Technological advances in both diagnostics and therapeutics have the potential to make the treatment of cancer more personalised. This POSTnote discusses the current application of these technologies in the NHS and the financial and logistical challenges involved in providing such treatments.
According to statistics, more than one in three people will develop cancer during their lifetime, with 300,000 cases diagnosed in the UK each year. Over 2 million people are living in the UK after being diagnosed with cancer. The past few decades have seen significant improvements in UK survival rates for certain cancers such as breast and colorectal but there has been poor progress for others, such as lung and pancreatic cancer. Cancer has been the top disease priority for the NHS, with the investment rising year by year, from £3.4bn in 2003 to £5.8bn in 2010. As the UK population ages and cancer incidence increases, in addition to the increase in personalised cancer treatment, the financial burden of cancer services to the NHS is set to rise.
Personalised cancer care is not a new strategy; decisions regarding a patient’s treatment are made taking into account the individual’s disease and personal circumstances, only that the extent to which treatment can be specifically tailored has been limited. Advances in technology and the understanding of cancer biology are leading to more detailed descriptions of a patient’s cancer and better targeted treatments. Such treatments limit damage to healthy tissue and thereby offer significant advantages over conventional chemotherapies.
C. Cancer Diagnosis
Mutations or modifications to DNA can change the amount or function of specific proteins in the cell. As cell behaviour is determined by proteins, such changes can lead to cancerous cell behaviour such as tumour growth. Different cancers contain different types and combinations of these molecular changes. Even within a primary tissue cancer type (such as “breast”), multiple subtypes exist and can be described based on these molecular changes.
For a traditional cancer diagnosis, a tissue sample, or “biopsy”, of the patient’s tumour is analysed. This has involved the visual examination of characteristics such as cell shape and the organisation of the cells. These characteristics are used to make judgements about whether the tissue is normal or cancerous, the stage of the disease and the tissue type of the original tumour in cases whether the disease has spread to other parts of the body. However, this diagnosis does not give information on the molecular changes that underlie the disease.
Cancer biomarkers are molecular changes that can be detected and used to inform:
• Prognosis: by indicating how the disease is likely to progress;
• Treatment: by predicting how the disease will respond to specific therapies;
• Drug dose: by indicating the sped and efficiency at which a patient’s body will process a drug;
• Disease monitoring: by giving an early indication of how the disease is responding to treatment or by showing when the treatment has stopped working.
Diagnostic tests by biomarkers are becoming increasingly important for cancer diagnosis. Examples are as follows:
• Immunohistochemistry (IHC): IHC is a test that uses antibodies to detect specific proteins on the surface of cancer cells. For example, 15-20% of advanced breast cancer patients have high levels of protein HER2 and this identification is important as treatment with Herceptin is effective only in these breast cancer patients;
• Fluorescent in Situ Hybridisation (FISH): FISH is a test that uses fluorescent proves to bind specific DNA sequences. For example, 3-5% of Non-Small Cell Lung Carcinoma (NSCLC) patients have a specific rearrangement in their DNA involving the ALK gene and only this group of NSCLC patients will benefit from treatment with Crizotinib;
• Gene Sequencing: Gene sequencing can detect mutations in DNA. For example, 50% of advanced melanoma patients have a specific mutation in their BRAF gene and only patients that have this mutation will benefit from treatment with Vemurafenib.
Diagnostic Test Regulation and Assessment
Diagnostic tests are regulated by the EU In Vitro Diagnostic Medical Device Directive. Test that fall under the medium, high or self-test categories, defined under the Directive, are assessed and audited through the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). Diagnostic tests developed by, and used in, NHS laboratories (so called “in-house” tests) are exempt from the Directive. NHS Laboratories using these tests are usually accredited by the Clinical Pathology Accreditation (UK) LTD AND ENROLLED IN External Quality Assessment schemes. These assess the accuracy and reliability of testing. However, there are still concerns from industry over the quality of these in-house tests.
There is limited assessment of the clinical validity (the accuracy with which the test identifies or predicts the patient’s clinical status) and the clinical utility (the clinical benefit and cost effectiveness of the test). National Institute for health and Clinical Excellence (NICE) has since established a programme to assess the cost-effectiveness of these technologies and to make recommendations for their use in the NHS. However, this will not result in an automatic requirement for their adoption. In addition, the Department of Health is currently establishing the National Laboratory Medical Catalogue, which will include diagnostic tests with proven clinical utility. It is hoped that these steps to assess the clinical utility of diagnostics better will improve the uptake of innovative technologies in the NHS and address concerns from industry.
Issues with Diagnostic Testing in the NHS
Currently molecular diagnostic tests are paid for by hospital pathology departments. Many Primary Care Trusts will not cover their cost; funding often comes directly from a clinician’s budget on an ad-hoc basis. In theory, the Cancer Drugs Fund can be used to meet the cost of a diagnostic test if it is required for treatment with a drug covered by the fund, although it is not currently being used for this purpose. Industry has been criticising the lack of clarity over the responsibility for test funding as it can lead to slow uptake of tests and the drugs that depend on them. Some pharmaceutical companies fund the diagnostic test that is necessary to identify patients that will respond to their drug to ensure that their sales are not impeded by the test implementation.
In addition to funding, access to biopsy material can also limit diagnostic testing. Common factors are the location of a tumour and the stage of the disease can make it difficult to obtain a biopsy. For example, lung cancers are particularly tricky to access and typically only small samples of tissue can be collected. If the patient’s disease is too advanced then it may not be possible to take a new biopsy. Currently many molecular diagnostic tests are ordered only in the late stages of a patient’s disease, making it less likely that a sample can be obtained or that the test will be performed in time to inform treatment decisions.
