Complementing Personalized Medicines

Mollie Roth discusses how complementary diagnostics can improve disease management and optimize therapy.

Since the human genome was first sequenced in 2000, the personalized medicine (PM) space has worked diligently to make real on the promise that co-development and launch of companion diagnostics (CDx) with targeted therapies would make drugs safer and more efficacious for patients. That promise has been born out in the intervening thirteen years with the introduction of over one dozen targeted therapies and associated CDx, including such blockbuster therapies as Herceptin, Tarceva and Gleevec.

These therapies utilize their FDA approved CDx tests to make more accurate predictions of whether an individual will respond positively to a targeted therapy based on the genetic or other molecular markers of the individual. To date, the majority of these treatments have been in oncology, where targeting specific molecular markers in the patient or the tumor represent remarkable improvements over standard chemotherapeutics.

From this initial narrow concept, the idea of PM has expanded to consider the patients’ entire journey through and engagement with the healthcare system. In order to truly bridge the gap between the concept of a targeted therapy and a CDx, the industry is now incorporating another potent tool in its arsenal — the “complementary diagnostic.”

While PM has primarily focused on how one test approved alongside a drug can better stratify patients for treatment, there are a host of other diagnostic tools that work across drug classes, benefitting all patients with the disease and potentially all drugs in the class. Certainly there is nothing new about such complementary diagnostics, per se; they have been around and in use for decades. However, when smartly implemented in the PM space these complementary diagnostics can work to provide even better patient care across a disease class. Where no targeted therapy and CDx option exist, these complementary diagnostics can provide an additional degree of highly relevant information at the patient specific molecular level.

These complementary diagnostics can also provide numerous benefits to multiple stakeholders across the PM spectrum beyond the patient, including the healthcare practitioner, the therapy manufacturer and the healthcare insurance companies. These benefits will be discussed below.

Complementary Diagnostics and the Age of Personalized Medicine

A complementary diagnostic is a diagnostic that is utilized by a healthcare practitioner to assess disease state and assist in diagnosis, patient management and treatment decisions. Unlike CDx, which are tied to one specific drug and are proven to work with and are approved for use only with that drug, complementary diagnostics can be utilized across a disease state, independent of one specific therapy but useful to guide therapeutic treatment across the classes of therapies. As described by Vijay Modur, former head of diagnostic discovery at Novartis's molecular diagnostics division, complementary diagnostics are “any test that is not a companion diagnostic requiring a drug/diagnostic regulatory link at the time of development.”

These types of complementary diagnostics serve as additional guides to provide healthcare practitioners with a more accurate understanding of the patients’ disease and a more robust navigational tool to make better treatment decisions and better implement and revise treatment. The next generation of complementary diagnostics discussed below utilizes advances in genomics and proteomics to provide these benefits on an even more individualized level.

Health care costs in the United States are increasing at a rate that has been deemed unsustainable for years. These increasing costs have placed enormous strain on national and personal resources and have taken center stage in the national debate about health care. While the amount of health care spent on pharmaceuticals is a relatively small percentage of the whole, it is not insignificant, totaling $325.8 billion in 2012 in the U.S.

That discussion has also focused on the rising number and cost of diagnostic tests, and their potential overuse in the provision of medical services. Unfortunately, that focus has tended to ignore the fact that costs for diagnostics represent only a fraction of overall health care costs and rarely reflect the true value they offer patients and healthcare providers. As explained by Jim Clement, Vice President of Pharmaceutical Manufacturer Relations at Aetna, “the use of these complementary tests will act as an enabler for the healthcare insurance industry to evolve from simply paying for service to the next generation construct of actually paying for outcomes.”

In fact, smart implementation of complementary diagnostics can not only benefit and improve patient care but they benefit additional stakeholders by reducing costs, improving return on investment, and providing significant clinical and outcomes value. For patients, complementary diagnostics can reduce treatment errors, provide better assessments of disease activity, help to identify and drive use of more efficacious treatments and get acute patients to treatments faster. The following sections focus on how some of these drivers accrue benefit to the different stakeholders in the space and some of the complementary diagnostics that are providing these benefits.

Adding Value to the Clinical Assessment

The use of complementary diagnostics can significantly aid in the clinical assessment, an evaluation of the patient's physical condition and prognosis based on information gathered from physical and laboratory examinations and the patient’s medical history, especially where it is hard to determine the degree of disease progression from patient self reports and external symptoms. In these instances, complementary diagnostics can improve the patient journey and ensure patients get better treatment by more accurately determining disease activity.

In rheumatoid arthritis (RA) for example, the disease at the molecular level is often more active than what a patient reports they are experiencing symptomatically or what the healthcare practitioner can identify during a physical examination.[1] Furthermore, RA patients frequently present with one or more confounding factors or comorbidities with similar symptoms. Left untreated, or even undertreated, RA can lead to debilitating pain and potentially irreparable joint damage causing loss of physical function, inability to carry out daily tasks of living, and maintenance of employment. The discordance between disease activity and patient or healthcare practitioner assessments is well documented in RA and it is often exceedingly difficult to make an appropriate and accurate differential diagnosis of RA disease activity.

