By Asher Mullard
After years of speculation, consternation and excitement about the arrival of biosimilars in the United States, the competition is at last playing out.
In the past 2years, the FDA has approved four biosimilars. That number — although still far behind the more than 20 biosimilars approved to date by the European Medicines Agency (EMA) — could double by the end of the year (TABLE1). And, although biosimilar developers have only launched two of these biosimilars so far, US$17.5billion worth of biologic drug sales in the United States could be at risk of competition next year.
As importantly, the FDA has finally published most of the key guidance documents on the regulatory requirements for biosimilar development. The most recent, and one of the most significant, was the much-awaited mid-January draft guidance on interchangeability. Whereas a biosimilarity approval already allows biosimilar developers to market their drugs, an interchangeability designation enables pharmacists to switch a reference biologic product to a biosimilar without permission from the original prescriber (subject to state law) — a potential driver of biosimilar adoption, and profitability and sustainability of the sector.
"I’m quite impressed with the way that the FDA has dealt with this," says Cecil Nick, vice-president at Parexel, a clinical research organization that runs clinical trials for biologic and biosimilar developers.
The agency walked a tightrope, he says, and found a good balance between the statutory requirements as laid out in the Affordable Care Act, the science of biosimilar assessment and patient safety. "It could have been much worse," he says. "Now that the framework is in place, we expect we’ll see more interest in developing biosimilars for the US market," he says.
Regulation watch
The FDA had previously recommended that biosimilar developers follow a two-step pathway to market, first establishing biosimilarity to a reference product before seeking an interchangeability designation.
The 30‑page draft guidance explains what this second step involves. Although the agency will consider the totality of the data, the draft guidance also calls for clinical switching studies that assess the effects of alternating at least three times between the reference product and the biosimilar.
"We applaud the FDA in saying that more data are needed on switching," says David Charles, chairman of the Alliance for Patient Access, an advocacy group whose funders include biologics developers. As a physician, he says he is reluctant to recommend biosimilars to his patients in the absence of explicit clinical data proving that they function exactly as expected. He points in particular to a possible risk of increased immunogenicity reactions with switching.
His concern is exacerbated, he says, by the FDA’s willingness to extrapolate clinical data from one indication to another — allowing, for example, data from an efficacy and safety trial in an inflammatory indication to provide the basis for approval in an oncology indication. "Different patient populations may respond differently, and also may have different comorbidities," he says.
These arguments do not hold water for Gillian Woollett, senior vice‑president at Avalere Health, a consulting firm that supports biologic and biosimilar developers.
The biosimilarity analysis is designed to demonstrate that a product is biochemically and functionally equivalent to its reference, she says. And the agency is already well versed in such assessments, running comparability analyses for biologics every time a manufacturing change is introduced —
ensuring that a product has stayed ‘biosimilar' to itself over its entire lifetime. These analyses rarely require clinical data, she says.
In Europe, she also points out, the EMA does not have an interchangeability designation. National health authorities there can and do allow switching, as yet without any safety issues. A recent analysis by Dutch, Finnish, German and Norwegian regulators assessed 10 years of switching studies and
concluded that "it is unlikely and very difficult to substantiate that two products, comparable on a population level, would have different safety or efficacy in individual patients upon a switch" (BioDrugs, published online 24 Jan 2017).
"I would argue that as a scientific matter, once your product is deemed biosimilar it is already interchangeable. The same product is being designated as interchangeable by the FDA. The critical question is how feasible it is to collect the additional data to achieve the interchangeable designation,"
says Woollett.
The switching studies can be particularly cumbersome and expensive, she adds, contributing to a high bar to entry for biosimilar developers. The cost of biosimilar development can be $250million or more.
The cost of generic drug development, by contrast, is typically $1–4 million.
And the benefits of an interchangeability designation as yet remain unclear. Although the designation might increase market share for sales that go through pharmacies, it won’t improve sales through doctors’ offices and hospitals, where prescribing physicians administer infused therapies. Even for therapeutics that are dispensed at least in part via pharmacies, payers have other means of driving uptake, such as through formulary design.
