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European Biopharmaceutical Review
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Since the completion of the Human Genome Project in 2003 when scientists
were able to sequence the whole human genome, the translation of this
information into the clinical setting for personalised medicine has
become a reality. However, a number of practical and logistical factors
and corresponding stakeholders must align before personalised medicine
can become standard practice.
Molecular Diagnostics
The
role of molecular diagnostics is to detect specific sequences in DNA or
RNA that may or may not indicate the presence of disease, including
single nucleotide polymorphism (SNP), deletions, rearrangements,
insertions and others (1). In the presence of infectious disease, for
example, molecular diagnostic tests will indicate whether or not a virus
has invaded (qualitative) and also to what extent (quantitative).
According to the US National Cancer Institute, physicians formerly
categorise cancer cells according to their pathology or physical
appearance microscopically. However, through the use of genomics and
proteomics, molecular diagnostics can determine how these genes and
proteins interact in cells. By focusing on gene and protein activity
patterns to uncover changes, it is possible to capture this information
as expression patterns, or ‘molecular signatures’ (2). It is from these
that physicians are able to make much more accurate cancer diagnoses.
DNA
microarray, or ‘gene chips’, are used to identify expression patterns,
having the ability to compare thousands of genes simultaneously by using
fluorescent dyes for each one. They are also able to distinguish
differences between the expression patterns of cancer cells compared to
normal cells, as well as the relative expressions determined by the
intensity and colour of the spot. Today, most microarray studies include ‘cluster analysis’ which groups together genes with similar expression patterns.
There
have been a number of successes using this method to identify specific
cancer genes, including HER2, BRACA1 and BRACA2 for breast cancer; KRAS
for colorectal cancer; and PLA2G2A for stomach cancer. Since the Human
Genome Project, some 2,972 genes with known phenotype/disease causing
mutations have been identified (3). Furthermore, microarray models have
also identified subtypes of cancers within lung cancer and lymphoma. An
important breakthrough has been the ability to predict the survival rate
of patients who receive chemotherapy agents. Patients with ‘younger’
lymphocytes have a 75% positive response rate to chemotherapy agents
compared to patients with ‘older’ lymphocytes, who only show a 25%
response rate (2).
Diagnostic Testing
While the
use of microarray models has given us a more sophisticated method of
classifying and diagnosing diseases, the science is very complicated and
guidelines are needed to ensure that the tests are valid, accurate and
consistent. The sensitivity and specificity of diagnostic tests should
be 100% to ensure that the test results are accurate each time. When
tests lack adequate sensitivity and fail to detect the presence of a
disease, a ‘false negative’ can occur which may lead to devastating
consequences for the patient if lifesaving therapies are delayed.
Equally, in the case of ‘false positive’ results, the incorrect
signalling that a disease is present may lead to unnecessary and costly
treatment, resulting in anxiety in the misdiagnosed patient.
In
the eyes of the FDA, all diagnostics tests (excluding companion
diagnostics) fall under the medical device category and, therefore, the
approval process is overseen by the Center for Devices and Radiological
Health, under the nucleic acid based tests category (4).
Since
molecular diagnostic testing is relatively new, developing a test can be
difficult because a separate approval process does not exist. Molecular
diagnostic tests are regulated under the US Clinical Laboratory
Improvement Act (CLIA) like all other clinical laboratory tests (1).
There
are two main categories for diagnostic tests: diagnostic kits and
reagents, and laboratory developed tests (LDTs) – with most molecular
diagnostic tests falling under the latter (3). The FDA division that
regulates in vitro diagnostic products as medical devices has
claimed the authority to regulate LDTs, but has to date only implemented
‘enforcement discretion’ and not actively regulated LDTs. The Center
for Medicare and Medicaid Services has also claimed jurisdiction over
LDTs and oversees the rules, enforcement and certification on behalf of
the CLIA.
While the concept of molecular diagnostic testing
brings us closer to personalised medicine and securing the wellbeing of
patients, regulations to ensure that tests are reliable, consistent and
accurate are essential. Reliability and confidence in the results
produced by these tests are of the utmost importance when considering
the consequences of misinterpretation. Although the FDA has regulated
and approved some personalised medicine LDTs such as Mammaprint® and AlloMap®, the vast majority of molecular tests have not been submitted for FDA approval.
Regulatory Response
In
response to these concerns, in July 2014, the FDA announced and issued a
guidance document detailing its plans to regulate LDTs (5). “Ensuring
that doctors and patients have access to safe, accurate and reliable
diagnostic tests to help guide treatment decisions is a priority for the
FDA,” said the Agency’s Commissioner Margaret Hamburg. “Inaccurate test
results could cause patients to seek unnecessary treatment or delay and
sometimes forgo treatment altogether. Today’s action demonstrates the
Agency’s commitment to personalised medicine, which depends on accurate
and reliable tests to get the right treatment to the right patient” (6).
