The Sentinel Subject

Sentinel: A soldier or guard whose job is to stand and keep watch.

In a first-in-human, healthy volunteer study of a new investigational drug, a single subject will routinely receive investigational drug 24 hours prior to the remaining subjects in a dose group. These subjects are known as sentinels. The dose level of the new investigational drug that the sentinels receive is selected based on review of the extensive nonclinical research in animals and is deemed to be well below the expected therapeutic dose.

The intention of the sentinel is to identify any unpredicted serious safety issues in a single subject prior to exposing a larger group of subjects. Once the investigational drug is deemed to be safe based on review of selected safety assessments in the sentinel, the remaining subjects will be dosed at either the same or escalating doses.

Regulatory Guidelines for Use of Sentinels

The European Medicines Agency (EMA)/Committee for Medicinal Products for Human Use (CHPM) have developed a ‘Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products’ (latest version July 2017). These guidelines specify that it is considered appropriate to design the administration of the first dose in any cohort so that a single subject receives a single dose of the active investigational medicinal product. Flexibility in this approach is allowed but should be on a risk-proportionate basis with a clear scientific rationale for any proposals not to use this strategy (EMEA/CHMP/SWP/28367/07 Rev. 1).

In Australia, the Therapeutic Goods Administration Australian Clinical Trial Handbook directs ethics committees, trial sponsors and manufacturers conducting early phase trials to adopt these EMA/CHMP Guidelines.

How is the Sentinel Selected?

Subjects are always informed if they are required to be the sentinel. The details of what it means to be a sentinel subject should always be clearly presented in the patient information sheet and further discussed by the investigator or delegate once eligibility has been confirmed.

The selection of the sentinel is based on the order to which subjects are enrolled in the study and the study design:

  • For an open label study, the first enrolled subject will become the sentinel of the dose group;
  • For a randomized, placebo-controlled study, the first 2 enrolled subjects will become the sentinels; 1 will receive placebo and the other the new investigational drug. This assignment will be based on a unique randomization sequence and the chronological order of enrolment.

Declining Selection as Sentinel Subject?

Sentinel subjects receive no additional reimbursement for being the first human to receive a new investigational drug as it is considered unethical to pay study subjects for increased risk.

All eligible subjects have the right to decline taking part in the study as a sentinel and can opt to be dosed after the sentinel with the remaining subjects in a dose group.

Admiration for the Brave Volunteers

All healthy volunteers who consent to play a role in the clinical investigation of a new investigational drug are to be admired, especially those who perform as sentinels. These brave volunteers take a leap of faith, trusting in the security net comprised of a robust regulatory framework, a carefully selected starting dose (based on preclinical testing), appropriate facilities and highly trained staff at the Phase 1 unit, and the ethics committee reviewing the study documentation. In doing so, they play a critical role in ensuring that new drugs are safely introduced to the wider community in the future. Without these volunteers, the emergence of new and potentially life-saving investigational drugs would not be possible.

Would you put your hand up to be the first human to receive a new investigational drug?

Written by Mary Cardone, Director of Delve Medical Writing