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Are Phase 3 Studies for Biosimilars Unethical? Avalere's Gillian Woollett Weighs In


“This comes down to the assiduous care you must do for any clinical studies using human subjects…you don’t experiment on human beings unless you’re really going to learn something,” said Gillian R. Woollett, MA, DPhil, senior vice president of Avalere Health.

A recent paper in BioDrugs, authored by Francois-Xavier Frapaise, MD, PhD, argues that, given advances in analytical methods for understanding the structure—function relationship of biologic medicines, phase 3 trials for biosimilar drugs may no longer be necessary. In a comment, also appearing in BioDrugs, Christopher J. Webster of BioApprovals and Gillian R. Woollett, MA, DPhil, senior vice president of Avalere Health, cite what they call an even more significant reason to put an end to most phase 3 studies for biosimilars: because these studies' outcomes with respect to biosimilarity are not in question, they lack scientific—and therefore ethical—validity.

In an interview with The Center for Biosimilars®, Woollett further explained her point: “This comes down to the assiduous care you must do for any clinical studies using human subjects…you don’t experiment on human beings unless you’re really going to learn something,” and in the case of phase 3 confirmatory studies for biosimilars, there is no reasonable expectation that these studies will further scientific understanding or contribute any new information that can aid in the regulatory evaluation of the product.

To the question of whether clinical trials of this kind may be ethically defensible if they benefit patients by providing a therapy to individuals who might not otherwise have the chance to receive a biologic, Woollett said that access is a separate issue.

“While access may be great in a clinical trial, that really cannot overcome the fact that if you don’t have an outstanding question—if there’s no residual uncertainty as FDA would put it—you should actually be approving the product” at that point, she said.

Read more from Dr Woollett.

Given the high level of analytical similarity that it is possible to demonstrate using current tools, there is little likelihood that there would be any such outstanding questions. Woollett used a favorite metaphor to illustrate her point: “Back when I was a kid, my father would say, ‘If you’ve done everything right, the lawnmower has to start.’ If we moaned that the old gas lawnmower wouldn’t start, he would say ‘you haven’t done everything right.’” The same, she said, is true of biosimilars: “With the exquisite fidelity that we’re going for on these analytical matches, the molecule has no choice but to do the same thing” as its reference. That statement holds true, she explained, even for a product like rituximab, which has a different method of action in treating malignant and nonmalignant diseases.

In Woollett's view, phase 3 confirmatory studies are often conducted in biosimilars because drug makers believe that data from these studies will be useful in marketing the biosimilar to clinicians who might otherwise feel uncomfortable with using the product.

“This is where I think we have to collectively do a better job of explaining what biosimilarity is all about” to prescribers, said Woollett, rather than continue to undertake costly, time consuming “feel-good studies” merely “to humor the lack of understanding” among clinicians.

She pointed to the adalimumab biosimilar Amjevita, for which Amgen conducted 2 separate phase 3 studies (in rheumatoid arthritis and plaque psoriasis) when the FDA had only requested 1 such study. “If you do clinical studies for marketing purposes,” said Woollett, such an undertaking involves “…that same issue of scientific validity and ethics. It’s also costing out the competition” without producing a better product as a result. “Consistent, science-based regulation is the only fair way to approach this,” said Woollett.

In terms of better educating physicians about the analytical basis of biosimilarity, Woollett said that the FDA needs to make a greater effort to serve as the primary source for information about biosimilars by making, clear and explicit statements about biosimilars so that professional groups can use these statements to educate themselves and one another about the nature of biosimilarity.


Webster CJ, Woollett GR. Comment on “The end of phase 3 clinical trial in biosimilars development?” [published online August 16, 2018]. BioDrugs. link.springer.com/article/10.1007/s40259-018-0297-y. Accessed August 30, 2018.

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