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International Clinical Trials
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Not all therapies have the same effect on each patient. Yet, until
recently, drugs have been developed with a ‘one-size-fitsall’ approach.
Pharmacogenomics uses information about a person’s genetic makeup, or
genome, to help determine the most effective treatment for a patient
with a specific disease (1).
A key benefit of pharmacogenomics
to clinical studies is that it potentially reduces the size and duration
of trials because the right patients are identified sooner. Studying a
drug only in those likely to benefit from it could speed up and
streamline its development, while maximising its therapeutic benefit to
patients.
Pharmacogenetic testing provides information about a
patient’s likelihood to have a therapeutic response and/or an adverse
reaction to a medication, enabling the potential for a tailored and
personalised approach to medication therapy. Genetics has been estimated
to account for anywhere between 20-95% of the variation in individual
responses to medications (2). When it comes to chemotherapy, the
potential for complications is very high and must be carefully weighed
against the benefit and overall outcome for each patient. Thus, a
treatment regimen should be tailored to the tumour’s genotype in order
to optimise the patient’s response. To minimise potential side effects
in patients, their genetic profile can help to identify how they will
metabolise and respond to the treatment.
Evolving Trial Designs
The
traditional treatment path for cancer has been tumour biopsy,
histologic diagnosis and a standard chemotherapy regimen. However, when
it comes to treating cancer, ‘one size does not fit all’. The
traditional approach does not account for the variability between
tumours or between patients, and the oncology community is recognising
the need for these treatments to evolve.
Considerable progress
is being made in genotyping to determine if a given regimen is
appropriate for a specific tumour. Examples include the identification
of human epidermal growth factor receptor 2 (HER2) in the selection of
transtuzumab as treatment for breast cancer, receptor tyrosine kinase
(RTK) molecules when selecting erlotinib to treat lung cancer, or
cetuximab for metastatic colorectal cancer. These RTK molecules may
either be overexpressed or mutated. Inhibition of the defective RTK can
aid in the initial complete remission induction and, in some cases,
prevention or delay of relapse.
The fundamental – and often
overlooked – step is to make the necessary linkages between specific
biomarkers and their underlying genotypes, then tailor drug treatments
to achieve optimal patient outcomes and minimise adverse reactions.
For
example, it was recently discovered that a mutation in the protein
phosphatase and tensin homolog (PTEN) has been identified as an
important biomarker in many tumours. PTEN is an enzyme that modulates
phosphoinositide 3-kinase (PI3K), an enzyme that causes a tumour to
grow. PTEN actually inactivates PI3K by removing a phosphate group.
Identification of the PTEN mutation suggests that treating patients with
an inhibitor of PI3K can do what the mutated PTEN cannot: inhibit
tumour growth.
While such discoveries are remarkable, it is
important to emphasise that there may be more than one mutation, which
means that a single therapy may not be curative. Furthermore, the
genotype may evolve with new mutations, or different genotypes may
emerge in different cell lines. Identification of reliable tumour
biomarkers can provide an early likelihood of treatment response to a
specific drug regimen and/or indicate patient prognosis.
Radical Change
The
manner in which clinical trials are currently being conducted is
undergoing radical change in an effort to identify appropriate molecular
targets. For example, the traditional strategy used in Phase 1 trials
to determine the maximum tolerated dose of a new oncolytic agent is
being modified. Pharmacogenomics allows for a genome-wide analysis to
identify particular biomarkers in specific tumour types, so that
targeted, molecular drugs can be developed. Therefore, a different
approach to clinical trials is evolving to provide the required
information for development of both new diagnostics and new therapies.
‘Umbrella’
and ‘bucket’ (also called ‘basket’) trials are examples of new clinical
trial structures designed to enrich the study population with specific
tumour-genetic attributes. In this manner, information on the genetic
drivers for a specific tumour type may be targeted. Examples of these
types of studies include the US Department of Defense BATTLE (3) and NCI
MATCH (4) trials. Such research can generate a huge amount of
information. Special statistical methodologies are being developed to
mine these rich data, in order to identify relevant signals appropriate
to a specific tumour and a specific patient.
Safety and Toxicity Profiles
Unfortunately,
most chemotherapy drugs have significant toxicities. It is important to
identify at-risk patients, so that their doctor can decide if the
expected toxicities are acceptable. For example, will a patient be at a
higher risk for side effects like severe mucositis, diarrhoea, nausea
and vomiting?
Genomic technology (single-nucleotide polymorphism
(SNP) profiling) is evolving as a predictive tool to identify patients
who are at risk for these toxicities – prior to treatment. Severe, and
even fatal, toxicities can occur in patients with certain polymorphisms
in enzymes that metabolise chemotherapy drugs. A polymorphism is defined
as a normal variation in a particular enzymatic gene, usually an SNP,
which can lead to modification of its function. Several classic examples
of polymorphisms that involve the metabolism of common chemotherapy
drugs include 5-flurouracil (5FU), Irinotecan and 6-mercaptopurine.
Fortunately, polymorphisms that contribute to these toxicities are not
common. In the case of 5FU, an enzyme – dihydropyrimidine dehydrogenase
(DPD) – that metabolises 80- 90% of 5FU to an inactive form is critical.
