Tag: FDA

FDA and FTC Say They Will Work Collaboratively to Deter Anticompetitive Behavior

A press release from the US Food and Drug Administration and the Federal Trade Commission announced the signing of a joint statement that focuses on anticompetitive behavior in the biosimilar market. According to the FDA and FTC, this statement describes “key steps the agencies will take to address false or misleading promotion about biosimilars within their respective authorities and deter anticompetitive behavior in this space.”

FDA and FTC Collaboration

When introducing the Biosimilar Action Plan in 2018, former FDA Commissioner Scott Gottlieb noted that biosimilar market competition is being hampered by reference manufacturers’ attempts to unfairly delay competition. “Strengthening the partnership and interagency coordination between FDA and FTC will help each agency address and deter anticompetitive behavior in the US market for biological products,” stated the federal agencies today. “Such behavior might include anticompetitive reverse payment agreements, abusive repetitive regulatory filings, or misuse of restricted drug distribution programs.”

Food and Drug Administration

In the press announcement, FDA Commissioner Stephen M. Hahn remarked, “Strengthening efforts to curtail and discourage anticompetitive behavior is key for facilitating robust competition for patients in the biologics marketplace, including through biosimilars, bringing down the costs of these crucial products for patients.”

FTC Chairman Joseph Simons added, “The FTC is committed to continuing to enforce the antitrust laws in healthcare markets, including those for biologics and biosimilars.”

The FDA and FTC have pledged to begin efforts in 4 areas:

  • They will coordinate to promote greater competition in biologic markets.
  • They will work together to deter behavior that impedes access to samples needed for the development of biologics, including biosimilars.
  • FDA and FTC intend to take appropriate action against false or misleading communications about biologics, including biosimilars, within their respective authorities. FDA is publishing a draft guidance outlining considerations for FDA-regulated advertisements and promotional labeling that contains information about biologic products.
  • FTC will review patent settlement agreements involving biologics, including biosimilars, for antitrust violations.

A Real Beginning for the Biosimilar Action Plan?

It is unclear what action(s) will arise from this joint statement. Although a few initiatives have been implemented, such as limiting the ability of Citizens Petitions to delay FDA decision making on biosimilar applications, both the FDA and FTC have not addressed other opportunities to attack anticompetitive behavior in this marketplace.

Legislation, such as the CREATES Act (first introduced in 2017 and is awaiting action in 2020), was intended to address the ability of prospective biosimilar makers to obtain biologic samples from reference manufacturers. It is unclear what teeth FDA or FTC will use to take a bite out of these delaying tactics.

In 2019, the Trump administration backed away from the removal of the drug rebate safe harbor, believing that it might somehow result in higher Medicare premiums. Pfizer’s 2017 lawsuit against Janssen Biotech seeks to address the use of exclusionary rebate contracts. No other significant actions against drug rebates have been taken to date.

The FDA has unintentionally encouraging misinformation by requiring the use of four-letter suffixes for the biosimilars but not their reference products. Interestingly, the FTC disagreed with this policy, and submitted comments to the FDA explaining why it believes this will contribute to misinformation.

The FTC has been opposed to “pay for delay” deals, which have principally been seen in the generic marketplace. Legislators have tried to move proposals through Congress or the Senate that prevent these arrangements, but these have not progressed very far. In the biosimilar arena, licensing arrangements that pay royalties to the reference manufacturer and allow biosimilar firms to start marketing their product after a certain date may not exactly fit this “pay-for-delay” description. Further, some argue that these arrangements may actually create an avenue for earlier access to the less-expensive biosimilar.

Importantly, the FTC has not yet taken any material action to address the anticompetitive patent thickets that prevent marketing of biosimilars for some of oldest biologic agents.

Is this statement by the FTC and FDA a first step in activating the Biosimilar Action Plan? Or is it a first step towards a collaboration that leads to a beginning?

A Payer’s Preference for Biosimilars, Interchangeability, and Incentivizing Providers to Use Biosimilars

In the last few weeks, we’ve seen a hail of biosimilars-related news, some of which significant, more having limited impact.

