Estimation of Safe Starting Dose and Safety Assessment and Risk–Benefit Analysis

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Chapter: Pharmacovigilance: Non-Clinical Safety Evaluation and Adverse Events in Phase I Trials

In addition to allowing identification of target organ toxicities, the aim of non-clinical safety studies is to yield data that will provide the basis for estimating the safe starting dose for clinical trials.


ESTIMATION OF SAFE STARTING DOSE AND SAFETY ASSESSMENT AND RISK–BENEFIT ANALYSIS

In addition to allowing identification of target organ toxicities, the aim of non-clinical safety studies is to yield data that will provide the basis for estimating the safe starting dose for clinical trials. The data should also inform the choice of dose regimen and dose esca-lations in early phase clinical trials and form the basis of risk–benefit analyses for clinical trial protocols.

Traditionally, selection of doses for first-into-human clinical trials has been based on the no observed effect level (NOEL) or no observed adverse effect level (NOAEL) and, where appropriate, the systemic exposures achieved at these levels. A figure for the maximum human starting dose can then be assessed using allometric scaling and the applica-tion of safety factors, as considered appropriate by the Sponsor and Investigator. There are currently no international guidelines on the estimation of the safe starting doses for a clinical trial; however, the FDA has issued draft guidance on this subject (FDA, 2002). The guideline describes an algorithm for deriving the maximum recommended starting dose for first-into-human clinical trials, recommending that a standard procedure is used to select this dose. The algorithm utilises the NOAEL observed in the most sensitive species and converts this to a human equiv-alent dose, using a conversion factor based on body surface area, or, where more appropriate, using scal-ing on a mg/kg basis. Safety factors are then applied to obtain the maximum starting dose.

There is no equivalent European regulatory guid-ance on setting the starting dose; however, accord-ing to the ICH GCP guideline (EMEA, 1995) the route of administration, dose levels and dosage regi-men proposed by the Sponsor and Investigator should be justified in the protocol. Sometimes the justifica-tions offered in the protocol are brief, but in any case the proposed dose and regimen should be thoroughly examined in the risk–benefit analysis that is included in the Investigational Medicinal Product Dossier that is submitted to the regulatory authorities as part of the clinical trial application in European Member States (European Commission, 2005).

In summary, the risk–benefit analysis examines the proposed clinical trial protocol, together with the main findings of the non-clinical safety studies and assesses whether the risks associated with the trial are acceptable. The European guidance on clinical trial applications (European Commission, 2005) indicates that the risk– benefit analysis should be a brief, integrated summary that critically analyses the non-clinical and clinical data in relation to the proposed trial. The author(s) of the analysis should use the relevant pharmacology, toxicology and kinetic results as the basis of extrap-olation to indicate possible risks in humans. Where appropriate, the safety margins should be discussed in terms of relative systemic exposure to the investi-gational product rather than in terms of applied dose. The analysis should include discussion of the clinical relevance of any findings from non-clinical and clini-cal studies, together with recommendations for further monitoring of effects and safety in clinical trials.

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