A Phase I first in human clinical trial on healthy volunteers, sponsored by Portuguese pharmaceutical company Bial, went horribly wrong in early January 2016, leaving one volunteer dead and five others hospitalised with organ failure and in some cases suspected brain damage. Bial was trialling the drug (BIA–102474–101) for a range of diseases including mood disorders, anxiety and as an analgesic and had engaged French contract research organisation BioTrial (the ‘CRO’) to manage the trial.
The trial, conducted at a single site in France at the private BioTrial Research Site (in Rennes), began on 9 July 2015, like any other trial, after receiving both ANSM and EC approvals to the trial protocol. The trial planned to include 128 healthy volunteers. The first sixty-four volunteers received single ascending doses (‘SAD’) until 9 October 2015. On 6 October, the multiple ascending dose (‘MAD’) regimen began with doses as low as 2.5mg. By 6 January 2016, when the ill-fated fifth cohort was scheduled to begin the highest dose of 50mg, four other cohorts had already received MAD (2.5mg, 5mg, 10mg and 20mg).
The first six months of the trial had passed by uneventfully, with no serious adverse events (“SAE”) being reported to the French authorities.
Following the disastrous occurrences of early January 2016, three formal investigations by various French authorities are currently underway, including by the General Inspectorate of Social Affairs (‘IGAS’), in an attempt to identify whether the devastating events were caused by procedural error(s), by the study drug itself, or both. The French National Agency for Medicines and Health Products Safety (‘ANSM’) constituted a special committee of experts to investigate the trial and inspect the CRO’s trial site. The European Medicines Agency (‘EMA’) has indicated that the ANSM findings could trigger a revision of the existing regulations, which is likely to have global ramifications on existing standards, as most jurisdictions seek to harmonise regulations.
7 March 2016: the ANSM special committee released meeting minutes which listed specific concerns, requested additional information from Bial and indicated that recommendations for revisions to existing guidelines would be included in its final report.
KEY ISSUES AND POSSIBLE REGULATORY REVISIONS
I. PROCEDURAL ISSUES: 4 February 2016: The IGAS preliminary report identified three errors on part of the CRO that placed the volunteers at risk.
(i) Trial Suspension: The CRO was criticised for proceeding to dose the rest of cohort 5 without checking on the status of the hospitalised volunteer. Both IGAS and ANSM criticised the decision not to suspend the trial despite hospitalisation of a healthy participant for a sudden onset event.
Analysis: whether the trial should have been suspended was a matter of medical judgment. However, it remains unclear as to why the CRO did not check on the health status of volunteer 2508 with the hospital the following morning, before proceeding to dose the rest of the cohort.
(ii) Reporting delay: The IGAS report criticised the delay in reporting the SAE to relevant authorities (the incident occurred on Sunday—notification was provided the following Thursday—regulation required notification “as soon as possible but no later than seven days”), while acknowledging that reporting was completed within the prescribed timeframes.
Impact: reporting time periods to authorities are likely to be reviewed.
(iii) Informed consent: The Bial informed consent form (‘ICF’) that every volunteer had signed, promised that they would be kept informed about any new significant information that could impact their decision to participate in the trial. The rest of cohort 5 was not informed regarding the hospitalisation and hence did not have the opportunity to review their consent to participate in the trial. The CRO stated that in the absence of an approved revision to the protocol, under current EU regulations it is not mandatory to obtain additional consent.
Impact: this is likely to trigger a review of ‘informed consent’ and the time points during the trial at which additional information should mandatorily be provided to the participants.
I. CLINICAL ISSUES
(i) Volunteer screening (exclusion) criteria: IGAS criticised the selection criteria for not having included a neuro-psychological assessment for a study drug that targeted the central nervous system.
Impact: revisions to phase I regulations have been proposed by IGAS to require neuro-psychological assessment (cognitive tests and clinical interviews) during participant screening for study drugs with a central nervous system tropism.
(ii) Justification for progression to first in man study: IGAS found Bial’s pre-clinical in-vivo data to be insufficient (particularly, no comparison done to the benchmark analgesic) to justify progression to first in human trials.
Impact: IGAS has recommended a revision to regulations requiring sponsors of trials to provide demonstrable pharmacological activity (against a benchmark comparison where possible) to justify progression to first in man trials.
(iii) DOSING: (a) Escalation: Bial’s dosing escalation (20 mg jump to 50 mg) was criticised by IGAS, for skipping doses.
Impact: IGAS recommends that Phase I dose escalation strategies must be developed through wide consensus in order to establish guidance for “more reasonable and careful practices”.
(b) Highest dose: IGAS heavily criticised Bial’s choice of highest dose, which was considerably higher than that needed for the therapeutic mechanism sought to be achieved. IGAS concluded that Bial’s maximum dose for this trial appeared to be unjustified.
Impact: IGAS has recommended that regulations be revised to require the submission of “detailed and well-supported arguments for choice of maximum dose”.
The ANSM has already issued precautionary measures that took effect on 31 March 2016, and apply to all ANSM approved trials:
- SUSAR: All suspected unexpected serious adverse reactions (‘SUSAR’), not only on an ANSM approved trial itself, but on any other trial involving a related drug anywhere in the world conducted by an affiliate of the company sponsoring the ANSM approved trial, must be reported immediately to the authorities.
- Upon the occurrence of new facts/developments in trials involving healthy volunteers:
- Suspension of trial: the trial must be suspended immediately.
- Informed consent: written informed consent will need to be obtained afresh from all participants before resuming the trial.
- Authorisations: fresh authorisations from authorities must be obtained prior to resumption
- Immediate reporting: ‘as soon as possible’ is replaced with ‘without delay’ reporting obligation to authorities (with the maximum timeline of seven (7) days unchanged).
- Dosing and dose escalation: all dose escalations (including SAD and MAD) will need to be justified with pharmacokinetic data. Sponsors will also have to provide a written commitment to authorities in this regard at the time of requesting trial authorisations.
It is clear that while the trial was conducted in compliance with applicable regulations, gaps have emerged from both a procedural and clinical viewpoint. If the ANSM measures are indicative of possible EU wide reform, we can expect changes in the areas of data robustness, safety, reporting and consent for phase 1 trials in particular but possibly for all trials as well. Guidelines for first-in-man trials issued by the EU in 2007 after the UK Northwick Park disaster are likely to be fine-tuned, clinical standards strengthened and a sponsor’s procedural obligations extended further to safeguard trial participants.