While less resource-intensive than pivotal trials, early phase trials often involve significant scientific uncertainty. Information on a therapy’s side effects, behaviour in the human body and early efficacy data gathered in phase 1 trials directly influence the design of subsequent studies and set the stage for the entire drug development and approval process.
In an ICON survey of 149 biotech professionals, 45% of survey respondents identified protocol design as one the most significant challenges faced when transitioning from preclinical to clinical testing. Here, we discuss considerations for several key elements of protocol development in early phase trials, including selection of healthy volunteers (HVs) or patients, trial design and endpoint selection.
Selection of HVs or Patients to get to the Next Decision Point
Typically, phase 1 trials establish a drug’s short-term safety and dose range and are conducted on very small cohorts of either HV’s or the target patient population. Deciding which population to enrol is one of the biggest decision points in early-stage protocol design, and can have significant impacts on the future development of the investigational therapy.
HVs are the standard choice for early-stage trials and are especially invaluable for therapies that may have applications in multiple indications. HVs are often easier to identify and enrol in clinical trials than target patient populations, reducing start-up time and costs. In addition, enrolling HVs allows for investigation of a drug’s pharmacology in the absence of disease and broadens the generalisability of early-stage safety and dosing data across patient populations.
Meanwhile, patient enrolment in early phases (if following HVs being labelled as phase 1b) is the norm when therapies are intended for life-threatening conditions without other treatment options, such as late-stage cancer, or for therapies liable to have serious adverse effects. Sponsors may also enrol patients in early phase trials if initial data on how a treatment impacts disease (e.g., with the help of biomarkers see ‘Endpoint Selection’) can accelerate later stage trials, saving time and money. Early phase patient data may be especially useful for treatments that are expected to have non-linear dose-responses, and for targeted therapies.
Healthy populations should not be enrolled in phase 1 studies if there is undue safety risk without counterbalancing treatment benefits. For many modalities, the FDA provides guidance on whether a treatment modality is too risky to enrol HVs. In the US, the FDA indicates that early-stage gene therapy trials are too risky for healthy populations. Meanwhile, bispecific antibody trials may enrol HVs as long as the evaluated potential for immunogenicity and toxicity is sufficiently low.
Because there is often invaluable, non-interchangeable early stage data from healthy or patient populations, it is increasingly common to enrol both groups using an integrated early trial. (Phase 1a/b) These tend to start with HVs and enrol a limited number of patients at an appropriate dose level. However, an integrated early trial does not escape the respective disadvantages of either approach, and so a decision to proceed with this enrolment strategy should also be carefully weighed.
