Pharmacogenetics
Will pharmacogenetic testing in clinical trials become mandatory?
3.5 One recent survey suggested that most pharmaceutical companies believe that within five years, at least 50% of clinical trials will involve obtaining genetic data from participants.3 Aside from economic considerations, there may be other pressures to incorporate pharmacogenetic testing into the process of developing new medicines. This could include testing samples taken from participants during the early stages of a clinical trial with a view to identifying pharmacogenetic effects on response to treatment, or testing patients during the phase of monitoring and surveillance if adverse reactions come to light. These pressures may come from regulators, concerned with ensuring the optimal conditions for the safe use of new medicines, or from the threat of legal challenges from patients affected by adverse reactions. We consider each of these in turn.
Regulatory requirements
3.6 There have recently been discussions by regulatory bodies including the Food and Drug Administration (FDA) and European Medicines Evaluation Agency (EMEA) regarding strategies for incorporating pharmacogenetic analysis into the process of licensing medicines. At a meeting in April 2003, the Science Advisory Committee of the FDA stated that it would not require pharmacogenetic testing in all clinical trials. However the draft proposal discussed at the meeting suggested that the FDA would require access to any data used in evaluating the safety or efficacy of medicines during development. This would include, for example, any data collected during the screening of patients before recruitment into a Phase I clinical trial and data used in determining dosage. In the case of pharmacogenetic data used solely for research purposes, the FDA plans to establish an Interdisciplinary Pharmacogenomics Review Group to consider data. However, these data would not be used in the process of approving or refusing a medicine. This ‘safe harbour’ would allow the FDA to become familiar with new technologies and products so that it would be equipped to evaluate similar information when products based on pharmacogenetic data begin to be produced.4
| Phase I |
| These studies assess the pharmacodynamics and pharmacokinetics of a potential new medicine in a small number of healthy human volunteers (20–80). The aims are to identify the dosage range to be explored in the clinical trials involving patients and, sometimes, to confirm that the medicine produces, in humans, the effects anticipated in preclinical studies. Phase I studies usually take several months to complete. |
| Phase II |
| Approximately 70% of new medicines tested in Phase I pass to Phase II. Trials at this stage usually involve around 100–300 patients, and are designed to investigate whether the potential efficacy of the new medicine is actually realised. These trials will also provide preliminary data on the safety of the new medicine, and information about dosage. Phase II studies may take up to two years to complete. Only if Phase II testing is successful will the medicine progress to Phase III. |
| Phase III |
| At this stage, the medicine is investigated in a larger and more heterogeneous patient population. These studies will confirm or refute the safety and efficacy of the new medicine under conditions more closely resembling clinical practice. The trials are usually double blind and will normally be either placebo-controlled or include comparison with standard treatment, where this exists. Phase III studies may take several years to complete. |
| !!Phase IV (Post-marketing surveillance or Pharmacovigilance) |
| Following regulatory approval, sponsors (typically pharmaceutical companies) conduct further studies to evaluate the longer-term effects of the medicine. Such studies might include the analysis of the cost-effectiveness of the new medicine in comparison to traditional treatments, evaluations of the medicine in a particular population, or assessments of the outcomes for patients after many years of treatment. During this phase, research may also be undertaken to test whether the medicine can treat other conditions. |
| Programmes to develop new medicines can fail at any of these stages. In Phase I, obviously pharmacologically inactive or unsafe medicines are usually discarded. In Phase II, treatments which are not effective will be detected. In Phase III, both efficacy and safety are further characterised. Those medicines which are less effective than existing treatments or which display problems of safety may be discarded. It is more costly to abandon a new product at the later stages of a trial because the length of time required, the number of patients involved, and the amount of data generated all increase as the trial progresses. In Phase IV, after medicines have been licensed, rare adverse reactions may still be identified which, if serious, could lead to the withdrawal of the medicine. |
4 FDA Advisory Committee (2003) Pharmacogenomic Submissions Must Not Jeopardize Drug Development, Abbott’s Spear Says. Available: http://www.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Stories/040903_SciBoardR.htm. Accessed on: 17 June 2003; Kling J (2003) US FDA contemplates collection of pharmacogenomic data, Nat Biotechnol 21: 590.