Safety First

When it comes to safety, drug manufacturers take responsibility for unknown outcomes. To minimise risk, safety planning and assessment should be key components of every drug development programme, especially when it comes to high-risk medicine. By definition, high-risk medicine includes biological molecules with novel mechanisms, new agents with a highly species-specific action, and drugs directed towards immune system targets.

In March 2006, a clinical study involving a group of healthy volunteers in the UK demonstrated the need to take responsibility for safety in order to minimise risk. The volunteers were given an intravenous (IV) dose of an experimental immunotherapeutic as a part of an ascending single dose safety and tolerability study. Within a few hours of administration, all subjects exhibited severe reactions which progressed to multiple organ failure.

As a result of this tragedy, sciatic and regulatory initiatives focused on designing a comprehensive approach to the safety assessment of ‘high-risk’ medicines have been enacted. For example, the EMEA’s Committee for Medicinal Products for Human Use (CHMP) published the ‘Guideline on Requirements for First in Human (FIH) Clinical Trials for Potential High-Risk Medicinal Products’ in July 2007 (see Figure 1). In addition to the CHMP guideline, which applies to both biologics and New Chemical Entities (NCEs), the International Committee on the Harmonisation of Technical Requirements for Registration developed guidance documents on the development of biologics. This article offers recommendations and strategies to address these new safety requirements, from preclinical and first-inhuman study design to monitoring.

The preclinical testing strategy encompasses pharmacodynamic (PD), pharmacokinetic (PK), toxicology and safety pharmacology studies. Key objectives of these studies are to establish a safety profile, demonstrate the relevance of the animal model, and provide a scientific basis for the calculations of the first human dose. Pharmacodynamic studies assist in the characterisation of the pharmacological effects and identification of the most appropriate animal model.