Building upon the success of its infliximab biosimilar uptake, Magellan Rx Management announced June 4 that it will extend its medical pharmacy program to the new oncology biosimilars (i.e., rituximab, trastuzumab, and bevacizumab) when launched. Magellan Rx had announced that its program saved 34% when it shifted utilization to infliximab biosimilars. This action was announced after UnitedHealthcare decided that it would prefer the reference biologic agents rather than the biosimilars starting in July, which caused much reaction.

In early May, the Food and Drug Administration (finally!) released its final guidance on interchangeability. Although there were no surprises in this document, it does lay out a definitive path for gaining an interchangeable designation. Other than Boehringer Ingelheim’s intention to seek the label for Cytelzo®, no other biosimilar manufacturer has publicly stated interchangeability as a goal. Boehringer cannot launch its biosimilar adalimumab, regardless of its interchangeability status until June 2023, so the strategic importance may be longer term. Switching biosimilars (for a reference product or for another biosimilar, with or without this designation) may be a more pressing question.

The Biosimilars Forum has launched an educational campaign on how aligning incentives in Medicare part B can save billions of dollars through the enhanced use of biosimilars. The industry group’s proposal includes using a shared savings model in which providers can receive savings bonuses when using lower-cost biosimilars. In addition, it is lobbying to increase provider reimbursement for prescribing biosimilars. This would be in the form of a greater percentage add-on rate in addition to the average sales price (ASP) paid for the therapy. These two actions could offset the current reimbursement disincentive, where providers bill higher amounts for prescribing higher cost (and likely higher rebate) drugs, currently at ASP + 6%. The organizations also call on the Center for Medicare and Medicaid Services to reduce patient out-of-pocket costs when a Part B biosimilar is used.

The Association of Affordable Medicines has also been focused on the issue of biosimilars in Part B medications, as well as on the potential implications of the US–Mexico–Canada Agreement. Passage of the agreement (still awaiting ratification on Capitol Hill) could have the unintended consequence of extending exclusivity for reference biologics; all other federal regulatory efforts are moving towards cutting delays in access to lower-cost biologics. The trade agreement therefore negatively affects the biosimilar industry, which frankly, cannot survive additional barriers erected in its path. The Association is hoping that harmonizing Mexico’s, Canada’s, and America’s biologic exclusivity period can be modified before the treaty is ratified.

Biosimilar Bytes

In the absence of really big biosimilar stories with far-reaching implications, let’s start with some interesting bits on biosimilars to begin this week.

First, insulin maker Eli Lilly asked the Food and Drug Administration a very interesting question, in comments on the agency’s guidelines on transitional drugs. Lilly requested clarification of the rules under which it might introduce an authorized brand of insulin (that is, a lower-priced version of an existing insulin brand). The insulins are one group of medicines that is scheduled to transition to regulation under the Public Health Services Act in 2020, and thus be subject to formal biosimilar competition.

Second, Boehringer Ingelheim, which received FDA approval to market its adalimumab biosimilar Cyltezo® in August 2017, received a positive ruling in its patent litigation case with AbbVie. A federal court judge ruled that AbbVie, which makes the originator product Humira® must turn over all papers related to the Humira patents. This may actually move the court case out of the discovery phase, according to Fierce Healthcare, and potentially closer to an actual, early biosimilar launch.   Third, Health Canada has decided not to add a four-character suffix onto the names of its biosimilars and biologics. Instead, it will rely on its specific drug identification number as well as the nonproprietary names to identify medications being taken. This of course, contrasts with the FDA’s practice. The FDA is the only major advanced regulatory system that requires the use of a suffix to distinguish biosimilars and their reference products. And it is not used by providers.

Celltrion’s Rituximab Biosimilar Earns Positive Review

The information package released by reviewers for the Food and Drug Administration (FDA) indicates that a positive recommendation for Celltrion’s rituximab biosimilar is likely at the Advisory Committee meeting on October 10.

The members of the Oncologic Drugs Advisory Committee will review the data and hear public comments before voting to recommend that the FDA ultimately approve or reject CT-P10 for the treatment of non-Hodgkin lymphoma. Celltrion did not perform clinical trials for rituximab’s autoimmune indications. However, if the FDA approves CT-P10, it may extrapolate the approval to other indications as well.

