A New Approach to Clinical Trials Group 4: AACR / SSP Program

Traditional Randomized Controlled Trial NCI Definition of a randomized clinical trial: A study in which the participants are divided by chance into separate groups that compare different treatments or other interventions. Using chance to divide people into groups means that the groups will be similar and that the effects of the treatments they receive can be compared more fairly. At the time of the trial, it is not known which treatment is best. This has been the base model of how clinical trials have been most commonly done and can be seen as far back as 500 BC*

Identifying New Models for Cancer Clinical Trials There has been an explosion of new discovery in cancer with the introduction of targeted ‘smart-drugs’ and immunotherapy. RCTs remain an important model in research and has proven for hundreds of years to be an effective way of studying new therapies and medications. With the continued interest and need for clinical trial drugs to serve populations that might not fit in the parameters of an RTC Trial, new models are needed to make sure therapies can benefit a real world population who will be using these therapies once out of trials. Three examples of these new models of Clinical Trials Include: Adaptive trials Basket trials Umbrella trials

Adaptive Trials Adaptive trials evaluate treatments by observing participant and modifying parameters of the trial protocol based on the observations made. The adaptation process generally continues throughout the trial Modifications can be made to the dosage or demographics during the trial Examples in application: A new CAR-T cell construct demonstrates and acceptable safety profile and tenfold improvement in overall survival early in a phase on trial. Phase one could be ended early or dramatically expanded to benefit more patients in urgent need of the novel therapy. In both examples, the basic concept remains the same; Adaptive trials can dramatically accelerate the timeline for moving discovery from the lab to the patient when there is clearly a superior benefit to patient survival quality of life.

Basket and Umbrella Trials Basket Trials address the idea that multiple cancers may have similar targets regardless of where they originate in the body. Example: A colon cancer patient and a breast cancer patient may both have tumors that express the same targetable surface protein such as HER2. In that case, both tumors would go into the “basket” of HER2 positive tumors and therefore be eligible for a trial testing a HER2 specific therapy regardless of organ site. This approach could be helpful in getting a new drug to market more quickly and to more patients than traditional trials. Umbrella Trials start with the idea of classifying a tumor by organ site but then dividing that into sub-categories based on identifiable and targetable mutations in the tumor. This would allow a site to open a trial for metastatic breast cancer, test patients for specific mutations and then move patients into different arms of the trial with potentially different treatment regimens based on that tumor profiling. This approach may be favored in a scenario where a disease specific advocacy organization is funding the trial.

Patient Reported Outcomes The idea that cancer treatments shouldn’t just be measured by how the drug effects the cancer, but how the therapy may effect the patient’s quality of life is becoming a greater concern as the need for clinical trial participants increases The increasing focus on patient reported outcomes is an attempt to regain that focus on the patient There is great potential for PROs to improve both the results and the patient experience of the clinical trial. Some ways in which PROs can contribute to trial success and successful adoption of new therapies: Accurate reporting of subjective side effects could help establish patterns that differentiate between treatment related side effects and symptoms of underlying disease. Constant feedback from patients could be used in an adaptive trial model to improve enrollment and retention as improvements (supportive care, dosing mechanisms, objective data gathering issues) are incorporated into an active trial.

Challenge Question Trends Identified Inclusion criteria modification for clinical trials (Co-Morbidities) Trend of clinical trials (sometimes ‘evergreen’ phase one) becoming preferred frontline intervention rather than a last resort due to rapid improvements in precision medicine. Exponential pace of discovery creating under enrollment due to number of options of treatments directed to very small patient populations (rare cancers, specific markers, etc). Realization that pediatric cancers are biologically different from adult cancers and require separate trials a different regulatory approach to ensure access to therapies based on mutations. Pharma using European trials for preliminary drug approval (creates a population that does not reflect US genetic diversity) Post approval follow-up of studies of trials that were conducted with patient populations that do not resemble US demographics. Regulatory incentives for industry to develop therapies for rare or orphan diseases (pediatric vouchers) Potential for wearables / IOT devices to extend objective data set for performance evaluation prior to and during trial enrollment. Equity – the recognition that certain populations are underserved by drug discovery Concept of PRO to evaluate quality of life along with efficacy when determining whether to move a therapy forward. BIG DATA - ability to aggregate and mine data from prior and ongoing trials to search for missed insights.

Works Consulted https://www.cancer.gov/publications/dictionaries/cancer- terms/def/randomized-clinical-trial https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149409/