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In March 2006, six volunteers participating in a phase 1 clinical trial in London hit the news when they suffered serious side effects. The drug (TGN1412) was being tested for the first time in humans and is a monoclonal antibody under development by TeGenero for the treatment of leukemia and certain autoimmune diseases.

Phase I studies are never without risk, in large part because the medicine being tested has, at that stage, been tested only theoretically and in animals. Despite this, there has been only an insignificant level of personal injury among phase I volunteers since current legal and clinical practice procedures were introduced in the 1970s, including only one recorded death. The severe reactions of the volunteers of the TeGenero trial are thought to have occurred because the type of drug being tested – a monoclonal antibody which is a form of biological medicine – was designed explicitly to target a specific human protein. The prior animal tests that were conducted using the drug revealed no drug-related adverse events, probably because the artificial antibodies in the drug were designed to latch onto human protein only.

Presently, the legal obligations that concern clinical trials in the EU are governed by EU Directive 2001/20/EC (the “CT Directive”), which has been implemented into national laws in the Member States of the EU. The CT Directive requires sponsors of clinical trials generally to ensure that such trials are conducted in accordance with the international principles of good clinical practice. Interestingly, it brought phase 1 studies in the UK into the regulatory regime for the first time.

In addition, the CT Directive provides that a clinical trial may be conducted only if the foreseeable risks and inconveniences have been weighed against the anticipated benefits to the trial participants and future patients, and the trial subjects have been adequately informed of the risks, inconveniences and objectives of the trial and have given their informed consent.

The Directive requires clinical trials to be conducted so that the rights, safety and well being of the trial subjects prevail over the interests of science and society. It further requires each individual involved in conducting a trial to be appropriately qualified and the trial itself to be scientifically sound and guided by ethical principles in all their aspects. Such non-clinical and clinical information on an investigational medicinal product as is available must be adequate to support the proposed clinical trial, and the appropriate manufacturing and import authorisation for the investigational medicinal product must be in place. According to the Directive, sponsors may delegate any or all trial-related functions but, in such cases, the sponsor remains responsible for ensuring that the conduct of the trials and the final data generated by those trials comply with the Directives.

As the above summary illustrates, the EU has in place a comprehensive set of rules that govern the conduct of clinical trials within its borders. The question, in light of the TeGenero incident, is whether, in particular in respect of the first trials in humans, these rules are enough. There has been much criticism from the pharmaceutical and scientific community as to the manner in which the TeGenero trial was carried out – namely that it was carried out so soon following the discovery of the antibody (approximately less than one year after it was discovered, and thus before any other results on the same compound that might have revealed a problem were carried out), and that, as this was the first time it was tested in humans, it should have been tested in only one volunteer to begin with to monitor the reaction, instead of immediately in six human volunteers.

In response to the TeGenero incident, an Expert Scientific Group was set up by the UK health secretary to assess the suitability of the present laws covering clinical trials. The Expert Scientific Group released its final report in December 2006. The aim of the expert group was “to review what could be learned from the TGN1412 trial and to make recommendations to increase the safety of future first-in-man trials” of medicines like that involved. It has come up with a series of recommendations designed to increase the safety of volunteers in future clinical trials covering pre-clinical and early clinical development, the process of preparation and review of trial authorisation applications, the determination and administration of the initial doses in man, the clinical environment for such studies and the development of skills and training to meet future needs.

A key implication arising from the particular set of circumstances surrounding the TGN1412 study is how any legal liability for the injuries suffered by the volunteers works out. The immediate and obvious target for legal claims is the study sponsor, but it is by no means clear to the outside observer that, assuming that the injuries suffered were caused by the study drug (and that, in principle, would have to be proved by the claimant), any liability at all will have accrued notwithstanding the serious injuries incurred. A claim would have to be based in the legislation on defective products or in negligence or, perhaps, breach of contract.

Although the law on defective products does not require the claimant to show that the injuries were anyone’s fault in the sense of negligence, the very essence of the “defectiveness” which has to be shown is defined by the safety expectations which the consumer of the product (the volunteer) was entitled to have. It must, therefore, be open to a sponsor in such circumstances to defend any claim by arguing that in a phase 1 study the volunteer’s expectation of safety was conditioned and informed by the experimental nature of the drug and all of the explanations which have under the Directive to be given to any participant in a clinical trial as well, of course, to the fact of his or her having given consent on a informed basis.

The alternative form of claim, based in negligence, would require a claimant to prove that the study was designed or performed negligently having regard to the body of knowledge possessed by experienced medical and clinical trial professionals operating in the pharmaceutical clinical environment – and that is by no means an easy legal burden to discharge. Even if the sponsor company itself were not experienced in conducting clinical studies on its drugs it had engaged the services of an internationally known expert clinical trials organization for that purpose.

The pharmaceutical industry in the UK has promulgated two sets of clinical trial compensation guidelines, one for trials involving healthy volunteers and one for studies on patients. Although there are differences between the two sets of guidelines, in broad principle they recommend that sponsors agree to a simple and expeditious procedure for the provision of compensation for injury caused by participation in clinical trials and that notwithstanding the absence of legal liability the company should pay compensation to study subjects suffering injury or death.

Until now the level of claims received or payments made these guidelines has, in relation to phase 1 studies, been remarkably low. However, the seriousness of the injuries in the TGN1412 study were such that the guidelines (if, as is assumed, they applied to the particular sponsor and study) could be severely tested, though no sponsor is bound by law to follow them as such unless they have been incorporated into some form of contractual arrangement such as the clinical trial agreement which is usually made with the particular institution at which the study was conducted.

It seems clear that the changes are necessary to take into account the major advances in scientific and medical research that are leading to completely new categories of medicines and treatments. The expert group’s recommendations will be scrutinized carefully and, no doubt, implemented as some form of guidance across the European Union in due course.

Morgan Lewis Life Sciences
www.info-morgan.com/lifesciences

Anthony Warnock-Smith
E-mail: awarnock-smith@morganlewis.com
Tel: +44 (0) 20 7710 5511
Keith Black
E-mail: kblack@morganlewis.com
Tel: +44 (0) 20 7710 5547

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