BioWorld International Correspondent

LONDON - Members of the UK biotech industry met last week to discuss how they are coming to terms with the practical consequences of the disastrous TGN1412 clinical trial, and in particular the extra scrutiny to which biological products with novel modes of action are now subjected when moving into first-in-human trials.

Experts who investigated what went wrong when six volunteers suffered life-threatening cytokine storms in the Phase I trial of the monoclonal antibody TGN1412 on March 13, 2006, made 22 recommendations in their report published in December.

Group Chairman Gordon Duff, told delegates at a seminar on the clinical development of novel biological products organized by the UK BioIndustry Association that one of his prime concerns was not to hamper innovation.

"I'm a strong believer in the future of biological molecules. They have already transformed the lives of countless millions around the world and [we're] just at the start of the road."

Duff said all 22 recommendations were subject to four tests: that they are relevant beyond TGN1412, increase safety in first-in-human exposure, are pragmatic to implement and do not hinder innovation.

Following publication of Duff's report, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) put in place new rules for authorization of Phase I trials with higher-risk compounds. "We've gotten to the situation where we have clearly defined processes in place," said Elaine Godfrey, pharmaceutical assessor at the MHRA's clinical trials unit.

The rules cover new compounds acting directly or indirectly on the immune system with a novel target or a novel mode of action, or with the potential to have a secondary effect on the immune system. In addition, they include trials where the target is so specific to humans that animal data are unlikely to be predictive.

Products falling into those categories now are referred to specially convened expert advisors. It is up to companies submitting an application to decide if a compound falls into the higher-risk category.

"At the time of assessment of an application, we may disagree with you," Godfrey said. "We had one application that the sponsor thought was high risk, but we didn't and downgraded it."

The MHRA will advise companies in advance of an application on the basis of a summary of the application.

For products judged high risk, companies need to submit a separate document addressing 10 specific points. They include a discussion of the function of the target, a rationale for the transition from preclinical to human tests, rationales for the starting dose and dose escalation and details of the study population, and in particular, the justification for using healthy volunteers.

Since the new system came into being, three higher risk applications have been received, and the MHRA is due to give decisions on them by the end of June. That is consistent with an historical analysis of submissions in the 30 months before the TGN1412 trial, which picked out applications that now would fall into the high-risk category. "The numbers are low, but they are not dissimilar to the numbers prior to March 2006," Godfrey said.

However, Sean Harper, senior vice president of global development and chief medical officer of Amgen Inc., said all regulatory agencies "are asking more questions" in the wake of TGN1412.

Companies are hesitant to proceed with high-risk molecules in Europe in the current regulatory environment, while the FDA generally has not favored using healthy volunteers in first-in-human studies of biologics. Meanwhile, regulators in Australia and elsewhere are asking for more cautious study designs.

Although the Duff report recommendations apply only to high-risk products, they have wider implications, in particular, the requirement for greater sharing of information among companies, clinicians and regulators. "This sounds like a small thing," Duff said. "In fact, it is a huge thing. It is difficult in a competitive environment to work out what sharing is needed."

That was brought home in evidence given to the expert group during its investigation. It was thought that the reaction suffered by the six volunteers was unprecedented in a first-in-human trial. However, the expert group was informed a similar reaction had occurred in a single volunteer patient in a cancer trial in 1993.

"The trial was stopped; the volunteer got better, but the data were never published," Duff said. The observations could have informed the TeGenero AG, the company behind TGN1412, when it was designing the trial.

Another recommendation with wider implications is the move from No Observable Adverse Effect as a measure for setting starting doses, to Minimum Anticipated Biological Effect Level. Using the latter measure, the starting dose in the TGN1412 trial would have been 20-fold lower.

Duff is concerned also that Phase I clinical trials have been divorced from mainstream medicine. Most units are remote from centers of medical culture and learning, he said. That means medical students in the UK do not get training in Phase I clinical trials.

"There is huge experience of Phase I in pharma and biotech. But when you talk to clinicians, they are poorly equipped to understand the way first-in-man clinical trials are carried out, and to understand the data that come out of them."

In light of that situation, Duff recommended that students should spend time in commercial units during their training.