Criteria influencing the clinical uptake of pharmacogenomic strategies

Medical need

Pharmacogenomic approaches are especially valuable where they help to avoid acute outcomes: adverse reactions with grave clinical consequences, severe effects on quality of life, and high financial cost. For example, hypersensitivity reactions caused by abacavir (Ziagen), an antiretroviral drug, in the presence of the HLA-5701^*B variant in white populations can have severe health consequences14—implying that genotyping before prescription can have an important positive effect on patients' quality of life. This is in addition to the serious and costly nature of HIV infection itself, which abacavir is intended to treat. Because of the substantial cost of treatment and potential for avoiding serious adverse events, disease management strategies are similarly under investigation for viral genotyping when treating hepatitis C patients with interferon and ribavirin.15

Where adverse reactions against existing drugs are mild in health and monetary terms, industry may conclude that large expenditure on regulatory issues and research and development will not justify the added benefit; alternately, clinicians may prefer to use traditional prescription by trial and error rather than incorporate molecular testing into their practice. From a broad health systems perspective, costs to consider include counselling, additional clinical visits to deal with complications, and other appropriate follow up.16

Clinical validity and utility of testing

The importance of effective genetic testing for pharmacogenomics means that many factors influencing pharmacogenomics have already been identified by studies analysing genetic testing. For example, tests should be both sensitive and specific for the variant(s) being studied. However, inherent uncertainties can none the less “represent a major limitation”1 to clinical validity since test results represent probabilistic rather than definitive information, and health professionals must interpret tests with this in mind. In the context of pharmacogenomics, this means that, although the identification and characterisation of differing genetic or molecular profiles is likely to make the response to a drug more predictable than before, in some cases individuals will inevitably respond or not respond to a particular drug when testing predicts otherwise (figure).12

Clinical validity of testing—the probabilistic nature of pharmacogenomics. Although pharmacogenomic test results will enable health professionals to predict drug response better, individual patients may still react in an unpredictable manner. Following testing, individuals classified as responders, for example, are likely to respond to a prescribed drug (far right), but may (rarely but significantly) be non-responders (middle area of overlap). Similarly, individuals classified as non-responders will probably not respond to a prescribed drug (far left), but may (rarely but significantly) be responders (middle area of overlap). A comparable situation will exist for the overlap between responders and patients predicted to experience adverse reactions. Adapted from reference 12

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Strategies will thus be more successful when a drug prescribed on the basis of genotype has a low probability of false positive and false negative responses both within and across populations. In the case of abacavir, HLA-5701^*B is neither 100% sensitive nor specific for hypersensitivity reactions: many people experiencing adverse reactions to drugs lack HLA-5701^*B, whereas others who can tolerate abacavir possess the variant. The inconsistency in people without the variant experiencing adverse reactions was seen in white people (48-60% sensitivity) but was particularly pronounced in Hispanic patients (20-22% sensitivity) and even more so in black patients, for whom presence of the allele was not statistically associated with hypersensitivity,17 a finding that points to the existence of multiple parallel pathways and complex heterogeneity. As the field evolves further, drug response caused by gene variants whose prevalence differs across regions and populations will therefore require recording and sharing of information, trial results, and increased regulatory collaboration across jurisdictions. This will help to ensure that the safety of patients and the “first, do no harm” tenet of medicine are upheld rigorously.

At the level of clinical trials, because the number of patients required to develop a robust test increases drastically as the prevalence of a relevant variant decreases, the most clinically valuable compounds will be those for which adverse response or optimal efficacy genotypes occur at a notable frequency—not just in the trial population but in the patient population as a whole. With clinical utility in mind, developers will naturally focus on identifying gene variants or expression patterns that are predicted to affect response dramatically rather than marginally, based on a current understanding of molecular characteristics and disease pathogenesis. Both of these criteria are fulfilled by trastuzumab (Herceptin), a monoclonal antibody targeting tumours with overexpression of the ERBB2 (HER2) protein, which account for roughly 25-30% of cases of metastatic breast cancer. Pre-screening for HER2 expression levels reportedly resulted in one ninth the stage III trial size population that would have been required otherwise18; for tumours with overexpression, combination treatments including trastuzumab showed statistically significant improvements in median times to progression of disease, duration of response, failure of treatment, and survival time.19

