Making prudent healthcare happen

Introducing prudent principles in precision medicine

  • Dr Berwyn Clarke, Principal, Pandion Biotech Consulting Ltd
  • Ifan Evans, Deputy Director, Healthcare Innovation, Department for Health and Social Services, Welsh Government


This article describes how ‘precision medicine’ uses genetic data and other diagnostic biomarkers to select the most appropriate treatment for individuals. This delivers better outcomes for people, is safer, and is also more cost-effective because people receive the right treatment first time.

Wales has a good foundation for the introduction of precision medicine, because of its national approach to services and its research excellence in key areas. Precision medicine and prudent healthcare are complementary, but it is vital that NHS Wales engages with industry and academia to deliver the most suitable treatment to people.


What is precision medicine?

Clinical medicine has changed significantly over the last ten years. In the past there has been a fundamentally ‘intuitive’ approach towards diagnosis and treatment, but new tools and techniques are available to allow more accurate diagnosis and precise treatment to be tailored to an individual patient. This is important because people differ in the way they respond to a medicine – the same drug will cure most people, have no therapeutic benefit in others, and in a few cases will cause harmful side effects. This is well known, but only now do we have the ability to understand and to take account of this variation on an individual basis:

“Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.”

Sir William Osler, Emeritus Professor of Medicine, Oxford University, 1849–1919[1]

Even though there have been huge and significant developments in clinical technology these two parameters of efficacy and toxicity remain major drivers for the evolution of personalised and precision medicine.[2] The main objective of this ‘precision medicine’ approach is to provide the right drug at the right dose to the right patient at the right time. This speaks directly to principles of prudent healthcare, particularly to the principles of do no harm, undertaking the minimum appropriate intervention, and including the patient in making clinical decisions. It means applying our technology and know-how to making the right diagnosis and selecting the right treatment for an individual patient, at the first attempt.

Precision medicine combines the use of new tools allowing more accurate diagnosis of disease with the tailored selection and use of therapeutics to have maximum benefit and minimal side effects for an individual patient.

A precision medicine pathway is always prudent

Consider a patient who has been diagnosed with cancer. Of the bewildering array of drugs and drug combinations that may successfully shrink a tumour and prolong a person’s life, some could instead make matters worse and give rise to significant side effects. Or, consider someone who attends a doctor’s surgery with a blood pressure related problem. On average, that person will be treated with four different drugs (Richard Hughes, personal communication) before their condition is adequately managed, because we do not know which drug or dose they will react to.

These examples of the essentially intuitive nature of 20th century medicine illustrate how it is based on a sequential trial and error approach, in which the risk of side effects from using the wrong drug is traded for the benefit that will eventually come from selecting the right one. But such an approach is not always beneficial to the individual patient. It also means healthcare providers spend a lot of money on drugs that do not work. However, at the present time, it is the best approach we have.

The precision medicine pathway is different. Here, the doctor draws blood and tissue and a central laboratory then sequences the patient’s entire genome from the sample. This data is then analysed and compared to a secure global ‘bank’ of cancer DNA, other tissue samples, and the outcomes of previous therapies. The completed analysis gives the doctor personalised information about the patient, in the case of cancer the tumour, and an individual therapeutic combination for that individual, including dosage and treatment regimen. These tools are available now for a small but increasing number of illnesses and drugs8.

If we adopt this approach more widely across the NHS in Wales it will reduce harm, improve patient outcomes, and deliver a better patient experience – three of the core principles of prudent healthcare. We will need to meet the additional cost of these new technologies by demonstrating their effectiveness. If accurate diagnosis allows us to only use the appropriate treatment (which includes withholding ineffective treatment from patients) it will reduce the overall cost of drugs. If treatment delivers improved health outcomes at the first attempt and reduces harm, we will reduce demand on the health system and more people will be able to remain economically active for longer.

We are fortunate that the NHS in Wales is well placed to deliver this type of modern-day healthcare because of its national approach to digital data and to providing core healthcare services such as pathology, imaging and genetic services. The size of Wales is also of a scale that allows us to balance the ability to work on whole population data, with an ability to make significant changes to practice and systems in a reasonable timescale. The precision medicine procedures that could be introduced to transform healthcare in Wales – like an all-Wales genetic testing service, a national clinical diagnostics portal, and a single patient record – are already available and could be readily integrated into our healthcare system. As precision medicine is adopted into standard practice, it has the potential to deliver immense health and economic value.

