Now that the Food and Drug Administration has approved Inflectra as the first biosimilar version of the anti–tumor necrosis factor-alpha agent Remicade, rheumatologists and patient advocacy groups are taking stock of how it may be used in practice, and what the future holds for biosimilar drugs, with so many questions still unanswered regarding price, substitution, and safety.

Inflectra, approved in early April and given the generic name of infliximab-dyyb under the FDA’s nomenclature for biosimilar products, will have the same indications as Remicade. The agency extrapolated the clinical trial data that Inflectra’s South Korea–based manufacturer, Celltrion, submitted for rheumatoid arthritis and ankylosing spondylitis to all other indications for which Remicade is approved.

It’s currently unclear how the FDA will note which clinical data in Inflectra’s labeling come from Inflectra and which from Remicade, and the same concerns lie with future biosimilar approvals if their results are extrapolated to indications not tested to show biosimilarity in clinical trials.

Labeling questions

It’s concerning to rheumatologists and the patients who will be using them that biosimilars such as Inflectra are not subject to the same pivotal trial experience as the reference biologics on which they are based, according to Dr. Jonathan Krant, section chief of rheumatology for Adirondack Health Systems in Saranac Lake, N.Y., and medical director for CreakyJoints , a community of patients with arthritis and caregivers, and its larger parent nonprofit advocacy organization, the Global Healthy Living Foundation ( GHLF ).

While the unique regulatory requirements in the biosimilar approval pathway reduce development costs and could potentially make Inflectra’s average wholesale price 30% less than Remicade – as was the case when Inflectra was first on the market in Europe – it’s not known how reduced costs may affect the safety of biosimilars.

“It worries all of us that manufacturers may cut corners to manage the cost constraints imposed by managed care,” Dr. Krant said in an interview.

Given that U.S. rheumatologists don’t have experience with biosimilars, Dr. Krant is anticipating some push back. “I think some physicians are going to fight back and won’t want to prescribe them, even if mandated, because of concerns regarding patient safety,” he said.

In a written statement, Dr. Joan Von Feldt , president of the American College of Rheumatology, welcomed the potential benefits on access to care that cost-saving biosimilars may bring to the U.S. health care system, but also said that “the safety of our patients remains our highest priority. As such, we encourage the FDA to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and the origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.”

Inflectra met the FDA’s “very similar” criteria to be approved as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade, the agency said. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

However, it may not hold true that Inflectra will have the same efficacy and safety for all indications that Remicade had due to potential differences in the mechanism of action through which Remicade exerts its effect across indications, which in this case may apply to the indications for Crohn’s disease and ulcerative colitis.

Health Canada chose not to extrapolate the indications for Inflectra (known as Remsima in Canada) to Crohn’s disease and ulcerative colitis because of “observed differences in the level of afucosylation, Fc-gammaRIIIa receptor binding, and some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays” that could not rule out the possibility that Inflectra and Remicade differ in their ability to induce ADCC. Unlike the other indications for Remicade, Health Canada said “ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases. This position is supported by the observation that certolizumab pegol, another anti-TNF [anti–tumor necrosis factor] that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn’s patients, compared with other anti-TNFs, namely infliximab.”

Other organizations suggest that extrapolation of indications is only appropriate when it is benefiting the patient to the greatest extent possible.

“GHLF is okay with extrapolation of indication unless the mechanism of action for the therapy is either scientifically or therapeutically outdated,” Stephen Marmaras , state and national advocacy manager for the GHLF, said in an interview. “Patients are okay with extrapolating data in order to expedite the approval process as long as you are extrapolating to best in class therapy for a particular indication. What [the GHLF is] saying is we want biosimilars to be an improvement on what we have, not the lowest common denominator. We shouldn’t be extrapolating indications data from products that aren’t considered to be the best product for that indication.”

