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The European Union's new guideline for first-in-man studies with high-risk products requires sponsors to make a more detailed risk assessment and risk estimation before trials begin. This task should be based on scientific knowledge and anticipated predictability of the nonclinical models, according to Dr. Thomas Sudhop, director of the division for scientific services at the German Federal Institute for Drugs and Medical Devices (BfArM) in Bonn.
Jenny Mueller and Nermeen Varawalla discuss the issues facing first-in-man studies at the Applied Clinical TrialsEuropean Summit in Berlin, Germany.
"In cases of concern, case-by-case decisions are necessary. This requires an open and scientific-based discussion by the sponsor in the documentation," he said at the Applied Clinical Trials European Summit, held October 29–31 in Berlin. "Early scientific advice before clinical trial authorization (CTA) submission might be helpful."
The guideline came into effect in September 2007. It was introduced in response to the TGN 1412 incident at London's Northwick Park Hospital, in which a CD-28 super-agonist antibody caused life-threatening adverse reactions in six subjects during March 2006.
To avoid such disasters, sponsors must discuss the mode of action, the nature of the target, and/or the relevance of animal models for all first-in-human trials in their CTA application, noted Sudhop. Details about structure-tissue distribution (including expression in/on cells of the human immune system), cell and disease specificity, regulation, level of expression, and the biological function of the human target and downstream effects are also crucial.
Sponsors should compare the available animal species to humans, focusing on target, structural homology and distribution of the supposed target, signal transduction pathways, and nature of pharmacological effects. High species-specificity enhances the difficulty in the nonclinical evaluation of the risk to humans, but does not necessarily imply that there is always an increased risk in first-in-human trials.
Among general clinical considerations are the route and rate of administration, number of subjects per dose increment, sequence and interval between dosing of subjects within the same cohort, dose escalation increments, transition to next dose cohort, stopping rules, and allocation of responsibilities for decisions on subject dosing and dose escalation.
"First-in-human trials should take place in appropriate clinical facilities and should be conducted by trained investigators who have acquired the necessary expertise and experience in conducting early phase trials," concluded Sudhop. "Units should have immediate access to equipment and staff trained for dealing with emergency and life-threatening situations. Intensive care unit facilities should be located nearby."
Ensuring the well-being of subjects is even tougher in sub-Saharan Africa, where safety reports may not reflect the actual safety profile and safety profiles from other ethnic populations may not be applicable. Furthermore, ethics committees only exist in around 20 of the region's 42 countries, said Jenny Mueller, clinical trials support manager at the Medical Research Council's Laboratories Unit in West Africa, in a special lecture at the Berlin congress. Where committees do exist, there are often long intervals between meetings; no appropriate legislation in place; their actions and decisions are not always implemented and monitored; and they may suffer from a lack of independence.
About 175 trials in sub-Saharan Africa are registered with the International Standard Randomized Controlled Trials, suggesting the region is not popular with the pharmaceutical industry. Female subjects are often particularly vulnerable because consent is not always an individual choice for women, they may not be able or willing to agree to contraception, and they may face coercion due to a lack of affordable medical care, said Mueller, who discussed similar issues in her October Applied Clinical Trials article, "Third World Barriers." Nurses often act on behalf of investigators, who do not always speak the local languages, and participants are not accustomed to questioning doctors. Data collection is difficult due to a frequent lack of source document availability and accurate information on concomitant medication, and because subjects often estimate birth dates have the same names.
"Proper design of case report forms is crucial, as is involvement of the study team, capturing only data needed to answer research question, and user-friendly design," Mueller said. "Use of electronic data capture (EDC) devices can help."—Philip Ward