No cancer trial uses a placebo including phase III. That is considered unethical to deprive a patient of a treatment. All phase III trials unless it is a new class of drug uses the current standard of care as the control arm for comparison to the test arm.

Phase II trials are limited in the number of patients enrolled. That cohort has higher eligibility requirements of being much healthier. The eligibility requirements for phase III are more reflective of the real world. The cohort consists of over a thousand patients whereas a phase II trial may range from 25-125 patients. Patients ina phase III trial can have an ECOG physical assessment score of II or III whereas in Phase I, the score needs to be better at 0 or 1.

With a much higher number of participants, the statistical data between control and test group becomes more accurate. A good example of a recent trial that looked very promising was CPI-613 (Devimistat) from Raphael Pharmaceutical. The limited data from the phase II trial was extremely encouraging. But one needs to keep in mind the test cohort included only the healthiest patients with an ECOG PS score of 0 or 1. The investigational new drug generated a lot of excitement and quickly moved to phase III with a very large cohort now including those with ECOG PS of 2-3. Raphael Pharmaceutical began planning for FDA approval and hiring personnel and arranging for increased production of Devimistat. When the team of biostatisticians did the statistical analysis between control and test groups, the trial fell apart. There was no significant statistical difference between the control and test participants.

How could this be? It goes back to using a small, limited cohort size of participants that were relatively healthy (ECOG 0 or 1). The phase III trial was more representative of real-work, conditions-it included patients whose cancer had spread further and the impact to their physical health was much more significant resulting in the higher ECOG PS of 2 and 3.

Another recent clinical trial,drug this happened to was SM-88 (Racemetyrosine) by Tyme Pharmaceutical. The same thing happened where the drug looked great in a small, healthier cohort with limited data. Once the trial was expanded to be more reflective of real-world conditions, it failed the end-point objectives stated by the study team/trial sponsor as not showing equal or better performance than an existing treatment- (overall response rate and progression free survival are frequent metrics used to gauge treatment effectiveness).