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Focusing on safety

New EMEA guideline and UK initiatives aim to increase the safety of first-in-human clinical trials

The seriousness of the adverse reactions suffered by all six volunteers in the first-in-human (FIH) clinical trial of TGN1412 at London's Northwick Park Hospital last year has focused the attention of regulators throughout Europe on increasing safety measures associated with FIH trials.

The European Medicines Agency (EMEA) has developed a Guideline on Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials with Investigational Medicinal Products, which came into effect on September 1 2007.

In the UK, the MHRA's Good Clinical Trial Inspectorate is currently seeking to implement an accreditation scheme for phase 1 clinical trial units. The UK has also implemented a system under which the MHRA obtains advice from a separate advisory group before approving higher risk clinical trials.

Q: What is in the EMEA Guideline?

A: The purpose of FIH studies is to investigate the safety of new products in humans, rather than to confer any therapeutic benefit on trial subjects. Such trials are, therefore, usually conducted on healthy subjects, and the safety of such subjects is considered of paramount importance. However, the difficulty with FIH trials is that it is not always possible to predict from non-clinical safety pharmacology and toxicology studies whether there are likely to be serious adverse reactions in humans.

For example, in the Northwick Park clinical trial, all six volunteers who were given TGN1412 (a monoclonal antibody being developed to treat leukaemia and autoimmune diseases) developed cytokine release syndrome and suffered multiple organ failure. However, cynomolgus monkeys that were given a dose that was 500 times larger than that given to the human trial subjects, did not develop the condition.

The Guideline is intended to assist sponsors in the transition from non-clinical to early clinical development by outlining certain risk factors. These factors should be considered when planning FIH trials, they need to be taken into account in developing risk mitigation strategies and addressed in clinical trial authorisation applications. This applies for all new chemical and biological investigational medicinal products (except gene and cell therapy products). Risk factors include:

  • the novelty and extent of current knowledge regarding the relevant mode of action, including the duration and reversibility of the medicinal product, and the type and steepness of the dose response, particularly where this is non-linear (eg over-proportional increase, U-shaped or bell-shaped)
  • the nature of the target and how it might vary between individuals in different populations of healthy subjects and patients
  • the relevance of animal species and models.

The Guideline suggests a range of additional non-clinical tests which sponsors may need to conduct to obtain the data required to adequately plan FIH trials. In addition to tests in relevant animal models, this may include the use of relevant homologous proteins, transgenic animals expressing the human target and the use of in vitro human cell systems.

The Guideline also suggests that, for products with higher risk factors, the relevant dose should be calculated using both the standard No Observed Adverse Effect Level (NOAEL) approach, and the Minimal Anticipated Biological Effect Level (MABEL) approach, with the lowest dose calculation arising under these different approaches being the one used.

The Guideline states that in most circumstances, the administration of the first dose should be designed so that only a single dose is given to a single subject.An adequate period of time should be allowed to observe and interpret reactions and adverse events between the administration of each subsequent dose to that subject and in the administration of the product to any subsequent subjects.

It also states that the trial design should include a specific plan for monitoring adverse events or reactions, and that all clinical staff should be trained to identify and respond to those events/reactions. Units conducting the trial should have immediate access to equipment and staff for resuscitating and stabilising subjects in the event of an adverse reaction and should also have ready access to Intensive Care Unit facilities.

initiatives in the UK

In the UK, the MHRA is implementing a number of additional measures e.g. for FIH clinical trials with certain risk factors, the MHRA now seeks advice from an Expert Advisory Group (EAG) and the Commission on Human Medicines (CHM) before giving approval. Sponsors are required to make available a data package covering a range of specific criteria for consideration by the EAG and CHM, before submitting their clinical trial authorisation application.

The MHRA has also proposed the introduction of a voluntary accreditation scheme for research units conducting phase 1 clinical trials. The scheme would comprise a two level classification system (Standard accreditation and Supplementary accreditation) to be assessed on the facilities, training and experience of the personnel of the research unit undertaking the trial and its ability to manage medical emergencies affecting trial subjects. Standard accreditation is proposed for low risk phase 1 trials which do not require EAG review, and Supplementary accreditation is proposed for clinical trials requiring review by the EAG. Units would be required to complete a detailed application for either type of accreditation and inspections would be carried out by the MHRA to enable it to make its assessment. Inspection reports and accreditation certificates would then be sent to ethics committees to assist them in their conduct of site specific assessments.

Summary

The new regulatory initiatives being introduced will hopefully assist in reducing the risks associated with FIH trials. However, they are also likely to add to the cost and time required for product approval, which may impact on small pharma companies with limited budgets in particular. The Expert Scientific Report published in the aftermath of the Northwick Park trial concluded that there is a need for balance between measures to optimise the safety ... without stifling innovation or raising unnecessary barriers to the development of useful new medicines.

Time will tell whether the EMEA Guideline, and the measures proposed by the MHRA will achieve this balance.

9th November 2007

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