Masterstudiengang "Drug Regulatory Affairs"

Language: English

 

Pharmacogenomics promises to revolutionise medicine with better defined dosing, identification of poor responders and identification of patients likely to develop adverse drug reactions. This is often referred to as a move to personalised medicine. To fulfil this promise pharmacogenomics has to be included in drug development programmes. Except for certain pharmacokinetic studies, there are few regulatory requirements to include pharmacogenomics into clinical trials. Sponsors, considering whether to include pharmacogenomics on a voluntary basis, have to understand the regulatory implications for the approval of the drug. This thesis discusses the criteria that may be considered when integrating pharmacogenomics into drug development programmes and assesses the regulatory implications.

In healthy volunteer Phase 1 pharmacokinetic studies and drug interaction studies, genotyping is mandated by the relevant guidelines if a drug is known to be predominately metabolised by one enzyme. The influence of genetic polymorphisms on drug metabolising enzymes of the CYP family is well established, and a number of validated tests are available. The influence of other metabolising or transporting systems is less well understood, and validated tests may not be available. In this case tests for these markers may be included in Phase 1 studies on an exploratory basis. Based on the Phase 1 results, genotyping may be continued into patient studies to further characterise the relationship between genotype and pharmacokinetics, genotype and pharmacodynamics and, ultimately, to predict drug response. The genetic aspects of pharmacokinetic variability may be translated into warnings in the SPC. As yet, there are very few examples where genotyping is recommended before dosing.

The decision to include pharmacogenomics in Phase 2/3 efficacy and safety studies may be based on several factors including the type of disease, the level of knowledge on the genetic involvement in primary or secondary pharmacodynamics and the availability and validity of the genomic tests. Depending on the validity of the genomic biomarkers, pharmacogenomics in safety and efficacy studies may be used for patient selection, as part of the confirmatory analysis, as part of the supporting analyses or in an exploratory fashion. Accordingly, the results may be reflected in different parts of the SPC, or may not be reflected at all.

When developing drugs for severe diseases with a clear monogenetic component to the mechanism of drug action (e.g. targeted cancer therapy drugs), the inclusion of pharmacogenomics seems obvious. Severe adverse events in a small number of patients may also lead to exploring pharmacogenomics. Here, excluding patients at risk may make the drug viable without significantly restricting the patient population.

When dealing with less severe diseases and adverse events, there is less incentive to study pharmacogenomics. For example, the identification of subgroups who are less likely to respond may restrict the market potential of the new drug. However, most pharmacodynamic drug effects are polygenetic in nature, and in most cases pharmacogenomics will merely provide different levels of risk (response or adverse reactions), but will not result in label restrictions.

Both, FDA and EMEA, encourage the integration of pharmacogenomics into clinical development programmes, including the use of exploratory markers that are unlikely to be used for regulatory decision making. To facilitate communication between the pharmaceutical industry and regulators, both agencies have established processes by which sponsors can submit and discuss pharmacogenomic plans and data. Joint meetings with both agencies are also possible.

In both regulatory territories all relevant information has to be submitted as part of submissions for new drugs. In the context of genomic data, FDA provides clear guidance on timing and format of mandatory and voluntary genomic data submissions. The main criteria for these submissions are the validity of the biomarkers and the intended use in label claims.

At this point, most pharmacogenomic tests are exploratory, and it is up to the pharmaceutical companies to include these in their clinical development programmes. Advantages may include better characterised drugs with clearer defined patient populations, more precise dosing and less adverse reactions. The disadvantages may include increased development costs, mandated genomic tests and restricted patient populations. The uptake of pharmacogenomics may be slow, but as science progresses and the regulatory requirements become clearer, pharmacogenomics is likely to become an integral part of drug development.