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Pink Sheet – Biosimilar Clinical Trials Face Enrollment Challenges

Pink Sheet – Biosimilar Clinical Trials Face Enrollment Challenges

Executive Summary

Education for investigators and patients about the biosimilar development process, including what’s already known about a product being studied, could help trial recruitment, FDA, industry and patient reps say.

Clinical trials comparing proposed biosimilars and their reference products present enrollment challenges that reflect a lack of understanding by clinicians and patients about the abbreviated development paradigm for biosimilars, stakeholders said at an Oct. 18 meeting.


“The biggest stumbling block we have is accruing patients to the clinical trials,” said Robert Rifkin, medical director for biosimilars and associate chair of the hematology research committee of McKesson Specialty Health’s The US Oncology Network.


The determination that a biosimilar clinical trial is safe to proceed takes into account the underlying analytical data on similarity, FDA’s Christl said.

During a panel discussion about biosimilar development, regulation and education at a meeting co-sponsored by Friends of Cancer Research and the Duke-Robert J Margolis Center for Health Policy, Rifkin talked about how patients and their families often have doubts and uncertainties about enrolling in a trial involving a biosimilar. He questioned how to get patients enrolled in trials for such products, which are not brand new molecules with all the “glitter and glitz and exciting promise.”


“I’d be interested to hear how FDA can help us do those trials, because it’s very difficult to explain to patients and physicians,” he said.


FDA, industry and patient advocate representatives suggested the answer lies in education, including what’s already known about a proposed biosimilar’s properties by the time the product reaches the comparative clinical trial stage.

Importance Of ‘Priors’

In the traditional development paradigm for new molecular entities and novel biologics, the emphasis is on demonstrating efficacy and safety in clinical trials. In contrast, the foundation for biosimilar development is the analytical characterizations of structural and functional similarity to the reference product, with clinical trials conducted to address any residual uncertainties.


The difference in development approaches has been a challenging concept for clinicians and patients to understand, as evidenced by FDA’s experience with its own advisory committees. (Also see “Biosimilar Advisory Committee Reviews: Necessity Or Nuisance?” – Pink Sheet, 20 Jul, 2016.)


In a biosimilar development program, products reaching the clinical comparative trial stage have “priors” in the form of extensive analytical characterization, evidence of pharmacokinetic similarity and, if relevant, pharmacodynamic similarity, said Leah Christl, associate director for therapeutic biologics at FDA’s Center for Drug Evaluation and Research.


Because of these priors, decisions to move forward with a clinical trial are often better informed, and based on more evidence, for biosimilars than with novel products, Christl suggested.


“There are some people who say – and I’m not going to attribute this to the agency – but there is some conversation that the concept of that ‘safe to proceed’ decision for a clinical trial is actually somewhat better informed for a biosimilar because of the priors,” she said. “You’re making this connect between the biosimilar product … and the reference product through this extensive information that underlies that.”

For example, the decision to move forward with a biosimilar clinical trial is informed by what’s known about the safety and efficacy of the reference product.


“With a new molecular entity a lot of times …you’re not really sure how it’s going to work,” she said. “You have some information about safety, but you have no information about efficacy. … You’re proving safety and effectiveness in that trial.”


“Here, you’re looking at whether there’s a clinically meaningful difference, but it’s underpinned by all of this information connecting the products from the similarity assessment that’s been generated to date.”

FDA uses that information in determining whether a biosimilar trial is safe to proceed, she said. The agency would not allow a trial to move forward “if they don’t think it’s going to be safe, if they don’t think the product is highly similar, if they don’t think that there’s going to be a similar safety and efficacy benefit to patients in that trial,” she said.

Education Starts With Investigators

Tailored educational efforts targeting clinical investigators can go a long way toward encouraging enrollment in biosimilar trials, said Carlos Sattler, vice president and head of clinical development and medical affairs at Sandoz Inc.


Sandoz’s Zarxio (filgrastim-sndz), which references Amgen Inc.’s Neupogen (filgrastim), was the first product approved under the 351(k) licensing pathway and is still the only biosimilar on the US market, although it will soon have some company. Pfizer Inc. has announced plans for a late-November launch of Celltrion Inc.’s Inflectra (infliximab-dyyb), a biosimilar to Janssen Biotech Inc.’s Remicade (infliximab). (Also see “Pfizer Sets Inflectra Launch Date; J&J Plans To Fight Back” – Scrip, 17 Oct, 2016.)


“Engaging with the principal investigator and the study staff and educating them very, very well and ensuring the understanding of biosimilarity … is incredibly useful,” Sandoz’s Sattler said.

“What we’ve learned actually based on experience overseeing trials globally as well as in the US is that engaging with the principal investigator and the study staff and educating them very, very well and ensuring the understanding of biosimilarity and the biosimilar concept, all the steps that go into developing this product prior to entering the clinic, is incredibly useful,” Sattler said.


If “you have a dedicated group of field scientists that engage with study sites, and one of their many goals is to educate about biosimilars, that makes it much easier for the study coordinator or the principal investigator to be able to explain the study to a potential patient and explain what the benefits and risks are … much more convincingly and with more confidence,” Sattler said.


Emily Alexander, senior director for biologics strategic development at AbbVie Inc., said educating investigators about the underlying analytical and preclinical data should aid enrollment.


“One of the interesting things is that in Europe we see physicians who have enormous interest in enrolling their patients in post-approval studies,” Alexander said. “I think there’s much more eagerness on that. So educating physicians about a lot of the assessment of the analytics and some of the other preclinical data that has actually already been done before the somewhat confirmatory clinical trials … I think that’s helpful for them to understand how far that product has already come in development.”


“Perhaps they can shift some of this eagerness from postmarket data collection into premarket data collection,” Alexander said.


Education, however, is not just for the investigators.


Kim Wright, a breast cancer survivor and Susan G Komen Advocate Scholar, suggested her willingness to participate in a biosimilar clinical trial would depend upon how well it was explained.


“Making the process as simple as possible and as attractive as possible, meaning there’s no downside to it,” Wright said. Patients should understand they would be “getting standard of care and equal to standard of care.”…