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International Clinical Trials

Biomarker Momentum

As the ability to measure and validate multiple biomarkers develops, pharmaceutical, clinical trials and diagnostic companies are discovering new ways to work together. Berwyn Clarke of Lab21 Limited investigates the trends and regulatory implications

Recent years have seen a transformation in the ways in which the pharmaceutical industry develops new medicines, and this has had significant effects on how clinical trials are conducted. Much of this change has been driven by the fact that regulatory bodies now require much more detailed information on the characteristics of the individual study subjects during trials. Biomarkers can be identified which can make drugs more effective through their use in the correct patients, and safer through identification of patients who are more or less likely to be susceptible to significant adverse effects. These biomarkers should also make treatment less costly through the improved ability to prescribe expensive drugs only to those patients most likely to derive clinical benefit.

The concept of using biomarkers in clinical management is becoming a routine part of the clinical development process, and increasing numbers of drugs are being licensed with the requirement that specific diagnostic tests are carried out before the drug can be prescribed. This concept of personalised or stratified medicine is nothing new; it has been recognised for many years that individual patients respond to particular drugs in different ways. In some therapeutic areas, for example in antiretroviral treatment, the use of sophisticated molecular diagnostics for the selection of the most appropriate pharmaceutical for the patient has been in place as a routine part of treatment for the past 20 years. As the use of biomarkers across all areas of medicine increases, and as the requirements of regulatory agencies become more stringent, increasing demands are being placed on pharmaceutical companies, on the CROs who conduct the trials and on the diagnostic laboratories and companies who are developing and using these new biomarker tests.


The recent resurgence in the use of biomarkers in personalised medicine has been largely driven in the oncology therapeutic area, particularly as a consequence of the development of new drugs such as panitumumab (Vectibix, Amgen) and cetuximab (Erbitux, Merck Serono) against colorectal cancer. The development of Vectibix in particular is an excellent example of how biomarkers can influence the acceptance of clinical data by regulatory bodies. In this case, the initial clinical trial data on an unstratified patient group was considered in Europe to indicate that the drug was ineffective, and the submission was rejected. However, when Amgen revisited the patient cohort used during the trial, they realised that the efficacy of the drug was associated with the presence in the tumour of a normal (wild-type) kras gene. In those patients whose tumours displayed specific mutations in the kras gene, it was clear that the drug had insignificant therapeutic benefit in terms of progression-free survival. When the clinical data was resubmitted with this new patient stratification information, a positive outcome was achieved on 20 September 2007, which permitted the use of the drug in patients with tumours with normal kras gene. This was the first time that the European Commission licensed a bowel cancer product with the stipulation that a predictive test should be carried out.

Approximately 60 per cent of patients with advanced bowel cancer have wild type kras, which infers that 60 per cent of all patients should derive clinical benefit from the drug. Unfortunately, this is not the case because these drugs (Vectibix and Erbitux) are only effective in 10-20 per cent of chemotherapy-resistant metastatic colorectal cancer, and the mutations in kras only explain 30-40 per cent of non-responsive cases. Further work from an Italian study revealed that mutations in a second gene, braf, were also significant in the response of individual tumours to these drugs. In this study, 11 of 79 patients who had normal kras, and thus should have been amenable to therapy, had mutations in braf, and all tumours with these mutations were resistant to therapy. Given the fact that kras and braf share the same biochemical pathway, the requirement to have both genes in wild-type form is unsurprising, but now indicates that patients could, theoretically, be tested for both these biomarkers. Unfortunately, this analysis is still inconclusive because 52 per cent of all non-responders do not fit the kras/braf profile – they have wild-type genes. This indicates that other molecular markers need to be studied to generate a more accurate predictive picture for these tumours.

It is now becoming clear that the greater the amount of clinical biomarker data that can be provided, the greater the likelihood that the disease can be managed more effectively. This quest for more detailed molecular profiling of individual tumours is a major initiative in many parts of the world. In the UK, for example, Cancer Research UK is in the process of profiling a set of specific genes implicated in cancer from 9,000 tumours and correlating mutational patterns in these genes with clinical outcomes. Although oncology is pioneering this new approach to clinical management, it is likely to be applicable to most therapeutic areas, and new tools are now being developed that can facilitate such studies.


The requirement for detailed molecular profi les of tissues requires parallel analysis of multiple biomarkers and multiple potential mutations within each biomarker. Although sophisticated multiplex analysis systems are in development, the majority of progress is being made using next generation sequencing (NGS) technologies. Several companies are developing these tools, but the most advanced are currently Illumina and LifeTechnologies, whose platforms are being increasingly used in clinical diagnostic laboratories and in clinical trials.

In October 2011, Life Technologies announced the launch of the Ion AmpliseqTM Cancer Panel, which allows parallel analysis of 46 cancer-related genes for over 700 known cancer mutations and can be completed in a single day. The availability of such sophisticated technologies should radically improve the rapid identification of new biomarkers and the use of such tools will, undoubtedly, be a prerequisite for the majority of clinical trials in the future across most therapeutic areas. Indeed, the challenge now for the pharmaceutical and clinical trials industries is to develop the sophisticated bioinformatics systems that are necessary to analyse the vast amounts of data that these technologies produce, and to enable identification of new biomarker patterns that correlate with drug efficacy, longterm response and/or toxicity.

