BioRationality: FDA Launches a New Opportunity to Remove Redundant Trials of Biosimilars

On October 16, 2023, the FDA announced a plan entitled “Enhancing Adoption of Innovative Clinical Trial Approaches,” which will lead up to a March 2024 conference to conclude the future steps in making clinical trials more effective and useful, emphasizing regulatory and compliance considerations, patient-centricity and trial infrastructure and organization culture in addition to the adoption of digital health technologies (DHT).

The FDA acknowledged more than a decade ago that the present clinical trial system needs changes and has suggested several novel approaches to design clinical trials, including risk-based and proportionate measures throughout a clinical trial's lifecycle (data collecting, monitoring, and quality management).^1,2 This method encourages scientists to prioritize participant safety and data integrity in data and clinical trial processes. It further helps investigators to focus on gathering and evaluating essential trial data and encourages sponsors to be proactive about trial quality. Quality considerations include trial features that protect participants, ensure trial findings, and inform decision-making.

Early attention to these aspects helps design trials efficiently, reducing delays from excessive complexity and burdens. Since the FDA has opened a portal to receive stakeholders' comments and specific suggestions to reduce redundant testing that can reduce the cost of development of drugs, particularly biologics, I am submitting a detailed document describing why the FDA should take decisive action—albeit within the limits of the regulations—to state that clinical efficacy testing is not necessary. This statement is needed to encourage developers with fewer resources to enter the field by removing their fear of ending up with a cost of hundreds of millions of dollars. Given below are my arguments that the stakeholders can use, along with their own, to submit as many comments as possible to the FDA portal:

• A comparative clinical study (CCS) must select an acceptable difference (equivalence margin) for study size calculation; this range is always arbitrarily selected since no data is available for biologic products to establish a correlation between the response and efficacy. It is labeled as “clinical judgment.”
• The study size is calculated based on the FDA-recommended power of 80% and false positive of no more than 5%. The actual difference determines the study size since the difference is minute after demonstrating similarity in analytical assessment and clinical pharmacology profiling. A recent study shows that if the significance level of actual proportions is set at 0.28 and 0.33, then more than 26,000 subjects will be required to demonstrate a difference, with an equivalence margin of 0.06. Notably, such a challenge in designing clinical trials has never been faced before. A good analogy is to divide the same batch of a product into 2 parts and subsequently determine whether a difference exists between the 2 products. The inherent inter- and intra-subject variability in the testing of biologic drugs, including those used in cancer treatment, further complicates the uncertainty of study power. In such cases, listing naïve patients is impossible, many of whom do not survive throughout the study course.
• Bayes' theorem can be employed to assess the precision of clinical efficacy testing outcomes by evaluating the probability of a particular study being accurate. Prior probability refers to the probability of an event occurring before acquiring fresh evidence. In essence, it denotes the optimal logical evaluation of the likelihood of a specific result, considering existing knowledge before the execution of an experiment. The posterior probability refers to the updated probability of an event taking place following the incorporation of additional information. Calculating the posterior probability involves updating the prior probability using Bayes' theorem. The Bayes theorem of conditional probability can be restated as Posterior = Likelihood x Prior /Evidence. The study design defines the likelihood and evidence required by the FDA, leaving the posterior probability dependent on prior probability or how often such studies have failed. Simply, clinical efficacy testing cannot fail, and whenever they have, the products are still approved, blaming the results on the study design.

Several studies have supported the arguments presented above, including a meta-analysis of studies in more than 12,000 patients; the fact that the European Medicines Agency (EMA) or FDA have never requested withdrawal or recall of any biosimilar, none of the over 200 trials for which results are reported showed any difference in comparative efficacy.³ PubMed database lists over 1,200 publications reporting CCS for biosimilars and none noting clinically meaningful differences. Of most tremendous significance is a recent preprint article by former EMA associates summarizing 33 monoclonal antibodies and 3 fusion proteins filings from July 2012 to November 2022 and suggested that analytical, functional, and pharmacokinetic test, including immunogenicity data, is sufficient to establish biosimilarity.

In summary, the CCSs are redundant, which should be made a strong point in the suggestions made to the FDA. An example of how the CCSs are approved is given by the Medicines and Healthcare Regulatory Agency (MHRA) of the United Kingdom, which had updated its biosimilar guideline to state:

“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. Therefore, a well-argued justification for the absence of an efficacy trial should be appended to CTD Module 1 of the submitted application.”

I recommend that the FDA concur with MHRA and harmonize the biosimilar approval guidelines. It is time for the stakeholders to make their voices heard.

Reference

1. Cohen D. FDA official: "clinical trial system is broken". BMJ. 2013;347:f6980. doi:10.1136/bmj.f6980

2. Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377(1):62-70. doi:10.1056/NEJMra1510062

3. Bloomfield D, D'Andrea E, Nagar S, Kesselheim A. Characteristics of clinical trials evaluating biosimilars in the treatment of cancer: a systematic review and meta-analysis. JAMA Oncol. 2022;8(4):537-545. doi:10.1001/jamaoncol.2021.7230