The draft guidelines, published by the EMEA's committee of medicinal products for human use (CHMP) earlier this week, aim to reduce the risk of adverse drug effects during first-in-man clinical trials of 'high risk' investigational drug products. The rationale behind the guidelines were discussed during this week's Drug Information Association Euromeeting in Vienna earlier this week by David Jones, principal scientific officer of the UK Medicines and Healthcare products Regulatory Agency (MHRA) and Dr Thomas Sudhop, head of the division for scientific services, of the German Federal Institute for Drugs and Medical Devices (BfArM). The need for the new guidelines was prompted by the Northwick trials disaster where six patients suffered multiple organ failure after being treated with TeGenero's TGN1412. According to Jones, one of the questions asked during the working party discussions about guidelines was "how could regulators ensure that a disaster such as occurred with TGN1412 could never happen again?" The answer "ban drug development" was given as it is impossible to eliminate risk during first-in-man trials, regulators can only try to minimise the risks as much as possible. The EMEA has defined 'high risk' medicinal products as those investigatory drugs about which there are concerns that serious adverse reactions may occur. These concerns may be derived from particular knowledge, or uncertainties about the mode of action, the nature of the target or the relevance of animal models where the preclinical studies may not be as predictive as in most cases. According to Jones, only 5 per cent of all first-in-man drug trial applications received in the UK this year have been classified as 'high risk'. The guidelines state that for high-risk medicinal products it is particularly important to fully characterise the primary and secondary pharmacodynamic profile of the drug in both in vitro animal and human systems and include in vivo studies on at least one animal model. These studies should be designed to gather as much information as possible about receptor binding and occupancy, duration of effect and dose response. The pharmacokinetic studies should include the exposure of all animal models used for in vivo studies to pharmacological doses of the drug as well as incorporating all the standard adsorption, distribution, metabolism and elimination (ADME) requirements specified in ICH S3, S6. "A large proportion of the UK public had wanted to get rid of animal testing, but since Northwick the public has realised the importance of these experiments and now wants more animal testing," said Jones. The relevance of the animal model also needs to be demonstrated as non-clinical studies with animals with highly species-specific medicinal products may: not reproduce the pharmacological effects in humans, give rise to misinterpretation of pharmacokinetic results and not identify relevant toxic effects. The calculation of the first in man dose for the majority of drugs is based on the 'no observed adverse effect level' (NOAEL) determined during preclinical studies in the most relevant and sensitive animal species. For 'high risk' medicinal products an additional approach needs to be taken, which involves the calculation of the 'minimal anticipated biological effect' (MABEL) in humans before additional safety factors are applied. The lower of the values obtained using the NOAEL and MABEL calculations should be used. In the TGN1412 trials, the reaction of cynomolgous monkeys was stronger than that of rhesus monkeys with neither exhibiting signs of the anaphylactic reaction observed in the human trial. The NOAEL level found was 50mgkg-1 in the cynomolgous monkeys and this was reduced by a factor of 500 for the human trial. This included an extra 10 fold safety factor added in by TeGenero, making the Northwick trial disaster even more surprising. According to Sudhop more than 1000 times the number of cyctokines were released during the adverse reaction than are normally observed. However, according to Jones, the new MABEL calculations would have led to the drug being administered at 1µgkg-1. The guidelines also specify changes to the clinical requirements and trial protocol design, with the most notable being the initial dose administration needing to be conducted sequentially with an adequate period of observation before subsequent administrations. Unusually, the draft has been released for a consultation period of only two months as the regulators are looking to get feedback on the proposed changes as quickly as possible from the industry. "If you don't comment on the guidelines it is a wasted opportunity to have your say," said Jones. The consultation workshop will be held in June and details as to how to sign-up for one of the 160 places available will soon be on the EMEA website.