Using precision medicine to do less harm

It is estimated that 20–40 per cent of all patients taking a prescription medicine are either on the wrong drug or on the wrong dose.[3] This means many patients are using drugs that offer reduced or no benefit to them, even though they still have potential side effects and could therefore do harm. In the UK, adverse drug reactions are estimated to cause six per cent of all hospital admissions and cost £500 million a year.[4]

In a prudent healthcare system, we must make using drugs more accurately and effectively a priority. Alongside initiatives such as electronic prescribing, regular drug use reviews, and helping patients to adhere to treatment, precision medicine is an increasingly important part of reducing potential harm from medicines.

The pace of change and adoption may currently be slow, but it is accelerating. We already have diagnostic tools to stratify and optimise some drug therapies. Between 1997 and 2004, 19 drugs were completely removed from the market because of adverse reactions associated with their use. Currently the Federal Drug Agency in the United States lists 138 specific drugs from multiple therapeutic areas which include pharmacogenomics warning or restrictions on the drug label, meaning these should only be administered when specific diagnostic tests are applied to indicate an individual patient is suitable for prescription.[5] An excellent example of this is the prescription of phenytoin. Studies have found that patients with a specific Histocompatibility Antigen (HLA) type have a high risk of developing Stevens Johnson Syndrome or Toxic Epidermal Necrolysis, so alternative anticonvulsive drugs should be prescribed for these identifiable patients.

This area of precision medicine is about avoiding prescribing drugs that can cause unpleasant or even fatal side effects in certain people, based on research evidence linked to genes and other biomarkers. This is good news for these individuals who might otherwise be exposed to risk of harm. And it is good for us as clinicians and healthcare providers, as we do not want to harm patients. But most of all it also good for the population generally, because it will allow the licensing and use of drugs which are effective in some people, but potentially harmful to others. Many such drugs have ‘failed’ in clinical trials, because the historic approach to drug development and licensing has tested safety and toxicity against the whole population. Precision medicine could change this and more drugs will be available but for precise groups of patients.

Adverse drug reactions will never be eliminated using these pharmacogenetic approaches since patient non-compliance, lifestyle factors and other factors will also continue to play a role. However we have sufficient evidence now to support the growing adoption of pharmacogenetics and precision medicine in the developed world.

Using precision medicine to identify the minimum appropriate intervention

Precision medicine is also about selecting those drugs that are likely to have the most beneficial effects in specific patients. Although this principle has been applied in the use of antiviral drugs for many years the real driver for this approach is in oncology. Despite significant efforts and investment from the pharmaceutical industry the efficacy of new cancer drugs had been very disappointing, with only 25 per cent of all licenced new drugs showing any new benefit. Over the last seven to eight years this trend has changed as we have realised that detailed analysis of the specific tumour in an individual patient can reveal clues about whether it will respond to a particular therapy.

This was initially demonstrated for new colorectal drugs developed by Amgen and MerckSerono  (Vectibix and Erbitux respectively). Clinical trials showed the integrity of a specific gene in the tumour, k-ras, had an enormous effect on whether the tumour was likely to respond to the therapy. Tumours with mutations in this gene were unlikely to respond but those with normal genes tended to indicate a very good response to therapy.[6] Similar findings followed rapidly for lung cancer drugs (Tarceva and Iressa) although the specific gene or biomarker in these cases was different.[7] So profound is the connection between the marker and response to therapy that these drugs are now only prescribed after specific diagnostic analyses are performed. As these drugs are extremely expensive it is prudent to have an indication before they are administered about whether a patient is likely to benefit.

This new medical paradigm allows the use of a specific drug only when the relevant ‘companion’ diagnostic is performed beforehand. Because of the clinical benefit for the patient and the efficiency benefit for healthcare providers, drug regulatory authorities are now routinely requiring the exploration of efficacy markers as components of clinical trials. Combining of diagnostics and pharmaceuticals in developmental trials will mean that the majority of new therapeutics will only be available when used with a companion diagnostic.

There are an increasing number of drugs in other disease areas that could be prescribed using the precision medicine approach, for example[8]:

  • Antipsychotics – aripiprazole, risperidone and haloperidol
  • Antidepressants – citalopram, venlafaxine, fluvoxamine, paroxetine, fluoxetine, sertraline and amitriptyline
  • Antiepileptics –phenytoin
  • CNS stimulants – atomoxetine
  • Antidiabetics – glimepiride
  • Cardiovascular drugs – irbesartan, warfarin, losartan and fluvastatin
  • NSAIDs – celecoxib
  • Analgesic drugs – codeine, tramadol
  • Hypnotics and anxiolytics drugs – diazepam
  • Gastrointestinal drugs – lansoprazole and omeprazole

The case for adopting a precision medicine pathway for these drugs in Wales will depend on a number of factors, including their potential benefits, side effects and their cost. Even so, the evidence is clear that precision medicine can be applied to an increasing number of illnesses and drug groups, and that new drugs are being developed and licenced on terms that will require a precision medicine pathway. As healthcare providers we will need to prepare for these changes in clinical practice.