The orirituximab biosimilarginal 351(k) application by Celltrion in April 2017 resulted in a complete response letter from the FDA. The rejection for this rituximab biosimilar cited multiple deficiencies, including “clinical, product quality, and facility” problems, as well as clinical study issues from the original submission.

According to the FDA reviewers, “In considering the totality of the evidence, the data submitted by [Celltrion] show that CT-P10 is highly similar to US-licensed Rituxan®, notwithstanding minor differences in clinically inactive compounds, and support a demonstration that there are no clinically meaningful differences between CT-P10 and US-licensed Rituxan in terms of safety, purity, and potency of the product.”

BR&R will cover the Oncology Drug Advisory Committee meeting and provide updates on its decision. If this rituximab biosimilar is eventually approved by the FDA, Teva would market the product in North America, based on a previous partnership agreement.

In other biosimilar news…Merck has inked an exclusive contract to supply its biosimilar infliximab (Renflexis®) with the US Department of Veterans Affairs. According to a report from Pharmaphorum, it will be the only infliximab biosimilar on the VA’s national formulary.

Phase 3 Studies in Biosimilars: Do They Tell Us Enough to Be Useful?

The argument for the elimination of the need for phase 3 studies in biosimilars is pretty simple: They cost a great deal but what do they add to our knowledge about the safety and efficacy of biosimilars? One of the primary tasks of the Food and Drug Administration (FDA), in educating health care professionals, media, the public, academia, and manufacturers, was to deemphasize the importance of the clinical trial in the totality of evidence approach they use to evaluate biosimilars.

Do we need phase 3 studies in biosimilars?The health care professional community, academia, and patient advocates may take another view: They are complex biochemical medicines and we cannot be sure of their safety and efficacy without carefully controlled studies in large populations. We have been ingrained for 40 years with the need for randomized, phase 3 clinical investigations that it may be very uncomfortable indeed to approve a drug without them.

Phase 3 Studies in Biosimilars: Statistically Speaking

At least one pharmaceutical company (Adello) is seeking FDA approval without phase 3 trials that study large groups of patients with the disease indication. In biosimilars, FDA is willing to extrapolate approvals without any clinical studies in other indications, and indeed, payers and providers are willing to accept this.

Furthermore, the FDA has taken many steps to speed access of biosimilars to approval. Other than altering the intellectual property and exclusivity timelines, what action can save more time in the process (much less money for the biosimilar developer) than the elimination of phase 3 studies in biosimilars?

In a phase 3 clinical trial of the originator biologic vs. a biosimilar, what do we expect to see? Since the expectation is that the physiochemical characteristics of the two molecules are exceedingly similar, and phase 1 trials should have proven equivalent pharmacodynamics, we don’t expect big differences in outcomes by phase 3. If phase 2 studies have been performed successfully, we believe this more emphatically.

At worst, we expect to see clinical effects that are on the edges of anticipated norms for the originator drug but within the range expected. One French investigator wrote this month in BioDrugs that typical phase 3 studies with 600 to 1000 patients are not statistically powered to detect more than major differences in safety. What is the real implications of 2 versus 5 drug withdrawals in patients taking medications that are much more alike than they are different? This author believes that well-designed phase 1 trials in volunteers can sufficiently detect the formation of antidrug antibodies and other immunogenicity differences between biosimilars and their originator drugs. This may be particularly true in patients with autoimmune disorders. When patients are routinely given methotrexate (another immunosuppressant) concomitantly with the biologic therapy, reliable evaluations of immunogenicity of the study medications are very difficult. Finding that hidden safety signal may not be possible.

More Pressure on Postmarketing Surveillance

In other words, it is easier to determine whether a biosimilar drug is “noninferior” to a reference product in clinical testing. The range of expected values is small (and there is little or no expectation that a biosimilar will demonstrate superiority). I’m no statistician, but I’d expect that to detect clinically significant differences among outcomes in this type of comparison, one would need study populations far exceeding that of the typical phase 3 study in biosimilars. Unlike in a clinical trial of a study drug versus a placebo or other standard therapy, large differences may be seen, and population sizes may be less important (hence, phase 2 trials of 100 patients may reveal red flags or lack of effectiveness).

