Is It Time for a Global Reference Product for Biosimilars?

On the last day of the 14th Biosimilars Summit, held January 22-23, 2019, in Alexandria, Virginia, the head of the FDA practice at Avalere discussed her point of view that enabling a global reference product for biosimilars would provide global access for patients.

Gillian Woollett, MA, DPhil, an immunologist, began her presentation by noting that FDA Commissioner Scott Gottlieb, MD, has been very different than the previous people who have held that position, noting that Gottlieb sees competition as the source of innovation in the United States, and he recognizes the risk taking and investment that biotechnology firms, and others, undertake in the pursuit of novel drugs.

Last month, the FDA released multiple guidance documents and a proposed rule that explain how the agency will approach a “seamless transition” of biologics and follow-ons.

Given the enormous expense involved, these issues are complicated by money, said Woollett, who has been trying to convince policy makers and industry that the safety of biosimilar drugs is not in dispute.

“It’s always about money, but especially in the US, it’s always about money,” noted Woollett.

In the United States, she said, “We have an idea that there is a healthy price, but we don’t know what that is.” A healthy price for a drug should be based on value, which is a combination of clinical outcome and price/need mechanisms to support competition separate from how it is approved, she said.

Given that perhaps 10 biologics are approved in the United States in what Woollett called “a good year,” out of the thousand or so that are in development, the timeline to approval is clearly too long. Compared with Europe, the US market for biologics is marked by prescribing patterns, payer coverage, payment models, interchangeability issues, and complexity of development, she said. FDA approval is only the first step to getting a biosimilar into the hands of patients, followed by a period of exclusivity and intellectual property rights before commercialization.

Do these steps make it feasible for there to be a “sustainable multisource specialty market in the US?” Woollett asked. “I think we’ve reached the point where that is a genuine question.”

While some at other sessions at the conference this week said part of the perceived issue of any misconception about biosimilars has to do with the very name itself—biosimilar—particularly the “similar” part, she said the issue has to do with the prefix “bio.”

“The name does not change the product in the tube,” Woollett said. The idea that a biosimilar is “interchangeable” as per the FDA designation that allows a pharmacist to switch patients is the part that leads to confusion. An approval that ends in an interchangeable biosimilar designation is 1 of 4 ways a drug or biologic can be approved under current pathways.

Scientific and regulatory principles are established for all biologics, no matter whether they are a biologic or a biosimilar, she said, and after approval, how complex they are is no longer a relevant argument, she said. The fact that regulations differ in the United States and Europe has nothing to do with issues of science, she said.

Even biologics can vary from batch to batch, she said, and “it’s a tremendous cost to have to argue and reinvent the wheel every single time.”

In her presentation, Woollett cited a 2016 European study which showed that infliximab (reference product, Remicade) has had 50 manufacturing changes; she said that it is reasonable to assume the same amount of manufacturing changes have happened here, but unlike in Europe, that information is not publicly disclosed.

Worldwide, biologics make up a growing share of the top 100 drug products, from 30% in 2008 to an estimated 52% by 2022.

The United States has had 16 biosimilars approved to 9 reference biologics, whereas Europe, which has less expensive medicine, has had 53 approved biosimilars approved to 15 reference products.

The fear is that without competition to bring in more biosimilars, there will not be enough room in healthcare budgets to pay for the next generation of therapeutics, such as gene therapy and precision medicine.

One way to speed approvals here and shorten the development timeline, Woollett believes, is to end phase 3 trials for biosimilar drugs because their outcomes with respect to biosimilarity are not in question. Therefore, since “all clinical studies are a tax on patients and must add value,” they are unethical if they are unnecessary, she said.

That biosimilars offer the same clinical outcomes at a lower price has yet to be recognized in the United States, she said. There have been no new safety concerns shown for biosimilars and, as such, no new monitoring mechanisms are needed, based on 700 million patient-days of treatment through late 2016, she said, citing EU data.

Given that the science is not in doubt, she proposed a global reference comparator for biosimilar development if 3 criteria are met:

• The chosen reference has been approved in an ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) compliant jurisdiction, to ensure comparability.
• The formulation of the chosen reference has the same pharmaceutical form, administration route, and content of the active pharmaceutical ingredient.
• There is substantial evidence that the chosen reference and the local reference product has been developed in their respective jurisdictions on the basis of the same original data.

In addition, a literature review she coauthored, looking at 14,255 patients, found no issues in switching from a biologic to a biosimilar.