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BioRationality—How to Promote Science to Secure Waiver of Comparative Efficacy Testing for Biosimilars


Sarfaraz K. Niazi, PhD, makes suggestions for what arguments will help convince the FDA to waive clinical efficacy testing requirements for biosimilar approvals.

A recent Biosimilars Council Position Paper presented arguments that“Comparative Efficacy Studies Are Usually Unnecessary” if analytical, functional, and pharmacokinetic methodologies are sufficient to detect clinically meaningful differences. The paper also suggested that the FDA require clinical efficacy testing “only when scientifically justified and unique risk-based considerations are identified considering, for example, the mechanism of action, the complexity of the product, or the delivery mechanism.”

clinical efficacy trial preparation | Image credit: Cavan - stock.adobe.com

Image credit: Cavan - stock.adobe.com

I have long explored this topic and published extensively on the scientific demerits of comparative efficacy testing that were missed in this position paper. Leaving room for deciding whether to conduct a comparable efficacy study will always lead to testing as an additional measure by every regulatory agency. The key reason why these studies are of little value is their statistical design flaws that will never be able to detect any difference. This thesis was recently confirmed in a paper in Nature magazine criticizing the comparative efficacy testing model even for new drug discovery, let alone when the comparator is already established as equivalent with more robust tests. The FDA has admitted that our current clinical trial system is broken.

The United Kingdom’s Medicines and Healthcare products Regulatory Agency has already concluded and stated that: “Although each biosimilar development needs to be evaluated on a case by case basis, it is considered that, in most cases, a comparative efficacy trial may not be necessary if sound scientific rationale supports this approach.” The European Medicines Agency has called for a position paper to adopt a similar policy, calling for comments by April 30. A reflection paper is anticipated soon.

The FDA has the authority to make the judgment without waiting for any changes to the Biologics Price Competition and Innovation Act, and the FDA has already done it for several products to waive comparative efficacy testing. Now, the onus of seeking this waiver lies with the developers. Still, unless the FDA makes a clear statement, developers will continue to consider this a requirement, keeping most small developers out of the market.

My suggestion to developer agencies such as the Biosimilar Council is to bring only scientific arguments and never mention that it increases the availability or affordability of biosimilars; the FDA has no reason to consider these as reasons. The position paper by the Biosimilars Council quoted historical data on the safety of biosimilars and the record of successful efficacy trials. I do not think that these arguments will convince any regulatory authority.

There is sufficient scientific knowledge that the Biosimilars Council should promote to turn the destiny of biosimilars, as it has already provided extensive teaching tools for all stakeholders that need not be regurgitated by the stakeholders. A simple understanding that in the end, only science will prevail, and nothing should be recommended that can even remotely risk the patients; with the strength of this argument, I anticipate the FDA to adopt the statement I have proposed: “Comparative efficacy testing is the least sensitive attribute and is not necessary to establish biosimilarity when analytical and clinical pharmacology profiling is comparable; it applies to all types of reference products.”

Let us all work together for rationality, not any type of hype. Biosimilars are supposed to save; they are supposed to increase access, but these are not the reasons that will impress the FDA. Being rational and pushing scientific merits will.

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