How Early Should Patients be Enrolled in Clinical Trials of an Investigational Substance

Traditional early clinical development programs have utilized normal healthy volunteers of both sexes in an escalating single-dose trial. These trials are often use small samples (6 to 12 volunteers including placebo per treatment arm) and may not provide a reflection of how the biopharma candidate will affect the targeted clinical population. However, the trials in this population do provide some value in giving an estimate of how well the test substance is tolerated without any significant safety problem.

An alternative approach would be to utilize otherwise healthy individuals with a diagnosis of the targeted indication in safety & tolerability multiple dose trials (Phase Ib). A patient population would give a firm profile of the pharmacokinetic behavior of the biopharma investigational agent.

Additionally, utilizing patients provides insight into adverse events that might be experienced in PHASE II efficacy trials. In the controlled setting of Phase Ib multiple-dose trial in the targeted patients, the investigator could evaluate if any adverse event that occurred in patients could be medically managed by adjusting or skipping a dose. The duration of the daily exposure in this type of trial might be planned to support the anticipated exposure of the patient for treatment of the targeted indication. Patients would be free to make choices of continued participation base on their own judgments regarding risk and possible benefit. This approach to a clinical trial should be under the mantra that safety is of paramount importance.

Another potential advantage of utilizing patients is to evaluate pilot assessments of potential endpoints to access efficacy/treatment effect. The goal of these assessments would not be to obtain a p-value of any observed difference but to model the observed treatment effects to project the likelihood of the response that could be detected in a Phase II trial.

The use of patients in early clinical development is not without risks. The conduct of these trials must be in highly qualified sites/locations with substantive medical coverage, access to the desired patient population as well as a system to keep the patients who participated aware of the progress of the drug under development.