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Drug Discovery Today

Volume 22, Issue 1, January 2017, Pages 173-179
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Defining drug response for stratified medicine

https://doi.org/10.1016/j.drudis.2016.10.016Get rights and content

Highlights

  • Different people can respond differently to similar drug treatment regimes.

  • The risk of adverse drug reactions can also vary between individuals.

  • Stratified medicine uses this variation to identify appropriate treatments.

  • Potential effects of variability need to be considered at the start of studies.

  • Definitions of variability, and methods to assess it, require standardisation.

The premise for stratified medicine is that drug efficacy, drug safety, or both, vary between groups of patients, and biomarkers can be used to facilitate more targeted prescribing, with the aim of improving the benefit:risk ratio of treatment. However, many factors can contribute to the variability in response to drug treatment. Inadequate characterisation of the nature and degree of variability can lead to the identification of biomarkers that have limited utility in clinical settings. Here, we discuss the complexities associated with the investigation of variability in drug efficacy and drug safety, and how consideration of these issues a priori, together with standardisation of phenotypes, can increase both the efficiency of stratification procedures and identification of biomarkers with the potential for clinical impact.

Introduction

Stratified medicine is the differential prescribing of medications, or treatment programs, to groups of individuals based on attributes other than the symptoms resulting from their disease [1] (Fig. 1). The term is often considered synonymous with ‘personalised’, ‘precision’, or even ‘P4’ medicine. Stratification could be seen as less ambitious, and more immediately realisable, than the other approaches because of its focus on identifying groups needing particular treatments rather than the direct optimisation of treatment for each individual patient [2]. Its purpose is to improve outcomes by refining drug dosages or by administering more appropriate treatments to specific groups of patients. It requires the identification of appropriate subgroups of individuals, through the use of biomarkers, and suitable measures of the benefits and costs of the potential treatments for each group. The advantages of stratified medicine flow from the existence of subgroups, or strata, of patients, such that individuals within the same subgroup tend to have similar responses to treatment, whereas those in different strata respond differently and require different treatment.

The evaluation of variability in individuals’ responses to treatments, in terms of both efficacy and safety (Fig. 2), is central to assessing potential benefits from stratified medicine. Although this requirement is obvious, fulfilling it is more difficult than is generally appreciated. A lack of clarity about the extent and causes of variability in the effects of a particular treatment can result in efforts being focussed on investigations of inappropriate or irrelevant biomarkers. Therefore, in this position paper, we consider issues relating to three areas with respect to drug response: (i) the variability of drug outcomes (in terms of both efficacy and adverse effects); (ii) the identification of subgroups that show differential efficacious responses; and (iii) the identification of subgroups most at risk of adverse drug outcomes.

This position paper was developed out of discussions during a workshop on ‘Defining Drug Response for Stratified Medicine’ held by the UK Pharmacogenetics and Stratified Medicine Network.

Section snippets

Variability in drug response

In 1997, Sir Richard Sykes predicted:

‘it will soon be possible for patients in clinical trials to undergo genetic tests to identify those individuals who will respond favourably to the drug candidate, based on their genotype. This will translate into smaller, more effective clinical trials with corresponding cost savings and ultimately better treatment in general practice. Individual patients will be targeted with specific treatment and personalised dosing regimens to maximise efficacy and

Efficacy and drug response

If efficacy is the beneficial response from treatment, then trials and retrospective studies provide estimates of the efficacy of specific doses of drugs for particular sets of individuals. The use of their results in traditional, ‘non-stratified’, medicine requires two sets of decisions: (i) what treatment would be most appropriate for individuals similar to those that were studied?; and (ii) what wider group of patients can be considered sufficiently similar to the study population to be

Defining drug efficacy

Hard endpoints, such as all-cause mortality or rates of cardiovascular death, are the simplest outcomes of drug action to interpret. However, very large studies with lengthy follow-up can be necessary to produce clear results from such outcomes. Therefore, surrogate endpoints are often used to evaluate the efficacy of drugs. Many of these surrogates, such as blood pressure, glycosylated haemoglobin and low-density lipoprotein (LDL) cholesterol, are measured on continuous scales. The use of such

The use of efficacy in stratification

As well as the issues that concern the definition of drug efficacy per se, there are further ones that affect the identification of strata, the groups of individuals who respond to treatment in distinct ways. Most of the issues around the definition of efficacy are exactly the same for stratified medicine as for any other decisions about treatment. Stratification can almost be considered as an add-on, taking the clinically relevant definition of efficacy and applying it to the splitting of the

Stratification to reduce adverse reactions to drugs

Medicines are not always effective in improving health: some patients have adverse reactions to drugs. These cause 6.5% of admissions into hospital [17], including 2.5% emergency admissions [18]. 14.7% of inpatients develop an adverse drug reaction (ADR) in hospital [19], and 25% of primary care consultations involve patients seeking help for an ADR [20].

ADRs can be classified as on target (predictable from the known primary or secondary pharmacology of the drug, and with a clear

Sources of variability in drug safety studies

Many of the issues discussed above with regard to drug efficacy studies are also important for drug safety. In addition, other specific areas also need to be considered for drug safety.

Concluding remarks

Many areas, such as cancer, and inflammatory and rare diseases, have made great progress in stratifying patients’ treatment to deliver ‘the right drug, at the right time, at the right dose’. Grouping patients into strata based on their genetic profile, or molecular basis of their disease, then treating them based on their strata (rather than the symptoms they present) has already improved healthcare. Not only do patients recover more quickly, but there is also the potential to improve drug

Acknowledgements

The article is based on a workshop held by the UK Pharmacogenetics and Stratified Medicine Network (www.uk-pgx-stratmed.co.uk/), which was funded by the Knowledge Transfer Network and Innovate UK at the time of the workshop. M.P. is an NIHR Senior Investigator and acknowledges the support of the MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, both in Liverpool. R.S. is also an NIHR Senior Investigator, and acknowledges the support of the NIHR Liverpool Pancreas

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