first-in-human healthy volunteer trials – SAD & MAD

HMR specialises in first-in-human (FIH) trials. Currently, about 1 in 3 of our trials is the very first administration of an investigational medicinal product (IMP) to humans. On average, we complete about 8–10 FIH each year, many of which are adaptive or ‘umbrella’ protocols that include single ascending dose (SAD) and multiple ascending dose (MAD) parts, and some or all of the following: food effect; older people; Japanese healthy volunteers; bioavailability; absorption, distribution, metabolism, and excretion (ADME); and patient cohorts. Our FIH experience includes many biological, biosimilar & ‘bio-better’ products, usually by intramuscular (IM), subcutaneous (SC), and intravenous (IV) injection. We can easily accommodate the wide variety of pharmacokinetic and pharmacodynamic analyses that a new IMP requires in early phase trials.

All trials at HMR are overseen by Dr Malcolm Boyce (Managing and Clinical Director), and benefit from the advice and support of Dr Steve Warrington (Chief Medical Adviser). Dr Boyce has over 40 years’ experience in clinical pharmacology ,and has been principal investigator or co‑investigator in over 800 phase 1 and early phase 2 trials. He is a fellow of the Faculty of Pharmaceutical Medicine, the Royal College of Physicians and the British Pharmacological Society, and an Honorary Senior Lecturer in Clinical Pharmacology at St Bartholomew’s Hospital Medical College.

The principal investigator (PI) is legally responsible for the clinical conduct of the trial, and oversees the entire process. Each PI holds, with the General Medical Council of Great Britain, full registration and a licence to practise, and is a member of the Medical Defence Union or equivalent. Our PIs for FIH trials have the Diploma in Human Pharmacology, or equivalent qualifications or experience.

Trials are also allocated to a dedicated project team: Clinical Project Manager (CPM), Research Physician (RP), ward team (10–12 nurses and technicians), and representatives from recruitment and screening, quality, pharmacy, laboratory, data management, statistics, and medical writing.

We have robust processes for progression from one dose level to the next. We know, from long experience, how important it is to have dose escalation and stopping criteria flexible enough to allow adaptive responses to emerging trial data, while ensuring the safety of trial subjects. Clearly explained, transparent rules are essential – they help to minimise queries from the MHRA and ethics committee, shorten approval times, and optimise trial progress by reducing or eliminating the need for substantial amendments.  Here are some of the most crucial components of an FIH protocol.

  • Clearly explained rationale for the starting dose
  • Limits on maximum dose (eg maximum exposure)
  • Dose escalation plan that gives flexibility to test lower doses, retest a dose, or change the dosing regimen
  • Clearly defined dose escalation rules, including:
    • description of procedure for review of data
    • minimum dataset for escalation  – minimum number of subjects, and type and amount of data eg safety data up to 72 h, pharmacokinetic data up to 24 h
    • dose escalation stopping criteria
  • Clear trial stopping criteria, MHRA recommendations

The MHRA has complimented us on our procedures for deciding, documenting, and releasing doses in escalating and multipart trials. We review our processes regularly to ensure that they comply with MHRA recommendations and European Medicines Agency (EMA) guidance on mitigating risk in first-in-human trials.

We offer flexible trial scheduling to ensure timelines are met: we have enough beds to accommodate last-minute re-scheduling. We never make unrealistic promises, nor do we ‘overbook’ beds. We have a longstanding reputation for the timely delivery of a high-quality service.