Much of the discussion around biosimilars recently, including at the DIA Biosimilars conference held last week, involved the necessity of phase 3 trials. More precisely, this published and on-line activity addressed how best to streamline the biosimilar development process.
The discussion has been ongoing for several years now, as not all biosimilar 351(k) applications have been required to include phase 3 trial data (e.g., Udenyca® and Nivestym®). The Food and Drug Administration has deemphasized the importance of clinical trial data overall relative to the analytic and pharmacokinetic similarity findings. The FDA is actively evaluating pharmacodynamic studies to determine their potential role in streamlining biosimilar development.
Overall, this makes a good deal of sense. We reported in 2018 on the question of using phase 3 biosimilar clinical trials to prove noninferiority to the reference product. Testing the safety of switching between biosimilars and their respective originator biologics have not revealed any important differences to date.
In 2015, Deloitte reported that biosimilar developers will have to pay between $100 million and $200 million to reach the market. In 2020, adjusted for inflation, that amount would be $130 million to $260 million. Streamlining the approval process would then save manufacturers both time and money, potentially allowing them to be brought to market sooner (and attracting more development activity).
With these intensified discussions ongoing, it was helpful to read the results of a new study published in JAMA Internal Medicine October 5th. The researchers, from George Washington University and the Johns Hopkins School of Public Health and its health system, amassed information on 24 phase 3 biosimilar studies for products approved by the FDA through October 2019.
The investigators revealed that each biosimilar phase 3 clinical trial enrolled a median of 538 participants (interquartile range, 372–644 patients). The median cost of each biosimilar phase 3 trial was $27.6 million ($18.0 million–$36.7 million). The trials lasted a median 55 weeks (46–78 wk). Frankly, these data pointed out further what I really didn’t know. I was under the impression that the phase 3 clinical trial would be far costlier. Based on the median amount, a biosimilar phase 3 clinical trial is around 13% of the $200 million development cost (28% if the development cost is $100 million). The high end of the range is closer to what I had imagined.
Time Versus Money for a Biosimilar Phase 3 Clinical Trial
However, large clinical trials cost more than money. They cost time. It may take a median 52 weeks to follow-up patient outcomes for a trial, but it takes longer to design it, obtain approvals (institutional and FDA), recruit patients from contracted providers, analyze the resulting data, and publish the results. If drug development time could be shortened by two years, that could make more of an impression on prospective biosimilar makers. Of course, this assumes that patent litigation would delay launch two years (or well beyond).
With the experience of 28 biosimilar approvals in hand as of October 13, it seems reasonable that testing the theory of nonsuperiority of the biosimilar to the reference agent is not a worthwhile investment in time or cost.
Streamlining the clinical trial process always comes with a risk—the risk that for some reason one biosimilar will be found to offer significantly less efficacy and/or safety than the reference drug. It does seem though that FDA and the international community is willing at this point to consider that risk small enough based on current approval requirements, particularly for biosimilars not seeking an interchangeable designation.