Information-sharing, a conservative approach to drug dosing and regulatory access to independent expertise were at the heart of the final recommendations on first-in-man trials published yesterday by an expert group under Professor Gordon Duff.
The independent Expert Scientific Group was convened in the wake of the disastrous Phase I study at London’s Northwick Park Hospital last March that left six healthy volunteers in intensive care. Following the severe adverse reactions triggered by TeGenero’s monoclonal antibody TGN1412, the ESG reviewed the provisions for first-in-man trials of potentially higher-risk compounds such as biological molecules with novel mechanisms of action.
The final report picked up many of the preliminary recommendations made by the ESG in July. These included careful consideration of whether healthy volunteers were suitable for first-in-man exposure; recourse to external expert advice when considering trial applications for higher-risk agents; a broader approach to dose calculation; and sequential administration of new agents, with appropriate observation periods between doses. The ESG also built on these recommendations, taking into account the 38 or so submissions from stakeholders (including four of the trial volunteers and their representatives) received in the interim.
The group further noted that stakeholders raised a number of issues outside its terms of reference, such as informed consent, clarity of information provided to volunteers, insurance cover and the role of Research Ethics Committees. “Although beyond our remit, we considered these wider concerns to be extremely important, and recommend that they should be taken up as a high priority,” the report said.
TGN studies "did not predict a safe dose"
The expert group also stuck with its earlier conclusion that preclinical studies performed with TGN1412 “did not predict a safe dose for use in humans, even though current regulatory requirements were met” – something the final report on the incident by the Medicines and Healthcare products Regulatory Agency did not concede. The ESG acknowledged, though, that the ‘cytokine storm’ experienced by the Phase I volunteers did not occur in the cynomolgus monkey, the animal model chosen to calculate the dose for human exposure to TGN1412, even though monkeys were given 500 times the dose administered to humans.
As in the interim report, the final recommendations suggested the Minimal Anticipated Biological Effect Level as a suitably cautionary approach to dose calculation, rather than the ‘No Observable Effect Level’ or No Observable Adverse Effect Level’ relied on in animal studies. The MABEL approach was proposed by a joint industry task force formed by the Association of the British Pharmaceutical Industry and the BioIndustry Association to provide input to the Duff inquiry.
One particular feature of the ESG’s final report was its emphasis on information-sharing and proactive communication between regulators, trial sponsors, independent specialists and other concerned parties, both at UK and transnational level, to mitigate the potential risks of human exposure to higher-risk medicines.
This might involve, for example, expediting the collection of relevant information from unpublished preclinical studies as a platform for EU and international regulators to exchange signals of potential risks through an (initially) confidential database. A similar strategy could be applied to safety information from Phase I trials, including those with negative safety outcomes. At EU level, a suitable model would be the existing EudraCT clinical trials database and the EudraVigilance database for filing adverse drug reaction reports, the ESG suggested.
More specific guidance required
The final report also proposed developing more specific guidance on first-in-man trials with high-risk compounds through European and, eventually, international channels. Closer to home, it recommended setting up an Expert Advisory Group to the Commission on Human Medicines, or similar body, to provide independent expert opinion to the MHRA in evaluating applications for trials with higher-risk medicines.
The MHRA said it had already implemented nationally the ESG’s recommendations on procedures for authorising trials. Some of the group’s other suggestions would need to be pursued at EU level and the agency had “already started discussions with other European regulators to take these forward as a priority," it commented. According to the UK’s Department of Health, an expert advisory group charged with reviewing clinical trial applications for high-risk compounds will be established in the New Year.
The ABPI, which has already started work on updating its own guidelines for the conduct of clinical trials in healthy volunteers, said it was “clearly essential that we take on board” the recommendations of the Duff inquiry, while noting there were “many more aspects to consider than the quite exceptional events surrounding the THN1412 trial." The revised ABPI guidelines will cover ground such as volunteer recruitment, exclusion criteria and the suitability of facilities for volunteer studies.
The BIA welcomed the ESG’s recommendations, particularly the proposal for European guidance on first-in-man trials. The manner and timing of implementation would now be key, it said, calling for sufficient regulatory resources and funding to ensure there was no delay in developing new medicines for patients.
However, lawyers for the volunteers in the TeGenero trial argued that the Duff inquiry had not gone far enough in uncovering exactly what went wrong at Northwick Park. One solicitor called the final report “the latest in a series of whitewashes”. Meanwhile, German newspaper Handelsblatt revealed that the bankrupt TeGenero had been sold – to an anonymous buyer. By Peter Mansell