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Research and clinical phases
Preclinical research
A lot of important international legislation exist in order to avoid the use of human as guinea pigs.
First, new drugs are generally first tested in animal experiments to show safety and effectivity. If a drug is safe and effective it may enter a clinical phase I study.
Most preclinical research starts with animal experiments often using transplanted tumours, although nowadays also transgenic animal models are used.
In the case of local IL-2, effectivity was shown in a transplanted syngeneic mouse lymphoma model in 1989.

A preclinical study is required prior to performing the clinical phase I or II studies.
Clinical phase I study
Clinical phase I studies have two aims: (a) showing that the drug is safe, and (b) showing that application of the drug is feasable.
In the case of IL-2, the first human clinical phase Ia studies date from 1984. Systemic administration of 100 - 200 million international units (IU) IL-2 leads to a major side effect (generalized vascular leakage syndrome). This effect is not observed after local (intratumoural) administration of up to 20 million IU IL-2.
The phase Ib study, showing feasability of local IL-2 application has to be shown again for each new kind of tumour.

A clinical phase Ia (safety) study is required to perform a clinical phase II study, a clinical phase Ib (feasability) study may be combined with a clinical phase II study.
Clinical phase II study
Clinical phase II studies aim to show the effectivity of a treatment. Depending on the difference in therapeutic effect between patients treated with standard therapy and those treated with the new therapy 10 to 50 persons are needed per group. Because of the high percentage objective responses (50 - 70%), 10 patients will often suffice to show effectivity in a phase II study with local IL-2. Studies with more patients will allow a more precise quantification of the clinical effect (and allow the determination of smaller objective responses).

Both clinical phase I and II studies are required to perform a clinical phase III study.

Clinical phase III study
Clinical phase III studies aim for validity of the therapy. After successful conclusion of the phase III clinical trial a new therapy will receive approval status. In the of the European Union (EU) this is done by the Medicines Evaluation Board (MEB). In the U.S.A. this is done by the  Food and Drug Administration (FDA). By this approval status, the drug becomes the new standard therapy.
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Our research is supported by Stichting ter bevordering van het onderzoek in de Experimentele Pathologie en in het bijzonder in de TumourImmunologie. Stichting EPTI, IJselstein, The Netherlands