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European Biopharmaceutical Review

Rapid response

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.


1. Keichle F, What is molecular diagnostics? 2014. Visit: www. is_molecular_diagnostics.html
2. National Cancer Institute, Understanding cancer series, reviewed 1 September 2006. Visit: 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: productsandmedicalprocedures/ invitrodiagnostics/ucm330711.htm
5. Herper M, FDA to regulate thousands of cancer, genetic, and other diagnostics, Forbes, 31 July 2014. Visit: 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: pressannouncements/ucm407321.htm
7. Voluntary Exploratory Data Submissions, 25 October 2011. Visit: ucm083673.htm
8. EMA, Pharmacogenomics Working Party. Visit: 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. deviceregulationandguidance/ guidancedocuments/ucm262327.pdf
10. FDA, List of cleared or approved companion diagnostic devices (in vitro and imaging tools). Visit: 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: 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: document_library/presentation/2012/ 11/wc500134979.pdf
14. FDA, Regulatory information-fact sheet: Breakthrough therapies, 9 July 2012. Visit: regulatoryinformation/legislation/ federalfooddrugandcosmetic actfdcact/significantamendments tothefdcact/fdasia/ucm329491.htm

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Regina Au is a Strategic Marketing Consultant at BioMarketing Insight, and has more than 20 years of experience in the biotech, pharma, medical device and diagnostic industries. She previously held sales and marketing roles at companies such as Merck, Genzyme Corp, NMT Medical and Radi Medical Systems. Regina has an MBA in Marketing from the University of Connecticut, a Microbiology degree from the University of Michigan, and a Masters in International Management from Thunderbird, School of Global Management.
Regina Au
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