Precision medicine and the whole genome

The identification of individual biomarkers such as k-ras has been a radical breakthrough in managing colorectal and lung cancers. Unfortunately, not all patients respond to the indicated drugs as predicted, even though their tumour profiles appear to match the relevant biomarker. Research has shown that other components of the target biochemical pathway may also be mutated, and if that is the case, then the patient may still not respond. This suggests that, for an individual tumour, future drug prescription to identify efficacy may require analysis of multiple factors simultaneously. As a result, we are now seeing new diagnostic platforms being developed to analyse multiple biomarkers at the same time.

The technology used to do this is evolving quickly, and as the price of genetic sequencing falls it is moving from sampling biomarkers to sampling the whole genome. This is a powerful emerging diagnostic tool because it enables more complex analysis of multiple pieces of clinical information at the same time – whole genome data can be used clinically to assess potential tumour susceptibility, and to provide all the pharmacogenetic information needed for a range of companion diagnostic markers.

The infrastructure for precision medicine

It is likely that within a decade, patients will provide access to their own pharmacogenetic profile as part of standard clinical practice. This information will only need to be collected once because an individual’s basic genetic information does not vary over time, allowing data to be stored for future reference and used against new drugs and precision medicine diagnoses. The technology for collecting this genetic information is already available. Our digital infrastructure in Wales is already part way there. A closer interface between NHS Wales and High Performance Computing Wales (HPC) could go a long way towards providing the required technology platform. We already have a good foundation for implementing a national system in every hospital and GP surgery in Wales, so clinicians have access to information about the drugs an individual will respond to, the dose advised and any contraindications that need to be monitored.

Technology is not the main barrier. Our major challenges most likely to emerge will be our resistance to change and the public concern about the generation and use of genetic information. It is extremely important that we offer a comprehensive programme to develop patient understanding and healthcare professional education. We will need to support this with a persuasive and co-ordinated effort to drive adoption and change in clinical practice. This would emphasise the close alignment between precision medicine and prudent healthcare to deliver treatment and care aligned with the principles of doing no harm, adopting the minimum appropriate intervention, and focusing on individual patient needs and preferences. We will also need to put in place a robust approach to information governance, including appropriate data security measures, patient consent for retention and use of genetic information, and mechanisms to manage access to data for research and innovation. Governance must also draw on the principles of patient equity and co-responsibility, which is embedded in prudent healthcare.

A precision medicine platform for collaborative innovation

This technology delivers so much data that new analytical tools will be needed to filter, analyse, interpret and report the required information, according to patient and clinician need. Although most of the current focus of precision medicine lies in the use of genomic information, there are other technologies that will provide vital clinical tools. These include other biomarker sources such as proteins in blood or body fluids as well as other metabolites that can be used as markers of health or illness.

This is an important emerging space for research, innovation, and health improvement. Wales is well placed to exploit this emerging market because we can combine expertise in data, diagnostics and drugs with a national clinical research infrastructure and a planned healthcare delivery system. Changes in research and practice will go hand in hand, as will development in diagnostics and pharmaceuticals.

There are many research programmes in Welsh universities that may also provide future tools for precision medicine, but we need to create a mechanism which translates research into clinical practice more efficiently and at pace. Wales has a strong clinical trial and pharmaceutical manufacturing supply chain and has invested in drug discovery and development through Ser Cymru, the National Research Network in Health and Life Sciences. We have outstanding research in genetics. The NHS in Wales has a national bio-banking service and an all-Wales genetic testing service. In the life sciences sector we have strong clusters of diagnostics and medical technology businesses. To drive innovation we need to ensure that there is a close interaction between Welsh businesses, our universities, and our healthcare system.

Globally, the current approach to bringing these sectors together is the establishment of high throughput, high-quality Next Generation Sequencing (NGS) service laboratories to deliver the necessary biomarker information to the clinician. For example, EKF Diagnostics, a Welsh diagnostics company, has recently acquired a US NGS service provider, Selah Genomics, which already offers such a service. It would be relatively straightforward to transfer this model to a centralised setting as the core of a new national clinical diagnostics centre in Wales. This centre would also be a key element in training and educating healthcare providers in new technologies and services. In addition it could also be linked to a biobank repository for clinical data and samples, providing a platform for future research and the evaluation of new technologies and approaches.