Without the use of phase 3 trials in biosimilars to attain comfort and security, the post-marketing surveillance machinery becomes that much more important. The observation of safety issues based on real-world prescribing and utilization will be a front-line defense, not a backstop, to identify unintended pharmaceutical outcomes. This means that more of the onus will fall on the conduct of registry trials, FDA’s Sentinel program, and notably the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC), which is in the process of preparing for its first comparative-effectiveness studies in long-acting insulins (Q4 2018) and granulocyte colony-stimulating factors (i.e., filgrastim, pegfilgrastim).

This would still be a significant leap of faith, based on the approvals and limited use of biosimilars today, but I can envision other companies gambling, with FDA’s consultation, on skipping this traditional step to drug approval. I wouldn’t bet against it.

Anti-kickback Safe Harbors, Drug Rebates, Biosimilars, and FDA

Over the next couple of weeks, I’ll be issuing a series of posts to further analyze some of the Food and Drug Administration’s (FDA’s) new Biosimilars Action Plan.

Drug rebate contracts Outside of patent litigation, the greatest barrier to biosimilar access is the current drug rebate contracts agreed to by pharmaceutical companies, health plans, and pharmacy benefit managers (PBMs). This contracting system persuades payers to maintain coverage of a heavily rebated biosimilar rather than providing access to a lower retail priced drug. Scott Gottlieb, MD, FDA Commissioner, has said that payers will need to start considering whether their rebate revenue on originator biologics are more valuable than the viability of the biosimilar industry overall. The real question is, what can the federal government do about drug rebate contracts?

Dr. Gottlieb believes that they are anticompetitive and cause higher drug prices over time; drug rebate contracts may be in direct conflict with the intent of the federal anti-kickback statues that allow them in the first place. In May, he and Health and Human Services (HHS) Secretary Azar indicated that they may ask for a review of the safe harbors provided for drug rebates.

Anti-kickback Safe Harbors and Drug Rebate Contracts

The anti-kickback statute has been in place since 1971, but these specific safe harbors, protecting drug companies from anti-kickback laws, were introduced more than 2 decades ago. The federal government provides an excellent resource for information about these safe harbors at the Federal Register website. In brief, the safe harbors define exceptions to situations where organizations are receiving “remuneration” for providing goods or services. A rebate given as an incentive to provide a drug (i.e., on formulary) or to utilize more of a product (i.e., “performance rebates”) would currently qualify for safe harbor protection.

Last week, HHS moved on this issue, filing the proposed rule “Removal of Safe Harbor Protection for Rebates to Plans or PBMs Involving Prescription Pharmaceuticals and Creation of New Safe Harbor Protection.” Although the content of the filing has not yet been released, the title and previous statements on the matter by Secretary Alex Azar, do not bode well for drug rebate contracts and payers and the PBM industry tied to them.

America’s Health Insurance Plans, a national trade group for payers, supported a study supported that disputes one of these assertions. The study, conducted by Milliman, concludes that among part D plans studied, rebates did not independently cause higher drug costs. The greatest rebates were found in drug categories with the most competition from other brands (not generics). Instead, Milliman found that the use of rebates was in direct proportion to the degree of competition in a drug category. “Over the four-year period from 2013 to 2016, brand drugs with manufacturer rebates in 2016 had higher price trends than brand drugs without rebates,” according to the report. In other words, the rebates helped mitigate the price increases.

Although a bold move by the Department of Health and Human Services, removing drug-rebate safe harbors will be tricky. It will threaten the bottom lines of the PBM industry. Rebates comprise a significant portion of their revenue. Health plans also receive a portion of that revenue; they claim that these rebates are used to hold down premium costs. In any case, plans and insurers will need to evaluate how to account for less rebate monies but perhaps lower drug prices. For these reasons, we can expect quite a pushback from these sectors should the federal government proceed.

Specialty Drugs Mostly Under the Medical Benefit

Furthermore, all biosimilars (approved and investigational) are classified as specialty drugs by their cost, storage needs, and/or route of administration. This means that they are more likely covered under the medical benefit than the pharmacy benefit. It is thus also likely that the PBM’s specialty pharmacy units or their specialty pharmacy partners will be directly affected by any biosimilar-targeted changes in the anti-kickback laws.

