvent the problem through amendments to BPCIA.

Another potential area may be to help biosimilar manufacturers take on the risk of launching before patent disputes are settled. Technically, any biosimilar manufacturer is allowed to launch after its 180-day exclusivity period expires postapproval. Pfizer (and its partner Celltrion) was the first to launch “at-risk.” Although biosimilars have been approved for drugs other than infliximab and filgrastim, manufacturers have been reluctant because of the financial penalties, including profits, which may be awarded by a court to the manufacturer of an originator product. This is why Sandoz has not launched Erelzi® (etanercept-szzs), which gained approval in 2016.

Analyzing FDA Chief Gottlieb’s Remarks: One Challenge With no Easy Solution

Food and Drug Administration Commissioner Scott Gottlieb, MD, undoubtedly understands the threat to a successful biosimilar industry in the US, and his well-reported remarks emphasize some of the key issues. The policies that the FDA Commissioner wants to bring to bear on the multifaceted problem may be harder to implement. In this post, we examine one of those issues.

FDA Commissioner Scott GottliebIn the CNBC interview on Wednesday, he stated, “We’re taking a hard look at how we determine interchangeability so that we can make determinations that biosimilars can be used interchangeably with the brand of drugs.” Dr. Gottlieb correctly pointed out that the interchangeability question is complicated by “variants in lot-to-lot manufacturing of existing biologics and also a lot of variance in the products over time where there’s drift in the sort of formulation of the biologics that are currently on the market.” The variations that manufacturers of any biologics encounter create a “moving target” for not simply a manufacturer trying to prove biosimilarity but also interchangeability. He acknowledged that unexpected clinical effects of these variations have not yet been seen but the potential exists, which is why certain variations are subject to testing by the regulators to address the problem.

Yet, it is not practical to eliminate the lot-to-lot variation that has been seen for decades, sometimes incurred by plant changes or subtly different manufacturing techniques. Does this mean that biosimilar makers will have to test their agent against more samples of the originator biologic and in studies with more patients? For the purposes of proving interchangeability, the variation could undermine confidence in the outcome.

According to the FDA Commissioner, “We’re going to be putting out a set of policies to compel the branded drug makers who have biologics on the market to tighten up their manufacturing, to have less variance of their biologics that are currently on the market.” Preventing this variation in biologic manufacturing sounds like a costly (and possible futile) exercise. Let’s say for example, that one plant must be shut down for a time owing to maintenance; how does one prevent the manufacturer of a compound that demonstrates slightly different structural folding produced at another plant? Only an expert in biologic manufacturing techniques can answer this question.

 

FDA’s Gottlieb to Health Plans: Move Away From Short-Term Rebates on Reference Drugs to Enhance Long-Term Biosimilar Savings

According to Food and Drug Commissioner Scott Gottlieb, MD, the managed care sector’s willingness to accept larger rebates from manufacturers of originator biologics to preserve formulary coverage may seriously hinder the long-term success of the biosimilar industry. And more importantly, the ability to control biologic costs through competition.

FDA Commissioner Scott Gottlieb, MDIn remarks made to a national meeting of America’s Health Insurance Plans’ (AHIP) in Washington, DC, Dr. Gottlieb worried that biosimilar manufacturers may start to believe that “the system is rigged against them.”

In terms of patent litigation, that certainly may seem true. However, Pfizer’s complaint that Janssen is undercutting its discounts by providing plans and insurers additional rebates would seem to be a practice that big pharma has used for years (Pfizer included). Therefore, Dr. Gottlieb is asking payers to turn aside those rebate offers and instead cover the biosimilars, at least for new patients.

He stated that the FDA is “invested in making sure that the new biosimilar pathway works, and that we can help facilitate a robust market for these products. So, we take note when we see market practices that can reduce the incentive for sponsors to invest in the development of biosimilars in the first place.”

Dr. Gottlieb put it to health plans succinctly: “Payors are going to have to decide what they want: The short-term profit goose that comes with the rebates, or in the long run, a system that functions better for patients, providers, and those who pay for care…Do they want to continue to benefit from monopoly rents today, or help generate a vibrant biosimilar market that can help reset biologic pricing—and drug pricing more generally— through competition.”

He suggested that payers help increase biosimilar uptake by lowering or waiving copays for biosimilars or removing prior authorization requirements when biosimilars can be prescribed. “FDA has a strong interest in seeing the biosimilar market grow,” he reiterated, “but some of that is going to be up to the choices you all make.”