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Opinion: How to Get FDA Clinical Efficacy Testing Waivers for Biosimilars


Clinical efficacy studies are not always required for biosimilars, and it's possible to resist if the FDA does ask for them. Sarfaraz K. Niazi, PhD, suggests a game plan.

My analysis of all biosimilars licensed by the FDA and EMA shows a common trend: Except in a few instances, all products were tested for clinical efficacy and safety; none of the tests failed, and where results were borderline, the FDA allowed adjustment of acceptance criteria to make approval possible. No product was tested in more than 1 indication, despite the allowance of all indications by the FDA and European Medicines Agency (EMA).

If you are one of the big pharma companies dabbling in biosimilars, you would prefer to conduct these studies because you are used to meeting with prescribers with published clinical studies in hand. Other companies, not as well grounded in the value of clinical studies, performed them because they kept thinking of biosimilars as new biologics and had great uncertainty in their abilities. This article is not for those who are fixed in their belief that clinical efficacy testing is needed. Here are a few points of advice for biosimilar developers. First, I continue to assert that big pharma will soon walk out of the biosimilars field; after my first prediction, I got a lot of wrath from big pharma, although several pulled out within a few months.

The Generics Experience Is Prologue

One should learn from history: The same things occurred when generic laws came into effect. First, big pharma predicted that use of generics would lead to the demise of millions of patients because only big pharma knows how to make safe products. That campaign was not successful, so they joined the party and began offering generic versions of their products (some still do). But when the bottom fell out with 70% to 90% price reductions, most big pharma companies went back to doing what they best, creating new products. The same will happen to biosimilars, once the price bottom falls.

It may be a surprise to some that clinical efficacy testing for biosimilars is not always a requirement for approval. When I reviewed all licensed products, I inquired why the FDA required these studies; to my surprise, the answer was that the developers offered these studies as part of establishing biosimilarity. If you provide the FDA or EMA with an extensive plan to test clinical efficacy and safety, the agency cannot say no. What if they discouraged these studies and there were safety issues?

The most glaring example of redundant efficacy testing was the approval of Retacrit (epoetin alfa) by Hospira, which conducted efficacy testing in 1000 individuals for its European submission. When Hospira applied for FDA approval using the same EU data, the application was rejected and the FDA required a stepwise approach which involves analytical characterization of the proposed biosimilar, then animal studies, possibly, and then comparative clinical studies. Instead of examining the extensive clinical efficacy proof, the FDA did not require any efficacy testing and accepted the EU study only as an ancillary study. The FDA and EMA are also not requiring clinical efficacy testing for products such as teriparatide, insulins, low-molecular-weight heparins, filgrastim, pegfilgrastim, and other cytokines with pharmacodynamic markers. Some products would not even need safety assessments, such as teriparatide, low-molecular-weight heparin, and insulins.

Here is how biosimilar developers should challenge the FDA if asked to do clinical efficacy testing:

  • Force the FDA to explain, in writing, where they see any “residual uncertainty,” a prerequisite before the agency will ask for “additional clinical testing.”
  • If the agency insists, counter that this study need not be in patients, as the Biologics Price Competition and Innovation Act does not require patient testing.
  • Suppose there are safety issues (such as variability in the posttranslation modifications). Developers could offer to conduct a limited safety study in healthy subjects.
  • If there is still no concurrence, then it could be argued that conducting efficacy testing in 1 indication (which is currently required and practiced) does not assure efficacy and safety assurance in other indications; therefore, the testing would be limited and wasteful.
  • A final argument should be to agree to a postmarketing study in an open protocol for a limited time.

In my recent interactions with both the FDA and EMA, there is an openness to receive creative approaches to establishing biosimilarity. We have more than 15 years of experience in seeing the approval of over 100 biosimilar products.

The reason I am insistent on helping biosimilar developers simplify the qualification process is that, so far, the approval of biosimilars has been disappointing; first, markets for biologic drugs are still very much controlled by big pharma; and second, this is keeping smaller companies from entering the field. The reason I am so confident is that I know exactly what it costs to manufacture biological products. Biosimilar antibodies should not cost more than $150/g to manufacture in Western countries. But, not surprisingly, the cost to patients is still about 100-fold; this must come down if the promise of biosimilars will be realized.

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