The Expert Scientific Group on phase I clinical trials, an independent committee established by the UK Secretary of State for Health to examine the safety and design of first-in-man clinical studies involving biologic molecules with novel mechanisms of action, new investigational agents with a highly species-specific action, and new drugs directed toward immune system targets, has published its interim report for public comment.1 The 350-page report contains 22 recommendations, covering the preclinical phase and the transition to clinical phases, including regulatory procedure, that the committee believes will increase human subject safety in first-in-man clinical trials. The recommendations focus on the calculation and administration of first doses, sharing of information relevant to safety, and regulatory access to external specialist opinion in the assessment of clinical trial applications for higher-risk new medicines.  

The recommendations include:

1. Careful consideration of the enrollment of volunteer patients rather than healthy volunteers
2. First dose should be administered to one subject only, leaving sufficient time for any adverse reaction to develop before further dosing or administration to additional subjects
3. A Minimal Anticipated Biological Effect Level (MABEL) approach to dose calculation, rather than the traditional "no effect level" or "no adverse effect level" in animal studies
4. The development of specialized centers to conduct first-in-man studies on higher risk investigational agents
5. Better collection and sharing of international drug development and phase I safety data, especially unpublished safety data
6. Safety-based data should be reviewed by the regulatory agency before the formal submission of the phase I trial application, and independent scientific expertise should be sought to provide added review of safety issues
7. Phase I trials with high-risk agents should be performed in an appropriate clinical environment with immediate access to facilities and specific antidotes (if known) for the treatment and stabilization of dosed subjects having acute serious adverse reactions.

A number of observers from regulatory agencies outside the UK participitated in the expert group, including the European Medicines Agency, the US Food and Drug Administration, and the Japanese Regulatory Agency. The final report is expected to be published by the end of November 2006, following the receipt of views and comments from interested parties on the draft recommendations.

TGN1412 (CD28-SuperMAB®) is an immunomodulatory, fully humanized, superagonistic, anti-CD28 monoclonal antibody under development for the treatment of autoimmune and inflammatory diseases such as rheumatoid arthritis and multiple sclerosis, and certain cancers such as leukemia. The serious adverse reactions (Cytokine Release Syndrome) experienced by the six volunteers who had received the investigational drug did not involve errors in the manufacture of TGN1412 or in its formulation, dilution, or administration to trial participants. Rather, it was concluded that an "unpredicted biological action of the drug in humans" is the most likely cause of the adverse reactions in the trial participants. Symptoms of adverse reaction occurred within hours of dosing. Greater than 500–1000-fold increases were seen in TNF-alpha and interferon-gamma levels within 4 hours of dosing. The clinical trial was a single center, double-blind, randomized, placebo-controlled, single escalating dose study of TGN1412 administered intravenously to healthy volunteers. The dosage of TGN1412 administered to the volunteers in the trial was 500 times less than that given to monkeys in preclinical testing, at least some of which had developed swollen lymph nodes. In response to the adverse clinical trial incident, which occurred in March 2006, the Secretary of State for Health appointed an expert independent scientific group to review the safety of such trials and make recommendations about how they are assessed and how to minimize risk in future trials.

—A Techman 

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Reference

1. Expert Scientific Group on phase one clinical trials: a consultation. Available at: http://www.dh.gov.uk/Consultations/LiveConsultations/fs/en. Accessed July 31, 2006.