Sponsors should think carefully about the justification for using healthy volunteers in Phase I studies of new compounds, recommends the UK expert group set up in the wake of the disastrous TGN1412 trial last March.
The recommendation was one of 22 made by the Expert Scientific Group (ESG) convened to look at the design and oversight of early-stage trials with higher-risk medicines.
While the choice of healthy or patient volunteers for Phase I should be made on a case-by-case basis, patients “may be more appropriate subjects than healthy volunteers on the basis of a ‘risk to benefit’ assessment in the case of higher-risk agents targeted at lethal diseases where all existing therapeutic options for the patient have been exhausted”, the ESG suggested.
TGN1412 was being developed for diseases in which T cells are involved in the pathogenesis of chronic inflammation or haematological malignancies such as leukaemia.
Many of the group’s other recommendations involved issues around dosing, such as calculating the starting dose for first-in-man trials, routes and rates of administration, and intervals between dosing. The group proposed a broader approach to dose calculation than reliance on a ‘No Effect Level’ or ‘No Adverse Effect Level’ in animal studies, such as using a Minimal Anticipated Biological Effect Level (MABEL).
New agents in Phase I trials should be administered sequentially “with an appropriate period of observation” between dosing, related to “the kind of adverse reactions that might be anticipated based on the nature of the agent, its target and the recipient”, the ESG recommended. As the interim report noted, volunteers in the TeGenero trial were dosed at 10-minute intervals – a strategy that attracted considerable flak from critics of the study.
Other recommendations addressed more general safety considerations. Phase I studies of higher-risk medicines should always be supervised by properly qualified staff with immediate access to emergency facilities, the group said. At the regulatory level, more information-sharing worldwide on Suspected Unexpected Serious Adverse Reactions at Phase I was encouraged, as well as earlier dialogue between regulators and product sponsors, and access to independent, specialised expert opinion on applications for trials with higher-risk compounds.
ESG chairman Professor Gordon Duff said the report was “not a further investigation” into the incident at Northwick Park Hospital, although it was clearly informed by what happened there. The group did reach the provisional conclusion that preclinical studies performed on TGN1412 did not predict a safe dose in humans, even though formal regulatory requirements were met.
This deviated somewhat from the final report on the trial by the Medicines and Healthcare products Regulatory Agency (MHRA), condemned as a “whitewash” by lawyers for the men hospitalised by TGN1412. The MHRA reiterated its belief that an unexpected biological effect was the most likely cause of the violent adverse reactions. “In this case the resulting activity seen in humans was not predicted from apparently adequate pre-clinical testing,” it declared.
The ESG’s overall intent, it explained, was to optimise the safety of future Phase I trials without stifling innovation. This approach was applauded by the BioIndustry Association (BIA), which formed a task force with the Association of the British Pharmaceutical Industry (ABPI) to provide input to the expert group. The BIA singled out the endorsement of the MABEL dosing concept, one of a number of recommendations by the ABPI/BIA task force taken up in the ESG report.
Sir Colin Dollery, co-chairman of the industry task force, stressed that its proposals were more to do with clarification and emphasis than any radical overhaul of existing regulatory guidance for biopharmaceuticals. It was clear, he said, that there were “no major safety-related issues not addressed in the existing guidance – as demonstrated by the fact that there have been tens of thousands of such trials without any major incident”.
The ESG’s interim report has gone out for public consultation with a tight deadline of 14 September for comments. A final report should be ready by the end of November.