However, by providing a specific and precise way to measure RA disease activity that complements a healthcare practitioner’s expert assessment and a patient’s reporting, complementary diagnostics help facilitate more efficient patient management. While no targeted therapies[2] have yet to be launched into the RA space, it is possible to improve clinical assessment through the use of a complementary tool such as VectraÒ DA from Crescendo Bioscience. The Vectra DA test has been validated to aid in the assessment of RA disease activity – not diagnosis of RA – and may help inform patient management decisions when used in conjunction with standard clinical assessment. Vectra DA simultaneously measures twelve immune, endothelial, bone, cartilage and metabolic biomarkers that reflect the underlying biology of RA.

Serum concentrations of Vectra DA’s twelve biomarkers are integrated into a proprietary algorithm that generates a single score from 1 to 100, classifying disease activity as low, moderate or high. As such, the test can detect active and significant disease activity at the molecular level often before it manifests in clinical symptoms for the patient. Research indicates what while clinical assessments may vary by as much as 20% in the same patient when different healthcare practitioners perform assessments, the variation in assessment when using Vectra DA is only 2%.[3] In effect, this tool acts as a disease activity “thermometer.”

The ability to quickly and accurately understand the degree of a patients’ disease activity can help healthcare practitioners in detecting disease activity before the resultant symptoms are sufficiently severe to be reported by the patient, avoiding delay in treatment and additional joint damage.[4] These types of complementary tools may optimize the limited time healthcare practitioners have with their patients and help reduce lack of treatment arising from under diagnosed disease activity. From the perspective of Jim Clement, Vice President of Pharmaceutical Manufacturer Relations at Aetna, “these types of metrics should be built into 360-degree compliance programs, that incorporate lab and other values into overall patient management programs, in order to improve overall patient care.[5]

Other complementary diagnostics allow healthcare practitioners to understand when therapy may not be warranted. For example, the Oncotype DX breast cancer test from Genomic Health is intended for use by women with early-stage I or II, node-negative, estrogen receptor-positive invasive breast cancer with an intent to treat with chemotherapy. The Oncotype DX test has been clinically validated to predict the likelihood of benefit from use of chemotherapy as well as possible recurrence in early-stage breast cancer. The test examines a breast cancer patient’s tumor tissue at a molecular level to predict the likelihood of whether or not chemotherapy will be beneficial. This information can help healthcare practitioners avoid the use of expensive and very physically demanding therapy and better individualize breast cancer treatment by helping to identify other treatment options.

Clearly, the benefits to the patient of avoiding often debilitating and difficult chemotherapy, and potentially delaying more appropriate treatment, are extremely valuable. But the use of such complementary diagnostics can also benefit a variety of payers including healthcare insurance companies and the system as a whole. By reducing potential and actual treatment errors, significant cost savings may be achieved from patients having to engage with the health care system less frequently and for less severe events. Conversely, it may be that patients are being undertreated when their actual disease activity does not match their self-reports. In these instances while patients may actually increase their short-term utilization of healthcare, their disease is likely to be better treated and their longer-term use of health care resources is likely to be reduced.

The expanded use of complementary diagnostics provides the potential to facilitate better care and realize reduced costs for the healthcare insurance companies and the entire healthcare system.

Avoiding Unnecessary Switches and Skipping Ineffective First Line Treatments

Treatment decisions often follow formal, algorithmic guidelines established by a variety of regulatory bodies within each disease state. “First-line” therapy refers to the standard treatment first given when someone is diagnosed with a particular disease, and it is usually recommended on the basis of clinical evidence for its efficacy in the treated population as a whole. However, in the last few decades there has been an increasing body of evidence that fully half of all therapies are actually ineffective for patients receiving them. But once first-line therapy gets established in treatment guidelines and clinical use, it can be very difficult to change, requiring significant investment in time and resource.

Complementary diagnostics can help change that standard of care by allowing patients to leapfrog over or cycle more quickly through those first-line, established, but often ineffective therapies, to newer and more effective options. This streamlining benefits patients, healthcare insurance companies and the therapy manufacturers. Consider for example the use of DMARDs and other first-line treatments such as methotrexate (MTX) for treatment of RA. For many patients, these first-line therapies will more than adequately control their disease. For these patients, the use of complementary diagnostics can potentially confirm, at the molecular level, that their disease is not progressing and reduce unnecessary switching between therapies.[6]

However, for those patients not benefitted by first-line treatment, complementary diagnostics can indicate the need for a faster change in treatment. For example, up to 30% of patients experience adverse side effects from MTX, which can limit the dose they can take or cause patients to stop treatment. So while MTX itself is a relatively inexpensive therapy (the patent expired decades ago), the longer-term costs from under or untreated RA are significant. Further, while waiting to see if the patient responds to MTX, RA can progress significantly, doing damage to the patient and ultimately causing increased costs for healthcare insurance companies as the patient requires increased resources. According to Ed Pezalla, M.D., MPH, “for some diseases you just don’t want to wait for disease progression to find out whether a patient is responding to treatment.”