As well as the huge progress that NGS systems bring to clinical management, there is also major growth in other diagnostic platforms and, surprisingly, a resurgence in technologies such as immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH). Recently, a new oncology drug used for treating non-small cell lung cancer was developed by Pfizer. This drug, crizotinib (Xalkori), which is a small-molecule kinase inhibitor, was approved by the FDA for the treatment of patients whose tumours possess a specific biomarker. This marker is a specific fusion involving the anaplastic lymphoma kinase (ALK) gene, and the only currently available assay which has been approved by the FDA is a FISH assay. Consequently, clinical management of these patients and the prescription of this drug is dependent on access to FISH technology within the reference laboratory – until alternative FDA approved molecular assays become available.


The increasing importance of the use of companion diagnostics in the clinic is now being recognised by the regulatory bodies in both Europe and the US. Recently, the FDA has issued draft guidance documents regarding the way it expects companion diagnostics to be developed and reviewed in parallel with new pharmaceuticals. Ideally, the expectation is that both the new diagnostic and the pharmaceutical products are reviewed simultaneously so that both can achieve regulatory approval at the same time. This means that the full set of analytical and clinical validation data for the new diagnostic must be generated in parallel with the clinical trials for the pharmaceutical itself. This has been exemplified recently with the licensing of Roche’s new melanoma drug, vemurafenib (Zelboraf ). This drug shows remarkable clinical efficacy against melanoma and was designed specifically to target those tumours possessing a mutation at position 600 (V600E) in the braf gene. Consequently, Roche has developed a new assay on their COBAS platform which analyses this specific mutation, and the data for this assay was submitted to and reviewed by the FDA in parallel with the data for the drug itself. The outcome of this is that melanoma patients in the US now have immediate access to a new effective licensed pharmaceutical as well as a fully validated, regulatory approved clinical diagnostic assay to ensure that the drug is used in the correct patient population.

This parallel approval of the drug and the diagnostic sets an interesting precedent for the industry. The onus is now placed squarely on pharmaceutical companies to ensure that appropriate biomarkers are identified, and to ensure that suitable diagnostic partners are secured to develop, manufacture and commercialise the appropriate assays in parallel with the pharmaceuticals. The melanoma example is, in some respects, atypical because the same company, Roche, has the capability to develop both the drug and the diagnostic within its own business.

In many instances this may not be the case since most pharmaceutical companies do not have their own diagnostic arms. Therefore, a model is now emerging where diagnostic companies able to develop regulatory diagnostic assays as well as to provide them as a service for clinical trials are becoming increasingly important. Such ‘vertically integrated’ diagnostic companies have fully accredited service laboratories which are compliant with clinical trial requirements and which also have the full capability to develop, optimise, validate and manufacture the diagnostic, and to obtain regulatory approvals for global commercialisation. As relationships need to be developed between the pharmaceutical companies and their diagnostic partners, as well as between the clinical trials organisations and diagnostic partners, the use of vertically integrated, ‘do it all’ diagnostics partners makes sense. This can also facilitate the global validation of the new diagnostic assays on exactly the same samples that are used for the pharmaceutical development.

In an ideal world, the healthcare industry might expect that the majority of new drugs will be licensed with the availability of fully approved companion diagnostic assays. In reality, the identification of the relevant biomarkers may not be straightforward, and the appropriate biomarkers may only be identified in retrospective clinical trials. In such situations it is likely that new drugs will be licensed with the requirement for patient stratification, but the required diagnostic assay may not have completed the full FDA regulatory approval process. In that situation within the US, the potential to run laboratory-developed tests (LDT) within accredited CLIA laboratories will allow these markers to be assayed. Again, this could emphasise the value of the ‘vertically integrated’ companies able to develop the fully approved assays, support the Dx and Rx clinical trials, and offer LDT services through their CLIA laboratories while the diagnostic is undergoing regulatory review. Outside the US, the regulatory requirements for companion diagnostic assays and for the provision of accredited laboratory services differ from those in the US, but the availability of both is as important for drug launch and patient care as in the US.


The introduction of companion diagnostics and biomarkers into clinical practice is gathering rapid momentum in many clinical areas. As technology improves, the ability to measure and validate multiple biomarkers in parallel is becoming more feasible and allows more accurate and personalised management of disease. These developments are providing new challenges to the pharmaceutical, clinical trials and diagnostics industries and creating new models for the ways in which these bodies work together. Together with the changing emphasis and strategies from the regulatory authorities, there are likely to be wholesale changes in the ways that pharmaceuticals are developed and clinical trials conducted.

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Berwyn Clarke has been involved in the pharmaceutical industry for the past 28 years. Berwyn was Head of Hepatitis C Virus Therapeutics at GlaxoWellcome between 1990 and 2000 before moving into the molecular diagnostic industry with Virco UK. Following a series of M&A activities, Berwyn became Vice President for Research at Visible Genetics Inc (VGI), a pioneering company in the use of molecular diagnostics for viral and cancer disease management. In 2005, with VC investment he co-founded a UK-based diagnostic company, Lab21 Limited, where he is currently Chief Scientifi c Offi cer with responsibility for product development and clinical diagnostic services. Email:
Berwyn Clarke
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