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International Clinical Trials
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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.
SINGLE MARKERS MAY BE INSUFFICIENT
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.
NEW TECHNOLOGIES
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.
IMPLICATIONS OF REGULATORY CHANGES AROUND COMPANION DIAGNOSTIC TESTS & SERVICES
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.
CONCLUSION
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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