Furthermore, tests that allow healthcare professionals to assess the underlying molecular level of disease activity provide robust evidence of which therapies in the class are actually efficacious and can provide potential cost savings. For example, three of the most widely used RA biologics – Humira, Enbrel and Remicade – rank among the top expenditures in specialty pharmacy, but there is still a lack of data to support the use of any one of these expensive therapies over the other. Complementary diagnostics can differentiate which therapies are actually reducing patients underlying disease activity at the molecular level. In turn, this can provide healthcare insurance companies with powerful evidence to compare a class of expensive therapies and potentially reward those companies with therapies that work best and reduce the use of — or the price point — of those therapies that are more frequently less effective.

Because complementary diagnostics are relevant across an entire disease state, they can be used alongside multiple therapies. Where clinical guidelines require years of evidence and resources to challenge and change, the smart implementation of a complementary diagnostic within an entire disease state can more rapidly move patients past such therapies to next in line therapies faster. Finding a therapy that is effective in reducing disease activity and that improves outcomes more rapidly is the ultimate goal. For the therapy and diagnostic manufacturers, this means a more rapid return on their significant investments in developing these drugs and tests as patients gain access to these therapies sooner. Even a modest increase in patients gaining access to a new therapy in a moderately conservative time frame of six months to one year can represent significant return through use of these complementary diagnostics.

Working together, the therapy manufacturers may be able to foster use of such complementary diagnostics faster than efforts to change treatment guidelines. Working collaboratively, the therapy manufacturers can ensure that the complementary test is developed and made available in the market, across the disease state, potentially benefitting each of their individual drugs. Because these tests work agnostically alongside all available treatments, they can help “raise all boats” and improve return on investment for all manufacturers of competing therapeutic products in the class. Devising a model to apportion those costs equitably will not be easy, but it is certainly not beyond the realm of possibility.

Conclusion

It is clear that utilization of complementary diagnostics can be of enormous benefit across a number of stakeholders in the PM space.

For patients and healthcare practitioners, complementary diagnostics offer the opportunity for an objective, reproducible, quantifiable and precise approach to determine disease activity or to help avoid ineffective, difficult and costly treatment choices. Diseases that were previously managed by subjective and difficult to reproduce measures, such as RA and other autoimmune diseases, would receive enormous benefit in helping to get patients to the right therapies at the right time.

The “added value” that the term “complementary diagnostic” implies is clearly a return on investment to patients. Similarly, there can be little argument that healthcare insurance companies benefit when ineffective drugs can be avoided, even when absolute cost is already low - such as when the patent for a specific therapy has expired. Additional savings can accrue from unnecessary switching between therapies and from the robust evidence that complementary diagnostics may be able to provide regarding which therapies in a class are actually efficacious for specific patients. The damage that can accrue to patients improperly treated or undertreated is significant to patients, healthcare insurance companies and the health care system as a whole.

The potential benefit to the therapy manufacturers is no less significant, although it faces a larger hurdle to overcome a business model where companies are entrenched in a “go it alone” business model. In the CDx space, a specific test is linked to and approved for use with a specific drug, which requires the therapy manufacturer to invest significant resources in the development, launch and adoption of that test. Because the CDx is only approved for use with one specific drug, it is the sole responsibility of that therapy manufacturer and their diagnostic partner to ensure that test is available for use with their drug. Both the entirety of the risk – and the reward – from development of that test sits with a single therapy manufacturer and diagnostic partner. Conversely, therapy manufacturers can work together to help develop and drive use of complementary diagnostics, sharing both the risks and rewards across the group.

Complementary diagnostics provide significant opportunities for innovative partnerships between many of the stakeholders in the PM space and, more importantly, the potential to drive significant benefit to patients, therapy manufacturers, healthcare insurers and the system as a whole.

About the Author
Mollie Roth is Managing Partner at PGx Consulting, LLC.

References

[1] Barton J, et. al. Arthritis Care & Research Vol. 62, No. 6, June 2010, pp 857–864

[2] The use of the term “targeted therapy” denotes those drugs that have been specifically co-developed and approved along with an FDA approved test that is included as part of the drugs indication for use in the drug label.

[3] Eastman PS, Manning WC, Qureshi F, Haney D, Cavet G, Alexander C, Hesterberg LK. Characterization of a multiplex, 12-biomarker test for rheumatoid arthritis. Journal of Pharmaceutical and Biomedical Analysis, 2012 Nov; 70:415-24

[4] Crescendo Bioscience case study, presented during Advisory Board meeting, Dallas, TX (Sept 2013)

[5] Excerpt of interview with Jim Clement, Vice President of Pharmaceutical Manufacturer Relations at Aetna, August 26, 2013.

[6] Methotrexate is the standard first-line treatment for RA, with standard weekly dosing for approximately 6-12 weeks before the effects are seen. It is estimated that the overall response rates to MTX vary between 35-65 percent, see S. Naik, “Towards personalized medicine – the role of methotrexate,” Indian J Med Res. 2011 March; 133(3): 253–255.

Financial & Competing Interests Disclosure

This work was partly supported by Crescendo Bioscience. The author has no other 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 apart from those disclosed. No writing assistance was utilized in the production of this manuscript.