This wealth of new information would be integrated with clinical records, enabling clinicians in Wales to deliver precision medicine. For example, making pharmacogenetic information available to GPs in primary care would enable diagnosis and prescription to be made immediately, without specialist hospital referral.


Precision medicine is no longer an optional exercise in any healthcare system. New drug labelling requirements, more accurate diagnostic tools and simple health economic factors are driving the shift away from historic intuitive approaches. This process is set to accelerate. It is very strongly aligned with principles of prudent healthcare because its main objectives are the reduction of harm to patients, and the selection of the minimum appropriate intervention, based on evidence. Both of these principles can be achieved by putting the individual’s data at the centre of clinical diagnosis and treatment selection. This will not in any way exclude discussions between patient and provider about preferred outcomes. In fact it improves that discussion because it introduces more certainty to the link between diagnosis, intervention and results.

Precision medicine is a challenge for every healthcare system in the world. It is not easy to collect genetic data on a whole population, to provide the infrastructure and create the trust to store that information, or to build the systems to analyse and use it in routine practice. It is also hard to find the expertise to develop new analyses, to drive innovation and to create value. But Wales is exceptionally well positioned to do this, and we could develop a truly world-class example of system wide implementation of precision medicine, building on all the assets and opportunities we already have. If we can do this, it will be of immense benefit to patients in Wales, and will make a significant contribution to achieving prudent healthcare.

Next steps
  • Establish a Welsh National Clinical Diagnostics Centre offering,
    • state of the art national testing
    • sample repository
    • health economics
    • training function
    • new technology assessment
    • IT hub for precision medicine.
  • Establish a National Precision Medicine Advisory Panel with
    • industry
    • academia
    • the NHS
    • Welsh Government Life Science Sector Panel
    • High Performance Computing.
  • Provide a Precision Medicine Strategic Development Fund
  • Establish national patient education and public awareness programmes regarding genetic testing
  • Establish precision medicine best practice by
    • visiting commercial laboratories
    • enabling establishment of a national high throughput, high-quality NGS service laboratory, based on the EKF Diagnostics / Selah Genomics model
    • providing data security and interpretation.


  1. Osler, W. On the Educational Value of the Medical Society in Yale Medical Journal 1903; 9:325
  2. Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med 2010; 363:301-304.
  3. Spear BB, Heath-Chiozzi M, Huff J. Clinical application of pharmacogenetics. Trends Mol Med 2001;7:201-204.
  4. Pirmohamed M, James S, Meakin S, Green C, Scott AK, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004;329:15-19.
  5. FDA US Food and Drug Administration [Internet] [updated 2014 August 18; cited YEAR MONTH DATE]; Available at
  6. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for Panitumumab Efficacy in Patients with Metastatic Colorectal Cancer. J Clin Oncology 2008;26:1626-1634
  7. Mok TS, Wu Y-L et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma N Eng J Med 2009; 361: 947-957
  8. Age of Personalized Medicine [Internet] [cited 2014 September 14]; Available at


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One Comment

  1. Excellent article. Shows clear benefits of this approach. Overall and commenting on several other articles in the document, there must be more collaboration between ABC academia, business and clinical to innovate where potential benefits to each are clear. Funding mechanisms should also be more innovatively structured and focussed. Funding is directed at academia and business but the clinical also needs to be
    resourced to get a true ABC culture developing and growing in an environment where it is not a financial or resource burden to the C of the ABC.

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Watch Dr Berwyn Clarke talk more about this article, click the video.

“Precision medicine combines the use of new tools allowing more accurate diagnosis of disease with the tailored selection and use of therapeutics to have maximum benefit and minimal side effects for an individual patient.”

Making it happen

  1. The introduction of precision medicine is not optional - drugs will increasingly require a specific biomarker test before they can be used, so healthcare providers must develop their capability in this area to have access to new treatments.
  2. Precision medicine is beneficial to patients and healthcare providers - it uses genetic data and other diagnostic biomarkers to select the most appropriate treatment for a particular individual at the first attempt, in order to deliver better outcomes for the patient, to be safer, and to be more cost-effective.
  3. Wales has a good foundation for the introduction of precision medicine – because of its national approach to services, its research excellence in key areas, and the way that precision medicine and prudent healthcare are complementary – but it is vital that NHS Wales engages with industry and academia.