"To the extent that these studies are very expensive and are for products that are already approved and commercially available, this raises the question of what is the return on investment," she says. Nonetheless, with the draft guidance document in hand, she welcomes the ability of companies to now at least start to make these calculations.
The FDA is soliciting comments on the guidance until 20March 2017. It also asked specifically for input into two topics that point to potentially complex long-term relationships between reference products and their interchangeable biosimilars.
First, will those same comparability assessments that ensure that a biologic remains ‘biosimilar’ to and ‘interchangeable’with itself after a manufacturing change guarantee that interchangeable products remain switchable over time too?
Or are new approaches needed, potentially with implications for both reference and biosimilar developers?
Second, biosimilar sponsors are expected to show that their products are interchangeable across all the indications on a reference product’s label. So, how should the agency handle the addition of new indications to a reference product’s label?
Further complicating matters, approvals for orphan indications confer 7years of market
exclusivity, points out Woollett."If the agency doesn’t allow a little bit of flexibility here, it knows that no biosimilar will ever have a complete label and it will never issue interchangeability," she says.
Now that the interchangeability draft guidance has been published, Nick hopes that the regulatory focus will shift towards re-examining the evidentiary standards for biosimilarity. Currently, companies must test their biosimilars against placebos or active comparators to establish comparable efficacy in at least one indication. Sandoz ran a confirmatory efficacy and safety similarity study of its etanercept biosimilar versus placebo in 531 patients with chronic plaque psoriasis to generate biosimilarity data, for example. But this can be particularly onerous for cancer biosimilars, he says, where the rapid pace of therapeutic change and medical impetus makes it difficult to set up trials with the old backbone therapies that were used to develop the reference product.
"There is a question mark around whether therapeutic equivalence really is the best end point for developing biosimilars, or whether pharmacokinetics, pharmacodynamics and immunogenicity data can give a better read," says Nick. This shift is already starting to happen with simpler biosimilars such as filgrastim, he adds. "As experience is gained, we are seeing a more pragmatic approach to data collection. I hope the same will happen with monoclonal antibodies."
How low will it go?
Analysts are meanwhile also learning from the first US biosimilar launches.
The key to creating a sustainable sector is finding the right combination of cost savings for the health-care system on the one hand and biosimilar adoption on the other, says Carol Lynch, global head of biopharmaceuticals at Sandoz, a division of Novartis. "If we get a disconnect between
those — steep price erosion but no adoption — that’s when we get unsustainable market conditions and decisions not to invest," she says.
In Europe, where biosimilars have been on the market for a decade and there is more pricing transparency, the first biosimilars shaved 14–55% off the price of biologic drugs.
Although this is a far cry from the 80–85% discounts associated with generic small-molecule drugs, it still amounts to considerable cost savings. The discounts, moreover, are highly variable from country to country and product to product, depending among other things on the biosimilar adoption rate. In one extreme example, the Norwegian government secured a 69% discount on the price of infliximab by being able to offer nearly 80% market share to a biosimilar competitor.
"I wouldn’t hang my hat too much on that discount level in the United States," says Lynch. But the early evidence suggests that the economics will work out favourably — for biosimilar makers at least — in the United States too, shesays.
Sandoz priced their filgrastim biosimilar at a 15% discount to the list price of Amgen’s filgrastim. They also offer further undisclosed
discounts beyond the list price, making it impossible to say what the overall discount is in the United States. In the 2years since launch, Sandoz has captured about 30% of the overall filgrastim market share in the United States, says Lynch. "Things are going exactly according to plan, if not slightly
better," shesays.
Pfizer’s recent launch of its infliximab biosimilar late last year — also at a disclosed 15% discount to infliximab’s list price — may offer an even better case study. Not only is it the first biosimilar monoclonal antibody to hit the market, but it will also provide a benchmark against the European experience, where the biosimilar was launched just 20 months earlier.
And, as more biosimilars join the fray, says Lynch, both the size of the discounts and the rate of biosimilar adoption are likely to increase. "We need to keep an eye on the number of approvals, and watch that it continues to accelerate in the next 18 to 24months," shesays.
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