Carefully stepping away from RCTS: clinical trial design in a new medical era

On June 21 and 22, the New York Academy of Science held a Johnson & Johnson-sponsored conference discussing the future of the randomised controlled trial (RCT) approach for evaluating the efficacy of new drugs. Currently, RCTs are still seen as the best scientific standard when quantifying the efficacy of novel treatment options. Moreover, the FDA still considers RCTs as the main tool to demonstrate a benefit for the patients and thereby the regulatory organisation typically requires a novel drug to be tested in RCTs to receive market approval. However, new approaches in drug development and unique characteristics in individual diseases call for novel and creative approaches to be utilised. Importantly, most stakeholders, including the pharmaceutical industry, regulatory bodies, academia, and patient advocacy organisations, agree on the need to reform the current clinical trial systems and call for innovative and adaptive solutions, while ensuring a high scientific quality standard.

Throughout the conference, the fundamental importance of RCTs was acknowledged as a tool to determine drug efficacy objectively, as a randomised, blinded experiment. However, the classic RCT design also has many limitations, which can represent unsurmountable barriers for drug approval. Examples for these limitations include orphan diseases, in which not enough patients can be enrolled to allow for randomisation, or breakthrough therapies which can create significant ethical problems when patients are randomised to receive a placebo or standard of care with significantly inferior outcome expectations. Additional problems, which are often associated with RCT design but not necessarily limited to RCTs, include the high cost, discrepancy between patient profiles of enrolled patients relative to the diverse general population, and the over-usage and over interpretation of surrogate endpoints. Additional drawbacks include compliance issues arising after market approval, along with the duration of the actual trials, especially in progressive disease like oncology, where patients might have to wait months for treatment initiation after enrollment.

Consequently, the main stakeholders represented during the conference support an expansion of existing trial approaches, like platform trials, single arm trials—particularly for breakthrough therapies—and alternative approaches of the RCT design, including randomised withdrawal, or randomised switching between treatment and standard of care.

Another important aspect raised during the meeting was the need for patients to actively participate in the clinical trial design, which can promote retention during the trial, support the usage of drugs after launch, and, most importantly, test drugs for endpoints considered as desirable outcomes instead of abstract aspects without impact on the patient’s quality of life.

Combining the needs and wishes of all stakeholders will ultimately result in more diverse and creative approaches in clinical design to effectively address the stakeholder’s questions—though, at the end of the day, RCTs are expected to remain the main approach for most drugs.