Dearth of clinically useful diagnostics limits growth of personalized medicine

Keywords::

• companion diagnostics
• market access
• personalized medicine
• pharmacogenomics
• reimbursement

Pharmacogenomics explores the ways in which genetic variations can be used to predict whether an individual patient will benefit from a drug, have a bad response or no response at all [1]. Knowledge of genetic variance can guide drug development or dosing tailored to an individual’s specific circumstances. This, in turn, may reduce the chance of adverse drug reactions, maximize the probability of better health outcomes and diminish costs [2,3].

Some personalized medicines are developed pharmacogenomically, concurrently with companion diagnostic tests. For example, the breast cancer biologic trastuzumab was codeveloped with a pharmacogenomics test, which was approved and recommended prior to prescribing by both the US FDA and the European Medicines Agency (EMA). Other examples include cetuximab, which was codeveloped with a companion diagnostic, but regulatory authorities do not recommend its use prior to prescribing. Currently, there is comparatively little codevelopment of therapies and tests. Tests are mostly developed post hoc as a way of personalizing a drug, with prime examples including abacavir, irinotecan and warfarin.

In some instances, tests select which patients should or should not take a particular medication. An example of this is the tests used in conjunction with trastuzumab to detect patients whose tumors overexpress the human EGF receptor 2 protein and, accordingly, are likely to respond positively to the biologic [4,5]. In other cases, tests are used to predict the probability of adverse events associated with use of a particular drug [6]. For example, there is a test that links hypersensitivity reactions to the HIV/AIDS drug, abacavir, to a specific genotype. In addition, there are tests that suggest ways of modifying dosage in patients with an innately poor ability to metabolize a certain drug. In the case of warfarin, for instance, tests detect variation in the way individuals metabolize the blood-thinning agent.

The number of personalized medicines and companion diagnostics in use in the USA has gradually increased over the past decade, from a handful of medicines and tests in 2001 to several dozen in 2011. The numbers, however, have not reached the potential hoped for when the human genome project was completed in 2001. Despite some ‘headline-grabbing’ success stories, such as imatinib mesylate and trastuzumab, pharmacogenomics has had limited impact on clinical practice to date. Moreover, the list of FDA/EMA-approved companion diagnostics is still relatively short (perhaps a dozen or so). Scientifically, the process of biomarker discovery and validation has been disappointingly slow. In addition, regulatory and reimbursement issues have limited uptake in clinical practice [7].

Gefitinib can be used as an illustrative example. The drug only works in approximately 10% of patients with advanced non-small-cell lung cancer [8]. In June 2009, the FDA partially withdrew the drug, no longer allowing its prescription to new non-small-cell lung cancer patients, as no useful EGF receptor biomarker test is (yet) commercialized in the USA to indicate likely positive responders. As a result, gefitinib bumped into considerable market access issues, with payers (public and private providers of health insurance) reluctant to reimburse and providers reluctant to prescribe [7].

Furthermore, lingering questions persist even with respect to the clinical effectiveness of FDA/EMA-approved biomarker tests. In particular, lack of evidence linking diagnostic tests to health outcomes has caused payers to be skeptical about the clinical usefulness of tests [7]. This reflects itself in the fact that only a minority of payers require documentation that a test has been conducted prior to prescribing [7]. Moreover, even when the diagnostic is included on the label, payers do not necessarily require it prior to prescribing and often do not pay for it.

What the aforementioned discussion implies is that marketing approval is generally a necessary condition of access to personalized drugs and diagnostics, but not a sufficient one. It is reasonable to view payers as the linchpin for market access, or a key bridge between drug/diagnostic development and clinical adoption. With very few patients paying for the full cost of therapies out-of-pocket, payers mediate the market for pharmacogenomics-based therapies through their reimbursement policies. Payers require evidence that pharmacogenomic therapies are clinically effective and cost effective relative to existing therapies – that is, they add value. Given accurate test results, payers can legitimately only cover those who are likely to benefit from such therapies [9]. However, this is where there continues to be a potentially significant translational challenge, which thus far has largely been unmet. Numerous tests have proven clinically useful as biomarker identifiers, yet many lack conclusive evidence linking their clinical usefulness to health outcomes [7]. From the payers’ perspective, tests only matter insofar as they impact outcomes by personalizing the prescribing process, and not merely as a way of stratifying populations without prescribing implications. For example, tests for irinotecan and warfarin indicate patient subgroups who may be prone to dosing problems, but do not specify exactly what to do next in terms of adjusting the prescribing regimen, nor whether adjustments actually improve outcomes.

