A Shift in Regulatory Thinking – Are Confirmatory Phase III Studies Redundant for Biosimilars?

24 Sep 18

A Shift in Regulatory Thinking – Are Confirmatory Phase III Studies Redundant for Biosimilars?

In recent years biosimilar regulatory requirements across the world have converged and a broadly accepted path has emerged. This path begins with applicants developing a comprehensive physicochemical data package, followed by a demonstration of biosimilarity through a PK/PD Phase I clinical trial, generally in healthy volunteers, and finally completing a confirmatory Phase III trial comparing safety and efficacy in a sensitive population.

But this stepwise approach, including expensive confirmatory Phase III studies, is being challenged.

Drivers of change

Biologic drugs are prohibitively expensive. The ultimate goal of biosimilars is to stimulate a competitive biologic drug marketplace that allows for significant cost savings. Such a market will result in a greater number of patients receiving appropriate levels of care and healthcare systems financially benefitting. Biosimilar savings in the U.S. alone are estimated at over $50 billion throughout the next decade.

Currently, a major barrier to entry obstructing biosimilar development is the need for confirmatory Phase III clinical trials. With global Phase III trials typically enrolling over 500 patients, they add significant time and cost to a biosimilar’s path to market, typically over $30m and two years to complete. The result is less competition due to fewer companies developing biosimilars, and for those that do bring a biosimilar to market, Phase III development must be costed into the drug’s selling price.

In the 12 years since the first biosimilar was approved in Europe, we’ve witnessed many biosimilars being used in the patient setting. As reported by Webster from BioApprovals (Aug 2018), there is yet to be a single case wherein a biosimilar was demonstrated to be highly similar to a reference product in terms of analytical and human PK studies, yet failed to demonstrate clinical equivalence in powered efficacy studies.

Will there be a shift? Scientific evidence

A recent publication in BioDrugs from Frapaise (June 2018) has sparked dialogue across the biosimilar industry on the relevance of these confirmatory Phase III clinical trials. Among several issues raised in the paper, Frapaise concludes that a streamlined approach to biosimilar development based on more comprehensive CMC packages and meaningful Phase I trials leaves “limited uncertainty on biosimilarity, which can be addressed – if needed – by post-approval, long-term follow-up studies”.

The paper also discusses limitations of recent confirmatory Phase III designs. Namely, the fact that they are not powered to detect significant differences between safety and efficacy profiles of the biosimilar and reference product. Frapaise comments that “many phase 3 biosimilar trials have enrolled 500-800 patients, and none of them have detected significant differences in efficacy parameters”.

In a follow-up letter to the editor from Webster and Woollett (August 2018), the pair support the conclusion drawn by Frapaise and add that a major reason to discontinue powered Phase III studies “is that they lack scientific validity because their outcome with regard to biosimilarity is not in doubt”. Therefore, in the absence of scientific validity, it is argued there is no ethical validity to conduct these trials. In another follow-up on the topic with The Center for Biosimilars, Woollett describes how Phase 3 studies are often conducted more so for marketing purposes rather than biosimilarity demonstration.

In an August interview with The Center for Biosimilars, Sandoz head of clinical development and medical affairs, Carlos Sattler, shared his perspective on the biosimilar development pathway. A key point made by Sattler was that Phase III trials for biosimilars have the objective of addressing any residual uncertainties regarding the biosimilar candidate, rather than demonstrating the safety and efficacy of the biosimilar itself. The potential to waive confirmatory Phase III trials was touched on in the interview, with Sattler stating that in the presence of suitable analytical data, “the FDA may only require a PK/PD demonstration”.

What are the regulators saying?

In the last 6 to 12 months, there has been consistent commentary from the U.S. FDA on efforts to stimulate a greater uptake of biosimilars in the U.S. In a speech by Scott Gottlieb in March, the FDA Commissioner stated that incorporating state of the art analytical techniques into biosimilar development “can support the conduct of smaller, targeted trials, and bring more biosimilars to market in a much more cost-effective and timely manner.”

The July FDA Biosimilar Action Plan was another encouraging sign for the possibility of streamlined biosimilar development. Among a variety of actions being undertaken by FDA, they “are modernizing regulatory policies to accommodate new scientific tools that can better enable comparison between biosimilars and reference products that may reduce the need for clinical studies.” Many specific details of this plan remain unknown; however we know that the FDA have been willing to accept biosimilar applications that have not incorporated Phase III trial designs (Adello Biologics – filgrastim biosimilar submission as reported by Biosimilars Review & Report).

What does this mean for biosimilar developers like NeuClone?

The requirement for Phase III confirmatory studies is the biggest barrier to entry for biosimilar companies like NeuClone. NeuClone has a deep pipeline of over 20 quality biosimilars as well as the ability to offer global supply – but financing and executing confirmatory Phase III trials remains the bottleneck.

Waiving confirmatory Phase III trials would signal a dramatic shift in the current biosimilar landscape. As it stands, 14 monoclonal antibody biosimilars have been approved in Europe (as of August 2018) and each of these has conducted at least one Phase III trial in patient populations. Biosimilars of less complex biologics (enoxaparin sodium and teriparatide) have been approved in Europe without conducting Phase III studies as reported by Mielke et al. (2018), however as this publication states, the “amount of information that is necessary to convince regulators clearly depends on the complexity of the molecule”.


We cannot predict the likelihood, extent or timing of regulatory reform regarding biosimilar development requirements. However, the progressive dialogue on streamlining the development pathway is encouraging. We look forward to further discussions that expands on the above dialogue and hope that the implementation of a more efficient clinical pathway for biosimilars is a matter of when, not if.