The trial protocol should contain information regarding the following issues, in compliance with the Guideline for Good Clinical Practice (CPMP/ICH/135/95), Chapter 6. Clinical trial protocol and protocol amendment(s):

• table of contents and synopsis

• risk-benefit assessment

• subject inclusion and exclusion criteria

• discontinuation criteria

• assessment of efficacy

• assessment of safety

• statistics

• direct access to source data / documents

• quality control and quality assurance

• ethics

• data handling and record keeping

• financing and insurance.

Which objections regarding the trial protocol are the most frequent content-related objections in authorisation procedures?

• The most frequent content-related objections regarding the trial protocol are:

• inadequate risk-benefit assessment

• contraindications stated in the Summary of Product Characteristics have not been taken into account in the subject exclusion criteria

• inadequate justification for choice of dose

• inadequate safety monitoring procedures (safety laboratory, ECG, etc.)

• methods of contraception have not been explained or are inadequate.

The trial protocol of first-in-man clinical trials involving a novel substance should include a critical discussion of whether the new investigational medicinal product is a potential high-risk medicinal product. The draft GUIDELINE ON REQUIREMENTS FOR FIRST-IN-MAN CLINICAL TRIALS FOR POTENTIAL HIGH-RISK MEDICINAL PRODUCTS (Draft, Doc. Ref. EMEA/CHMP/SWP/28367/2007 Corr., dated 22 March 2007) outlines three criteria which classify an active substance as a high-risk substance:

1. New or not well-known mode of action. A pleiotropic mode of action, if a substance acts on a receptor that is expressed ubiquitously as is generally the case in the immune system, is considered a high-risk mechanism.

2. New or not well-known structure and biological function of the target; most newly developed active substances act on a single target, e.g. a receptor or a physiological reaction. Caution should be exercised in cases in which the exact structure and biological function of the target as well as its tissue distribution are not well-known.

3. Relevance of the animal studies which precede first-in-man clinical trials: here it should be ensured that the animal model chosen closely resembles humans with regard to pharmacology and toxicology.

For active substances which meet the high-risk criteria, dosing should no longer be based exclusively on the „No Observed Adverse Effect Level“ (NOAEL), but on the „Minimal Anticipated Biological Effect Level“ (MABEL). A detailed justification is to be given for choices of initial dose, dose escalation increments, and maximum dose. In first-in-man clinical trials, careful consideration should be given to the question whether an intravenous administration is necessary. If so, the active substance should be administered as slowly as possible. This would allow immediate interruption of the infusion should adverse reactions occur. Moreover, the active substance should not be administered to several subjects concurrently (sequential design). Furthermore, the clinical trial protocol should describe in detail the requirements for dose increases as well as the measures that will be taken in case of a medical emergency.

Whether the extension “treatment” is an amendment to the protocol or whether it is considered an “open-label extension study” depends on the objective and on the design of the previous study.

• If the primary and secondary objectives of the previous study can be further pursued,

• if the primary endpoint can be maintained,

• if only descriptive secondary endpoints are additionally included, and

• if the design is not changed substantially,

(an) amendment(s) to the protocol can generally be submitted.

However, the objective of an open-label extension study is mostly different from that of a blinded randomised previous study, in which case the design of an extension trial will generally be preferable.