“If we’re just judging on expediting the approval process for indications that are not considered to be really treated well by this particular drug, you have to always assume that the insurance company is going to go with the lowest common denominator,” he added. “What that could lead to, from a slippery-slope perspective, is the chipping away of the use of cutting-edge therapies.”

Substitution concerns

Inflectra was not approved as interchangeable with Remicade or other infliximab biosimilars. The FDA has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

One of the biggest concerns that physicians have is that biosimilars will be substituted for the reference products without notification, Dr. Krant said. “State by state we’re looking at potential substitution rules which allow pharmacists to switch out these cheaper molecules for the reference product,” he said, and without timely notification, patients and rheumatologists won’t know whether it was the reference product or a biosimilar that was associated with an adverse event or loss of efficacy.

The ACR and patient advocacy organizations such as the GHLF are against forced switching of patients for nonmedical reasons. Patients’ and rheumatologists’ confidence in biosimilar safety will be key to their uptake and the overall expansion of access to biologics to more patients, Mr. Marmaras said.

Patient costs uncertain

Although rheumatologists hope that with biosimilars’ lower costs, access will expand, there is no guarantee it will do so by saving patients money.

“It’s a common misperception that a 30% decrease in the cost of a several thousand dollar-a-month drug is going to automatically open all the doors to access,” said Dr. Sean Fahey , a rheumatologist in Mooresville, N.C., and chair of the insurance subcommittee of the ACR’s Committee on Rheumatologic Care. “Most of my patients who use biologics do so either through copay cards from the pharmaceutical industry or through Medicare and a secondary [payer] covering their out-of-pocket costs for the infusible biologics. This is clearly saving the system money, which is important no doubt, but unless it’s significantly less expensive, it actually might not change the patient’s out-of pocket [cost] all that much.”

The patient assistance programs from biologics manufacturers that offer copay assistance, access hotlines, and administration benefits could be in jeopardy with the rise of biosimilars. Since the programs are bundled into the average wholesale price of the drug, the savings offered by the reduced wholesale price of biosimilars may squeeze them out, Dr. Krant said.

“There’s going to be a lot of hue and cry from the patients who cannot self-administer or have problems with compliance because of copays in the first place,” he predicted.

Another factor that could affect how much biosimilars such as Inflectra will be used is the amount of rebates or discounts that payers receive directly from the pharmaceutical manufacturers.

“We know for the Medicaid population what the average sales prices are, but for private payers, we don’t know if they’re giving 2%, 5%, 18%; we have no idea what the data are. This could affect how much market share Inflectra gets,” said Dr. Fahey, who is also president of the North Carolina Rheumatology Association .

It may be awhile before Inflectra is available on the U.S. market. In a statement following the approval of Inflectra, Remicade-maker Janssen said the “patents for Remicade remain valid and enforceable until September 2018. A commercial launch of Celltrion’s infliximab-dyyb in advance of this date would be an infringement of our patents, and we intend to defend our intellectual property rights.”

Janssen notes that its patient support program for Remicade “continues to offer a copay card for patients with commercial insurance that reduces the patient out-of-pocket cost to no more than $5 per infusion. Eligible uninsured and underinsured patients may be able to access Remicade through the Johnson & Johnson Patient Assistance Foundation.”

Pfizer, which owns the rights to marketing Inflectra in the United States, did not respond directly to a question about whether it would have a payment assistance program for Inflectra. “While we cannot comment on specific commercialization strategies at this time, we are working to bring these important therapies to market in the U.S. as quickly as possible,” said Rachel Hooper, Director of Public Affairs, West, for Pfizer.

It seems likely that once Inflectra does come to the market, it will account for many patients who are newly started on infliximab because of the lack of information available about whether there is, or is not, significant risk of immunogenicity with switching or loss of efficacy, Dr. Fahey said. “What is less certain is whether the payers will try to force us to move people from the Remicade brand to the infliximab biosimilar, and what the potential consequences of that is going to be.”

Dr. Krant, Dr. Fahey, and Mr. Marmaras had no relevant disclosures.