A final consideration is the longer term utility of information derived from a pharmacogenomic test: the results of genotyping at one of the cytochrome P450 loci, which encode enzymes that metabolise many drugs (including codeine and clozapine, among others),20 represent a case where test results ordered for one prescription may well be relevant and revealing for other diseases and future prescriptions.

Relative ease of use

Rapid, reliable, inexpensive, and easily interpretable molecular tests improve the value of pharmacogenomic approaches for clinicians, especially where current non-genetic methods of monitoring drug response are inefficient or unavailable.21 Genomic technologies used to predict drug response must also be robust and widely accessible in diverse settings in clinical practice. Widespread clinical uptake of trastuzumab, for example, was enabled by the approval of an immunohistochemistry test that uses well established methods and readily available equipment to determine HER2 expression levels and select patients who are most likely to benefit from treatment, thereby avoiding some unnecessary prescription. Conversely, although evidence points to a major genetic role in essential hypertension, existing techniques to monitor blood pressure already allow doctors to adjust drug selection and dosage quickly when necessary, making new strategies involving pharmacogenomic testing less appealing.

In the case of patients with acute lymphocytic leukaemia and a high risk thiopurine methyl transferase (TPMT) genotype, which produces a thiopurine metabolising enzyme associated with extreme toxicity to the drug 6-mercaptopurine, some researchers have argued against molecular testing and in favour of the current standard, regular red blood cell counts.22 They believe that moving to molecular testing could delay important treatment and would entail additional cost and complexity. There are also fears that its interpretation might confound doctors, although an ongoing debate has prompted the US Food and Drug Administration to undertake a formal review of the genetic risk of 6-mercaptopurine.

The importance of easy to use molecular testing to inform prescription is underlined by the statement that regulators would be willing to assess diagnostic tests alongside their linked, pharmacogenomics based drug candidates,23 as was done with trastuzumab in the United States. It also meshes well with the argument that predictive genetic testing has increased utility when traditional screening and surveillance methods are inefficient or expensive.

Existing choice of treatments

As knowledge of biological pathways grows and the mechanisms of drug action and metabolism become clearer, pharmacogenomic opportunities and strategies should be evaluated in the context of the existing choice of treatments. This context will be fed into by other criteria already established. Where many drugs are already available and are known to target a variety of pathways, the availability of correlation studies—along with robust, rapid, and reliable molecular profiling in the clinical setting—will assume greater importance. Where few drugs exist for an illness but often result in severe and costly adverse events, clinical pharmacogenomic testing will be critical to avoiding adverse reactions to drugs, and a more urgent need arises to develop medicines designed for a particular underserved molecular profile or population.

The suggestion that drug development resources should be concentrated on cases where fewer treatment options exist none the less leaves the door open for clinical diagnostic testing to refine prescription where only a limited set of drugs is available: in particular, modulation of dosage is an already existing and powerful tool, enabling doctors to improve treatment response or minimise adverse effects. Variants of CYP2D6, a cytochrome P450 enzyme found in the liver,20 can result in a spectrum of activity depending on the medicine in question, from people with a slow metabolism who experience adverse effects because of an accumulation of drugs in the body, to people with an ultrarapid metabolism who only experience a therapeutic effect when prescribed drugs at a high concentration. Patients with acute lymphocytic leukaemia can similarly be treated by modulating the dosage on the basis of their TPMT risk profile. One consultant argues that pharmacogenomics will reap its largest revenue gains by expanding the clinical uptake of existing drugs (by greater flexibility in the adjustment of dosages)18 rather than by stratifying existing markets through a greater selection of drugs.