The
LDTs guidance “provides the anticipated details [for] an LDT oversight
framework, including pre-market review for higher-risk LDTs, such as
those that have the same intended use as FDA-approved or cleared
companion diagnostics currently on the market. [It] would also propose
to phase in enforcement of pre-market review for other high-risk and
moderate-risk LDTs over time” (6). The FDA established a programme in
2004 called Voluntary Exploratory Data Submission, which is a
“nonregulatory, flexible mechanism for scientific exchange between FDA
and external scientists” (7) that aims to help understanding of
pharmacogenomics before regulatory standards are set (3).
This
is good news for patients and healthcare professionals, giving them the
confidence to use molecular diagnostic tests in their decision-making.
However, for manufacturers, it is increasingly challenging and expensive
to incorporate all the necessary policies, procedures and studies for
approval.
Within the EU, nearly all tests under the jurisdiction of in vitro device regulation are classified as low-risk and are not subject to
pre-market review. This is because there has been no evidence that
clinical validity is needed for these tests, and there has also been
ambiguity regarding the status of LDTs (8).
The EMA and FDA have
simultaneously coordinated the evaluation of pharmacogenomic technology
with their respective agencies, while, at the same time, sharing
information. The EMA formed the EU Pharmacogenomics Working Party, which
provides recommendations to the Committee for Medicinal Products for
Human Use on all matters relating directly or indirectly to
pharmacogenomics (9). There has also been bilateral cooperation between
the FDA and EMA in validating genomic data for use in regulatory
decision-making bodies, such as the Predictive Safety Testing
Consortium. The FDA and EMA have held bilateral voluntary genomic data
submission processes (7).
Companion Focus
According to the FDA, “an in vitro device (IVD) companion diagnostic is an in vitro diagnostic
device that provides information that is essential for the safe and
effective use of a corresponding therapeutic product. The use of an IVD
companion diagnostic device with a therapeutic product is stipulated in
the instructions for use in the labelling of both the diagnostic device
and the corresponding therapeutic product, including the labelling of
any generic equivalents of the therapeutic product” (10).
Companion
diagnostic tests are developed in the same manner as single molecular
tests, with the exception that they are co-developed in conjunction with
a therapeutic drug. These tests are regulated under the FDA’s in vitro companion diagnostics legislation as a medical device (11). The drug
aspect, however, is regulated by the US Center for Drug Evaluation and
Research. One of the main concerns when dealing with two different FDA
agencies is that the drug could be approved before the companion
diagnostic test is. This occurrence would be counter-productive because
many healthcare professionals would be unlikely to prescribe a new drug
to a patient without first using the companion diagnostic test to
confirm the presence of disease and predict the patient's response to
the therapeutic.
In 2011, the FDA released its Draft Guidance for In Vitro Companion Diagnostic Devices,
with the final document released in 2014, to help clarify its intention
to conduct simultaneous reviews of a drug and its companion diagnostic
(8). While the guidance was being reviewed, the FDA, Health Canada and
EMA either mandated or recommended that, in certain cases, biomarker
testing must be performed before the drug is administered (3).
New Proposals
The
FDA's focus on personalised medicine has been demonstrated by the
creation of a Deputy Director for Personalised Medicine in the office of
In Vitro Diagnostics and Radiological Health. Dr Mansfield said:
“Companion diagnostics are medical devices that help doctors decide
which treatments to offer patients and which dosage to give, tailored
specifically to the patient. The companion diagnostic is essential to
the safe and effective use of the drug. They go together” (12).
For
oncology products “the Agency requires a companion diagnostic test if a
new drug works on a specific genetic or biological target that is
present in some, but not all, patients with a certain cancer or disease.
The companion diagnostic test is used to identify who would benefit
from the treatment (and possibly those who may not benefit), or could be
harmed by use of a certain drug for treatment of their disease” (9). In
2012, the European Commission issued a proposal for a new risk
classification that requires genetic tests and companion diagnostics to
be subjected to pre-market review by the European Association for
Medical Devices for Notified Bodies (7).
The Association will
clarify the need to have evidence for clinical test validity, explain
the status of LDTs, and confirm the definition of companion diagnostics.
Nevertheless, greater coordination is needed between the FDA,
EMA and the health technology and assessment bodies that “provide
recommendations on the medicines and other health interventions that can
be paid for or reimbursed by the healthcare system in a particular [EU]
Member State. Recently, they have been gaining a greater influence on
the access of novel medicines to patients, mainly due to increased
pressure on healthcare budgets” (7,13).