The Trump administration also indicated the desire to move several drugs from coverage under Medicare part B to part D. Whereas Medicare does not currently negotiate prices with pharmaceutical manufacturers, private Medicare insurers can. This may enable price negotiation under part D providers and Medicare Advantage plans. Ironically, might this be a rebate-related negotiation?

Is Celltrion Paving a New Road for Biosimilars? A New Route of Administration Being Tested for Infliximab

When payers, patients, or physicians discuss biosimilars, they assume that the biosimilar works just like the reference product. They also assume that the biosimilar is administered in the same way as the originator biologic. Celltrion is actively researching a new subcutaneous infliximab. This could result in a first for the biosimilar industry.

Sponsored by Celltrion and conducted in multiple sites, the research results were announced at the annual meeting of the European Congress of Rheumatology in June. The investigators presented outcomes data on the use of a subcutaneous (SC) form of infliximab-dyyb. Currently, infliximab is only available as an intravenous (IV) infusion at the physician’s office that takes at least 2 hours. Subcutaneous infliximab was given on a biweekly basis.

subcutaneous infliximabThe researchers studied 48 patients with rheumatoid arthritis, finding that outcomes were not clinically different through 30 weeks of follow-up. Three dosages were tested, and in this small study, no ACR20 differences were reported in any subgroup receiving infliximab infusions or SC injections.

Hypersensitivity reactions did occur in one patient each receiving the lowest dose (90 mg) SC and the middle dose (120 mg). None were seen in the group receiving the highest infliximab SC dose (180 mg). Injection site reactions occurred in two patients apiece in the 90 mg and 180 mg dose cohorts. receiving subcutaneous infliximab. The formation of antidrug antibodies was detected in nine patients receiving the standard infusion, but less than half that number in each of the subcutaneous groups.

Currently, infliximab treatment requires a lengthy office visit for each infusion (every 8 wk in the maintenance phase). It is one of the key limiting factors to its use. A self-injectable formulation should result in lower administration costs, and the potential for covering the agent through the pharmacy benefit.

A phase 1, open-label trial of subcutaneous infliximab has already been conducted by Celltrion in patients with Crohn’s disease. That trial found similar outcomes between the SC and IV formulations. Another phase 1 trial is wrapping up, this one evaluating safety and pharmacokinetics in healthy volunteers. Celltrion is also sponsoring a phase 3 trial of more than 300 patients with rheumatoid arthritis. Preliminary results will not be available until December 2018.

It is not yet clear, however, what type of data the Food and Drug Administration would require for approval of a new formulation of a biosimilar. The regulatory agency may decide to treat this as it would a new route of administration for any approved product, which would focus on pharmacokinetic and pharmacology factors. Celltrion seems to be covering all of its bases.

Teva and Celltrion Receive Rejections on Trastuzumab and Rituximab Biosimilars

Celltrion and its partner Teva were dealt a significant blow today, as the Korean manufacturer announced that the latest two biosimilar candidates were rejected by the Food and Drug Administration (FDA).

Celltrion logo1As first reported by Dan Stanton in the Biopharma Reporter, the FDA issued complete response letters as a result of inspection problems uncovered at Celltrion’s manufacturing facility in Incheon, Korea. Celltrion initially receive the negative inspection report in January of this year, which highlighted deficiencies in aseptic practices and processing, and failure to investigate variations in batches.Teva

Under the partners’ pact, signed in 2016, Teva would commercialize the two biosimilars. Teva has a separate concern, however, in that the same Celltrion plant cited by the FDA has been tabbed to produce its CGRP-inhibitor fremanezumab for migraine prevention. This migraine prevention antibody, which also has the potential to reach sales of $1 billion, has a PDUFA date of mid-June.

In a statement published by Mr. Stanton, a Celltrion spokesperson said, “Celltrion is making progress addressing the concerns raised by the FDA in a Warning Letter issued in January and is committed to working with the agency to fully resolve all outstanding issues with the highest priority and urgency.”

The issuance of the CRLs may be extremely poor timing for the partners. Although Mylan signed an agreement with Roche to delay the launch of its approved biosimilar version of Herceptin® until at least 2019, the other competitors have not. Amgen/Allergan expect word on their 351(k) submission within the month, and Samsung Bioepis should hear in the fourth quarter. On the rituximab front, Sandoz should receive word early in the third quarter.

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.