If DPD is not normally functional, or is absent, lethal levels of 5FU
can accumulate in the patient. Partial deficiency of this enzyme occurs
in 3-5% of the population.
In some cases, an enzyme polymorphism
may be present that fails the critical activation step of a prodrug;
such is the case with clopidogrel. 30% of the population has a mutation
in one of the P450 cytochromes, CYP 2C19, required to activate the
prodrug. If the patient has this allele, or a mutated form of the
enzyme, clopidogrel is not activated. Therefore, in these patients,
clopidogrel provides no platelet inhibition to protect from strokes or
heart attacks.
Dose targeting is another important advancement
in minimising toxicity and improving efficacy. One example is busulfan
in stem cell transplant. Prior to the initiation of treatment, the
patient is given a small test dose of busulfan. Blood levels of the drug
are then monitored to provide the peak drug level and the rate of drug
clearance. From these data, an individual patient dose of busulfan can
be determined to ensure that treatment efficacy is optimised and
toxicity reduced.
Informed Decisions
An
additional aspect in genomic applications to cancer diagnosis,
classification, treatment and monitoring is its use in assessing
treatment efficacy. Companion diagnostics – the use of medical devices
to determine the risks and benefits of a particular therapy to a patient
– can be used to monitor a patient’s response to a given therapy. With
the information gathered, the doctor can make an informed, immediate
decision regarding therapy or dosage adjustments.
Take, for
example, HER2 in breast cancer and FMS-related tyrosine kinase 3 in
acute myeloid leukemia. As the tumour is treated, the biomarker abates,
and a companion diagnostic tracks the progress. Thus, the rate and
extent of successful treatment can be determined. Likewise, the
recurrence of the biomarker can indicate recurrence of the cancer.
Faster, personalised and more informed treatments are possible with the
right information.
Economic Impact
The impact of
pharmacogenomics has critical downstream effects on its implementation –
not only on the fields of haematology and oncology, but also on other
areas of medicine.
Identification of a regimen that can
effectively target a specific molecular defect in a tumour represents,
of course, a major medical breakthrough – one that has the potential to
positively impact pharmacoeconomics. First, for any given tumour,
pharmacogenomics has the potential to reduce the number of
tried-and-failed therapies, lessening the accumulated toxicities from
exposure to multiple ineffective regimens, minimising the number of
adverse events, and so on. The implications are farreaching when it is
possible to identify the right therapy for the right patient early in
treatment.
Additionally, by enriching the treatment population
with appropriate patients, and by reducing the size and duration of
clinical trials, the path for new drug development and time to market is
being accelerated. Specific study subjects are identified and screened
to maximise potential efficacy, and to exclude patients whose SNP
profile may indicate prohibitive serious adverse events. All of these
aspects are important in risk management during the drug development
process.
The ability to improve overall patient outcomes and
reduce toxicities, while enhancing the pharmacoeconomic impact of the
correct regimen for specific cancers in a particular patient is critical
– and has now become possible. Of course, the expense of developing
companion diagnostic tests is still significant, and new approaches to
curb these costs are imperative. SNP analysis, cell surface epitope
identification and tumour micro particle diagnostics all offer real
potential to lessen the economic burden of companion diagnostics and
enhance outcomes for patients and payers in the future.
Caregiver and Payer Education
A
significant barrier to the rapid implementation of pharmacogenomics to
all oncology patients derives from the fact that not all haematologists
and oncologists are wellversed in the importance of pharmacogenomics.
Education for all healthcare providers and students is therefore
mandatory. Practicing providers may need educational tools offered by
pharma and CROs. The encouraging news is that most clinical centres are
now adopting genotyping and phenotyping (observing interaction of an
organism’s genotype and environment) as a standard of practice.
Success
of these new approaches to drug and protocol development in the world
of personalised medicine depends on early identification of toxicity and
efficacy of treatment. These elements are necessary to avoid more
severe toxicity, or continuing with a therapy that is ineffective.
Patients, payers and providers all benefit from avoiding ineffective and
unnecessary toxic therapies that, in principle, can be prevented by
pharmacogenomics screening.
To capture these emerging data,
consistent patient and nurse involvement is essential. The patient must
be educated in what is important in their care and treatment regimen, so
he or she is able to document and report important events. Clinical
trial and marketed product nurses, through doctor and patient services,
can effectively participate in this process by acquiring, organising and
communicating relevant information. Nurses, whether onsite or in call
centres, are able to obtain and record critical data, which is then
brought to the doctor’s attention.
Oncology and Beyond
Even
in these early stages, pharmacogenomics is redefining the approach to
new drug development; clinical evaluation of new molecules; diagnosis
and classification of cancer diagnosis; treatment regimen selection; and
post-treatment monitoring of patients. Further maturation in all of
these areas will be important, and requires continued education at all
levels of participation.
References
1. National Human Genome Research Institute. Visit: www.genome.gov
2. Wang L et al, Genomics and drug response, N Engl J Med 364: pp1,144-1,153, 2011
3. Visit: www.clinicaltrials.gov/ct2/show/NCT00409968
4. Visit: www.clinicaltrials.gov/ct2/show/NCT02465060
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