Research Reservations
The
UK’s National Institute for Health and Care Excellence (NICE) does not
yet have a formal programme for the assessment and reimbursement of
companion diagnostics. If the companion diagnostic is linked with a new
drug, it falls under the technology appraisal for new drugs and the two
are assessed together (14). However, if the companion diagnostic is
linked to an established drug or non-drug treatment, it falls under the
diagnostic programme.
NICE has had reservations regarding the pharmacoeconomics of using pharmacogenetics for a number of reasons (13):
- To
date, the use of pharmacogenetic testing in clinical practice is very
limited. The evidence is often insufficient and it is debatable as to
whether it provides good clinical value
- More evidence of analytical validity, clinical validity, clinical utility and cost-effectiveness is needed
- There
are methodology issues and insufficient evidence-based rationale for an
association between genotype and phenotype in most of the 20 studies
reviewed in 2008
- Most of the 34 articles reviewed in 2010 showed clinical validity, but only two showed clinical utility
- In
a 2010 US-based evaluation of warfarin, using pharmacogenetic and
clinical factors to predict a more precise initial and maintenance dose,
with fewer and smaller dose adjustments and international normalised
ratio measurements, resulted in a small clinical benefit but uncertain
economic value
Personalised Regulation
The
growing advances in genomics and how this area fits in with personalised
medicine is uncharted territory for everyone, especially when it comes
to ensuring reliable, consistent and accurate diagnostic tests and
treatments. The FDA has invited external scientists to promote a better
understanding within the Agency about pharmacogenomics, before
regulatory standards are issued and coordinated bilaterally with the
EMA.
Industry and regulatory authorities are finally coming
together as a unified community ready to make personalised medicine
work. Ongoing discoveries will ensure that the field will continuously
evolve, and the need to develop adaptations and responses to emerging
technologies is inevitable. As our understanding of molecular
diagnostics deepens and all the stakeholders achieve buy-in, the
progress in research, regulatory approval processes and adoption of the
technology will be aligned in personalised medicine.
References
1. Keichle F, What is molecular diagnostics? 2014. Visit: www. gomolecular.com/discover/what_ is_molecular_diagnostics.html
2.
National Cancer Institute, Understanding cancer series, reviewed 1
September 2006. Visit: www.cancer.gov/cancertopics/ understandingcancer/
moleculardiagnostics/page4
3. Personalized Medicine Coalition, The
case for personalized medicine, 4th Edition, 2014. Visit: www.
personalizedmedicinecoalition. org/Userfiles/PMC-Corporate/file/
pmc_the_case_for_personalized_ medicine.pdf
4. FDA, Device-nucleic
acid test: Human genetic test and microbial test approvals. Visit:
www.fda.gov/medicaldevices/ productsandmedicalprocedures/
invitrodiagnostics/ucm330711.htm
5. Herper M, FDA to regulate thousands of cancer, genetic, and other diagnostics, Forbes,
31 July 2014. Visit: www.forbes.com/sites/
matthewherper/2014/07/31/fdato- regulate-thousands-of-cancergenetic-
and-other-diagnostics
6. FDA takes steps to help ensure the
reliability of certain diagnostic tests, FDA news release, 31 July,
2014. Visit: www.fda.gov/newsevents/newsroom/
pressannouncements/ucm407321.htm
7. Voluntary Exploratory Data Submissions, 25 October 2011. Visit: www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ ucm083673.htm
8.
EMA, Pharmacogenomics Working Party. Visit: www.ema.europa.eu/
ema/index.jsp?curl=pages/contacts/ chmp/people_listing_000018.
jsp&mid=wc0b01ac0580028d91
9. In vitro companion
diagnostic devices guidance for industry and Food and Drug
Administration staff. Visit: www. fda.gov/downloads/medicaldevices/
deviceregulationandguidance/ guidancedocuments/ucm262327.pdf
10. FDA, List of cleared or approved companion diagnostic devices (in vitro and imaging tools). Visit: www.fda.gov/medicaldevices/ productsandmedicalprocedures/ invitrodiagnostics/ucm301431.htm
11.
FDA, Personalized medicine and companion diagnostics go hand-inhand, 31
July 2014. Visit: www.fda. gov/forconsumers/consumerupdates/
ucm407328.htm
12. EMA, Health-technology-assessment bodies. Visit:
www.ema.europa.eu/ ema/index.jsp?curl=pages/partners_
and_networks/general/general_ content_000476.jsp&
13. George E,
HTA of companion diagnostics, Workshop on pharmacogenomics: From science
to clinical care, 8-9 October 2012. Visit:
www.ema.europa.eu/docs/en_gb/ document_library/presentation/2012/
11/wc500134979.pdf
14. FDA, Regulatory information-fact sheet:
Breakthrough therapies, 9 July 2012. Visit: www.fda.gov/
regulatoryinformation/legislation/ federalfooddrugandcosmetic
actfdcact/significantamendments tothefdcact/fdasia/ucm329491.htm
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