Inspection of ‘first in human’ clinical trials
Clinical trials of medicinal products given to humans for the first time (first in human - FIH) must, as any other clinical trials, be approved by the Danish Medicines Agency before initiation. The Danish Medicines Agency reviews and assesses all FIH clinical trials, including all trial sites, with a view to determining whether to inspect the trial before the first trial participant is included. There will be FIH trials where we assess that there is no need for an inspection, either because we know the trial site from previous inspections, or because the investigational drug has a very low risk profile. This is assessed on a trial by trial basis.
The inspection takes place when the trial site is ready, i.e. after the initiation visit and after any unresolved issues related to the initiation visit have been clarified. The principal investigator must inform the Danish Medicines Agency approximately 4 weeks before the expected first patient first visit (FPFV) so that the Danish Medicines Agency has time to plan, notify and carry out an inspection, if any.
Focus on the safety aspects of inspection of FIH clinical trials:
The main purpose of the early inspection is to make sure that the required safety aspects are in place before the first trial participant is treated with the new active substance. This means that the inspection focuses on:
- the physical surroundings and available facilities
- staff competencies and organisation
- agreements with other departments, e.g. intensive care units
- how it is ensured that patients are administered the medication correctly, e.g. staggered dosing, dosage levels
- safety procedures, e.g. committees.
Agreement with an intensive care unit
The physician responsible for a clinical trial (principal investigator) must make an agreement in writing with an intensive care unit before an FIH clinical trial is initiated. This should ensure that acute emergency staff is available in case of serious adverse reactions or events related to the treatment.
The agreement must include information on the investigational medicinal product, the trial design (plus inclusion rate) and the date of expected start-up and completion of the clinical trial.
The intensive care unit must declare that it accepts that the clinical trial is carried out, and that it will inform the principal investigator if the intensive care unit predicts capacity problems so that the trial treatment can potentially be cancelled or postponed.
The agreement must specify that the principal investigator must inform the intensive care unit if any essential new knowledge emerges concerning the safety of the investigational medicinal product, or if any changes are made concerning the trial design or the duration of the clinical trial.
Resuscitation equipment:
Trial subjects participating in FIH clinical trials are estimated to be at special risk of serious adverse reactions/incidents, including the risk of cardiac arrest. The principal investigator must therefore ensure easy access to the necessary emergency equipment. EMA's guideline concerning FIH clinical trials (1) states as follows: 'Units should have immediate access to equipment and staff for resuscitating and stabilising individuals in an acute emergency.'
In the assessment of the Danish Medicines Agency, ‘immediate access’ means that resuscitation equipment, including defibrillators, should be available for multiple adjacent treatment or observation rooms if the equipment is placed in the immediate vicinity of the treatment site, and that staff trained in the use of resuscitation equipment must be present during treatment of trial subjects.
(1): Link to 'EMA's guideline on FIH trials'