First Time in Man (FTIM) Clinical Trials in the EU
Until the implementation of the Clinical Trials Directive in May 2004, Phase I clinical trials conducted in the UK were not subject to regulatory control: ethics approval was sufficient. It might then be considered ironic that less than 2 years after regulatory controls were introduced a Phase I clinical study in the UK should give rise to such a serious, severe and well publicised safety alert as TGN1412.
As a direct result of that event, and within a timeframe of almost unprecedented brevity in CHMP history, the "Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products" was issued. The guideline covers review of nonclinical safety prior to the first administration in humans and the design and conduct of trials in the initial phase of single and ascending doses during the clinical development. A large number of situations have been identified where special consideration or heightened precautions are warranted, for example:
- The product has a novel mode of action, or acts on a target which is connected to multiple signaling pathways
- The physiological response is of long duration or not easily reversible
- The available animal species/models or surrogates are perceived to be of questionable relevance for thorough investigation of the pharmacological and toxicological effects of the medicinal product
- Assays are not qualified and/or validated to ensure their reliability, thus the doses used in nonclinical studies may be poorly defined and mislead the interpretation of what is a safe dose
- There are differences in the product quality attributes of the nonclinical and clinical material
The use of the no observable adverse effect level (NOAEL) and minimal anticipated biological effect level (MABEL) to calculate the starting dose is discussed, as are several protocol elements designed to minimise risk, including administering the product to only one subject initially and allowing adequate observation time before dosing second and subsequent subjects.
The UK authorities have gone a step further in the assessment of FTIM studies with products that might present unusual risk, by introducing an assessment by an Expert Advisory Group (EAG) and the Commission of Human Medicines. As the EAG meets only every alternate month this extra step has to be factored into your clinical trial programme. The clinical trial authorisation application (CTA) must contain data specifically to address the safety concerns pertinent to the product/protocol under assessment and has to be submitted according to the EAG meeting timetable. The decision is received about 5 weeks later.
Experience since the introduction of the FTIM guidelines suggests some CAs are more cautious than others in their approach to these studies, and there is undoubtedly discussion between the assessors in different countries.
If this all seems rather daunting, don't worry! Akos can help you with project planning, dossier preparation, submission and support to get your Phase I FTIM study up and running with minimal delay to your development programme.
To discuss your regulatory questions with Akos please contact us:
Tel: +44 (0)1582 766 339
Email: regulatory@akos.co.uk