Compounding these evidential issues is the fact that payers are concerned about the added costs that result from testing many individuals to identify relatively few who may benefit from a particular therapy or a change in dosing regimen. In this context, it is not that per-unit tests are expensive – they are not, with some priced at as little as US$40 and very few over US$300 per test [7] – rather, it is the budgetary consequences of reimbursing for every eligible member of the population [10].

Should payers begin routinely paying for clinically effective genetic tests to guide the prescription of companion drugs, then personalized medicine may have reached a turning point [11]. Furthermore, should medical professional societies incorporate evidence-based testing in their clinical practice guidelines, then this may facilitate institutionalization of personalized medicine. A robust example of this occurred in 2008 when HIV treatment guidelines were revised to incorporate HLA-B*5701 screening into routine care for patients before initiating abacavir treatment [12].

However, in order to achieve increased clinical adoption of genetic tests and targeted therapies through more favorable reimbursement and incorporation in clinical practice guidelines, manufacturers will need to bring more and better clinical evidence to the marketplace [13]. Where is the evidence going to come from? First, as part of the enactment of the Patient Affordability Act of 2010, comparative effectiveness research (CER) has received a substantial infusion of federal funding, culminating in the establishment of the Patient-Centered Outcomes Research Institute [14]. If implemented appropriately, CER can tackle the evidence gap that exists with respect to personalized medicines and companion diagnostics. For this purpose, CER must be structured to account for individual variability, by accessing vast sources of data and correspondingly facilitating the translational process for molecular diagnostics. Second, some payers have made reimbursement conditional on the results of biomarker tests. For example, payers have made reimbursement of imatinib mesylate contingent on a positive biomarker test that screens for the BCR–ABL fusion gene [101]. Biomarkers may limit the size of a drug’s target patient population, but can significantly enhance the drug’s clinical effectiveness and cost–effectiveness for the eligible population. Third, where there continues to be an evidence gap in terms of knowledge of an association between biomarker tests and health outcomes, the Centers for Medicare and Medicaid may consider expansion of coverage with evidence development programs, similar to the ones already in place for several drugs and diagnostics, including irinotecan and the CYP2C and VKORC1 diagnostic tests for warfarin. Here, Medicare covers irinotecan’s off-label use as a colorectal cancer agent and CYP2C and VKORC1 diagnostics, provided beneficiaries enroll in prospective data collection registries [15]. This allows for generation of data over time, as well as an evolving reimbursement policy.

In a promising sign for post hoc development of companion diagnostics, in 2009 the EMA announced the marketing authorization of a companion diagnostic for gefitinib, which it now only approves for non-small-cell lung cancer patients with mutations in the EGFR gene that make them sensitive to the drug [102]. Subsequent to the EMA decision, NICE published updated guidelines recommending prescribing and reimbursement of gefitinib as first-line treatment for patients with locally advanced or metastatic non-small-cell lung cancer if they test positive for the EGFR mutation with the newly authorized diagnostic [103].

On the regulatory front, the FDA is attempting to resolve translational challenges by coordinating and clarifying the process that drug and diagnostic developers should follow, including delineating a timeframe for companion diagnostic approval. Under a recently proposed FDA policy, targeted drugs put forward for regulatory approval would have to be reviewed simultaneously with their companion diagnostics. Here, the FDA is seeking better integration of biomarker research into drug development strategies. The motto has become “do not ask for approval of a new drug with a molecular indication unless it comes with a proven diagnostic for the targeted genetic anomaly” [16,104]. In what may foretell a wave of the future, Pfizer (NY, USA) recently submitted a new drug application for crizotinib to the FDA, together with a gene diagnostic test (a FISH test to validate ALK-positive tumors) being codeveloped with Abbott (NJ, USA) to identify patients most likely to benefit from the drug [105]. As an experimental therapy, crizotinib appears to be successful in preventing the growth of lung cancer tumors in patients with ALK-positive test results.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.