Future Testing in the NHS
Several recently launched initiatives aim to make molecular diagnostic testing more routine and standardised across the NHS, ensuring that appropriate tests are performed at an earlier stage in a patient’s disease. These initiatives are also developing clinically validated “multiplex” tests. Examples of such initiatives include projects supported by the Technology Strategy Board’s Stratified Medicine Innovation Platform (SMIP) and the Cancer Research UK-led Cancer Stratified Medicine (CSM) programme.
There have been several cancer datasets, of which the largest is being compiled by the International Cancer Genome Consortium (ICGC). The ICGC is coordinating 39 global projects. Data from the CSM will be deposited into a secure database that will be available for authorised researchers to access. These databases can be applied widely, including:
1. Meta-analysis – to inform the development of new drugs and to identify disease biomarkers;
2. Datasets that include clinical information (such as treatment administered) can be used for the retrospective identification of patient groups that respond to treatment;
3. To identify tumour characteristics that result in the resistance of the cancer to treatment.
The value of such data for UK growth was highlighted in the Growth Review (2010) and in the 2011 Autumn Statement. However, the recent announcement of the Clinical Practice Research Datalink was met with public concern over the safety of patient data, the access to these data by industry and the protection of patient identity when such data is used for research.
D. Cancer Treatments
Features that are unique to certain cancers can be identified by meta-analysis of datasets and therapies can be developed against these targets. Such “targeted” therapies will be effective only in patients with these cancer types. As these therapies affect specific features of a cancer, damage to healthy tissue is limited. They therefore offer a significant advantage over conventional chemotherapies.
Current Limitations of Targeted Cancer Treatments
Although many targeted cancer treatments have demonstrated effectiveness against disease progression, very few have shown an overall survival benefit to patients, with most cancers becoming resistant to these treatments within a few months. This resistance is acquired though through the accumulation of genetic changes which drive the evolution of the tumour. New research suggests that different regions within a patient’s tumour contain distinct molecular changes. Such disease complexity also has implications for diagnosis. For example, analysis of a single biopsy may not predict the response of the whole tumour to a targeted therapy.
Clinical Trials and Licensing
The use of biomarkers in clinical trials is hoped to reduce the number of targeted cancer treatments that fail at the clinical trial stage, and may reduce the time of these trials. Tests that identify these biomarkers and are used in the clinical trial of a drug are termed “companion diagnostics”. The US Food and Drugs Administration has started licensing targeted drugs alongside specific companion diagnostics. However, in the EU, although targeted drugs are given marketing authorisation for use by particular patients, the diagnostic test used to identify these patients is not specified.
Affordability of Targeted Cancer Drugs
Targeted cancer drugs incur R&D costs similar to chemotherapies but are aimed at a much smaller potential market; hence the cost per unit is often considerably more than traditional therapies to be economically viable. Current clinical approach of using two or more of these drugs in combination would increase costs still further. The potential cost of these treatments to the NHS is therefore a real concern.
1. NICE Assessment of Targeted Cancer Drugs
To date, NICE has assessed 5 targeted cancer therapies that require a diagnostic test to identify candidate patients. The cost-effectiveness assessment of such drugs carries particular challenges including:
• Assessment of the diagnostic test: currently it is assumed that the test is clinically valid and readily accessible. New guidelines being compiled will stipulate certain performance requirements of these tests;
• Estimating the proportion of patients that will be eligible for treatment.
Clinical data on newly marketed targeted cancer drugs are often limited. The use of “real-world data” (data collected after clinical trials) can therefore be important for the assessment of their cost-effectiveness. Real-world data will become increasingly important for the assessment of drugs under value-based pricing (VBP). VBP will be introduced in the UK in 2014 and should ensure that the pricing of all new drugs closely reflects the value to patients. The collection of such data may be assisted y the Earlier Access to Medicines Scheme. This would allow patient access to certain drugs before licensing but after the completion of phase III clinical trials. Many targeted cancer drugs exceed the NICE threshold for cost-effectiveness. NICE thus recommends many such drugs only under patient access schemes. For example, single fixed price schemes offer the drug to the NHS at a fixed cost per patient, irrespective of the duration of treatment.
2. Cancer Drugs Fund (CDF)
The Cancer Drugs Fund (CDF) came into effect in England in March 2011 and ends in 2014, with £200m per year funding for patient access to cancer drugs that have not yet been assessed or have not been recommended by NICE. Each Strategic Health Authority (SHA) is responsible for compiling their own list of recommended drugs and this has led to regional variation in access. Critics of the CDF argue that the money could be put to better use elsewhere in the NHS. There is also concern over NICE being over-ruled by SHAs.
E. Commissioning Cancer Care
Personalised cancer treatment requires the orchestration of many cancer services. Current commissioning of services through contracts with individual providers has been criticised by health care professionals as causing fragmented services and delays in treatment, while the industry feels that it slows uptake of molecular diagnostics and targeted cancer drugs. NHS London aims to begin commissioning groups of service providers from April 2012 to provide patients with seamless cancer care, only that the commissioning responsibilities have yet to be decided. Cancer Networks has been valued by many people, with its role in coordinating the planning, commissioning and delivery of cancer care across multiple PCTs. The DH has stated that these networks will be retained and strengthened in the new NHS commissioning structure.
• New diagnostic tests are being used to predict which patients will respond to certain cancer treatments. Provision of these test in the NHS is currently variable and there is a need to assess better their clinical accuracy and the benefits of testing;
• The British and international research communities aim to identify new therapeutic targets using large databases of clinical and biological cancer data;
• Emerging cancer treatments are designed for specific groups of cancer patients. Such therapies incur high R&D costs for small markets and are often not recommended for use in the NHS. The Cancer Drugs Fund has improved patient access to such treatments. This fund is due to end in 2014.