HOW TO ORGANIZE MULTICENTER DRUG TRIALS IN CHILDREN

J. Boos

Department of Paediatric, Haematology and Oncology, University of Munster Albert-Schweitzer- Str. 33, 48149 Munster

Drug approval procedures world-wide were developed in the light of serious and epidemiologically relevant toxic events (e.g. thalidomide, stilben, chioramphenicol) that affected children in great measure. Procedures were thus aimed at supplying patients with those drugs that combine a desired treatment benefit in a given disease with justifiable risks, in order to achieve a positive benefit-risk ratio.

Inasmuch as all individuals concerned with the process of drug development link specific scientific, medical, or economic expectations to a new substance, and are thus not free from BIAS, pertinent trials have been subjected to standardised guidelines all over the world (ICH-GCP Guidelines).

Whereas drug approval procedures are mainly dedicated to consumer protection, those guidelines have been designed to ensure correctness of test results and the protection of test subjects and patients who are exposed to a new substance within the framework of drug trials.

This marks an important distinction and one needs to be well aware of the consequences, since those guidelines translate into immense expenditures for drug testing. As a consequence, drugs are currently tested only in the major and economically most relevant indications. Rare diseases and economically less relevant patient groups will systematically receive off-label or off-license treatment and thus forego important safety and consumer protection aspects of drug legislation.

Drug trials in children will have to be designed with a certain amount of flexibility and may deviate from the cited guidelines to a certain extent.

The following issues deserve special emphasis:

– discussion of priorities and selection of trial drugs because only few of the theoretically relevant trial questions can be investigated in children;

– definition the main objective, the character of the trial (phase I, II, etc.), the inclusion and exclusion criteria, end points and other essential parameters;

– estimation of case numbers based on the supposed effect;

– definition of responsibilities (drug quality, statistics, safety, general investigator, etc.);

– organization of sound financial footing;

– design appropriate test manuals such as the Clinical Investigator Brochure, Investigation File, Informed Consent Form and above all a good Case Report Form for documentation.;

– discussion of ethical issues and advice sought from the appropriate Ethics' Committee;

– insurance coverage to be provided for test subjects;

– introduction of qualified institutions to the trial (Investigators meeting or initiating visits);

– special care must be taken to observe the regulations regarding unexpected adverse events (UAE) and severe UAE (SUAE) of the GCP-Guidelines in order to protect children from toxic effects that may be observed but not registered.

"How to organize …" seems to be a short and precise question. The answer, however, is difficult and depends on a multitude of specific questions related to the kind of drug, to the target group of children, to the indication looked for, and to the country where the trial is going to start. The structured sequence of preparation, trial conduct, and evaluation must above all provide the best possible safety for all children involved and protect those who receive treatment against avoidable risks, will facilitate trial realisation and is indispensable to obtain valid results. This presentation can only try to describe and discuss valid regulations and current developments pertaining to drug trials in children.