Masterstudiengang "Drug Regulatory Affairs"

 

On 13 March 2006 six healthy volunteers participating in the first-in-man trial of the monoclonal antibody TGN1412 experienced serious adverse reactions provoked by a cytokine storm, which, within hours, led to multi-organ failure requiring intensive care treatment and varying degrees of long-term disabilities. This tragic outcome unprecedented in the history of Phase 1 trials aroused immense public and scientific interest TeGenero failed to correctly predict the reactions of humans to TGN1412 administration despite having adhered to regulatory guidelines during its non-clinical development including calculation of the trials starting dose. Parexel, the Contract Research Organisation, followed a standard design to prepare the clinical trial protocol for the TGN1412 first-in-man trial, apparently disregarding the extraordinary mechanism of this first-in-class monoclonal antibody.

The discrepancy between the disastrous outcome of the TGN1412 trial and the generally good safety records of Phase 1 clinical trials revealed that conventional development strategies that worked well for traditional chemically synthesised small molecule products may be inadequate for novel, biotechnology-derived proteinaceous therapeutics. This suggested that safety provisions for first-in-man trials needed optimisation, but without needlessly setting up additional barriers to the development of innovative medicinal products. Apart from guidance on the design and conduct of first-in-man trials, criteria to discriminate between conventional products and products that potentially constitute a high risk to trial subjects were needed. Steps were first taken, at national level and later at EU level.
This thesis outlines TeGeneros activities in the run-up to the TGN1412 trial and provides a detailed overview of its implications comprising

• the immediate reaction of the MHRA, the concerned competent authority.
• the subsequent regulatory actions at national level, in particular the steps taken by the competent authorities of three EU member states the United Kingdom, Germany, and France.
• the recommendations that were consequently made at EU level in the form of a CHMP draft Guideline on requirements for first-in-man clinical trials for potential high-risk medicinal products.

To clarify the various aspects of the incident and the recommendations made for safeguarding subjects in future first-in-man trials, the thesis provides comprehensive background information on clinical trial authorisations in the EU, internationally agreed standards for the non-clinical development of biotechnology-derived medicinal products particularly with regard to monoclonal antibodies, a historical synopsis of the use of monoclonal antibodies for therapeutic purposes, and immunological facts needed to put across TGN1412s molecular mode of action. In addition, the key aspects of the TGN1412 trial design are discussed in the light of alternative options. To point to the area of conflict in which regulators have to move the regulatory actions triggered by the TGN1412 incident were highlighted against the background of current regulatory efforts to promote the development of innovative medicinal products.

The adoption of the CHMP draft guideline on first-in-man trials on 22 March 2007 revealed the far reaching implications of the TGN1412 incident on the regulatory requirements for first-in-man trials. In the run-up to its drafting, the concurrence and concordance of regulatory activities at national level reflected the manifest public pressure to better protect future trial subjects from similar tragedies and the essential consensus among regulators on the potential for improvement in the existing clinical trial regulations. One year after the incident public interest remains high and one senses that further changes in the field of clinical trials are imminent. It remains to be seen how and when these will be made and whether they will be scientific, aiming at improving the predictability of human reactions to novel medicinal products or administrative, providing for assured and fair compensation for injured trial subjects independent of the outcome of legal proceedings and in which EU member state the trial is conducted.

Pages: 56, Annexes 14, pages: 30