A clinical trial protocol is a detailed description of a planned trial. It should concisely state what will be done in the study, and how, and provide justification for the study design.
International guidelines such ICH E6 (R2) detail the sections that should be included in a clinical trial protocol. ICH E6 (R2) guidance provides a unified standard for the European Union, Japan and the USA to ensure mutual acceptance of clinical data by the regulatory authorities in these regions. The European Medicines Agency (EMA) also has a guidance that outlines specific requirements for FIH studies to ensure subject safety.
ICH E6 (R2) guidance includes a list of the essential documents required before, during and after completion of a trial. Essential documents are needed so that the conduct of a trial, and the quality of the data produced, can be evaluated. They demonstrate the compliance of the investigator, sponsor and monitor with Good Clinical Practice (GCP) standards and all applicable regulatory requirements.
A clinical trial protocol is typically based on a trial synopsis, which is an initial summary of a planned trial. A protocol generally goes through several rounds of review, with input from clinicians, statisticians and clinical trial design specialists. The protocol forms the central part of the documentation submitted for clinical trial authorization.
Defining a regimen for a phase 1 trial
A FIH study may be either a single ascending dose (SAD) study or a combined SAD and multiple ascending dose (MAD) study, depending on the anticipated dosing strategy.
Combining the SAD and MAD in one study decreases overall costs and timeframes. The SAD study is conducted first and is followed by the MAD study if safety and tolerability data are acceptable. A protocol may allow for a MAD study to begin before a SAD study is completed, if supported by the data generated in early SAD cohorts.
Both SAD and MAD studies should include several cohorts exposed to increasing doses of drug. The number of cohorts included should be based on the need to determine safety and tolerability of the drug, and to establish a therapeutic margin, the dose range across which a drug shows efficacy without causing major side effects, without exposing large numbers of subjects to a new drug unnecessarily.
The starting dose in the SAD part of a study is calculated based on the highest drug concentration that has been shown to have no harmful impact in preclinical toxicology studies (the no observed adverse effect level, NOAEL).
The maximum dose is also guided by the NOAEL. In general, dosing in an FIH study should target doses/exposures that do not exceed the NOAEL. However, if no adverse safety or tolerability effects are evident as the NOAEL is reached, the study may continue to escalate doses to achieve exposures higher than the NOAEL.
Safety and tolerability data from each cohort is used to inform the decision whether to move to a higher dose. The study protocol must specify procedures for dose escalation and stopping rules.