Personalized Medicine Education and Advocacy

Thought leadership in personalized medicine

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It’s Time to Protect Patient Care and Rethink the Way We Define and Assess Clinical Utility in Molecular Diagnostics

Guest Blog
by Elaine Lyon, Ph.D., Medical Director of Genetics, Genomics and Pharmacogenomics at ARUP Laboratories, Professor of Pathology at the University of Utah School of Medicine, Co-chair of the FEND task force, Senior author of the FEND publication


Elaine Lyon, Ph.D.

Recent advances in genomic medicine continue to provide many new opportunities to improve our modern health care system. However, before we can truly realize the full promise of precision medicine, we need a more practical and patient-centered approach for evaluating clinical usefulness for these types of molecular testing procedures. Current models for clinical utility evaluation clearly fall short of ensuring best care and usefulness for the patient, their family, their provider, and the health care system. While personalized medicine is driving health care progress today, this restricted definition of clinical utility is putting on the brakes and impeding progress.

Since the new molecular pathology Current Procedural Terminology (CPT) codes were implemented, the roles of clinical validity and clinical utility have been the subject of intense discussion. Many stakeholders have adopted very narrow definitions that do not address all the important applications, including diagnosis, prognosis, risk assessment, prediction of future disease, as well as monitoring and selection of therapies.

The ongoing shift of payer expectations from a “reasonable and necessary” to a “demonstrable clinical utility” requirement can be a difficult and unrealistic expectation for laboratories. Since the new requirement was created with therapeutic products in mind, applying the same standards to a test that is designed to establish a diagnosis for an inherited condition is difficult. Even if the test performs flawlessly, the patient may never be “cured” or ‘’treated;” symptoms may only be managed.   In addition, many of these procedures are for diseases so rare that a statistically valid study would be almost impossible, or would at least take many years to complete. Ultimately, we need to capture evidence for the clinical utility of these procedures outside of a traditional randomized control trial setting. To achieve maximum benefit, we need to recognize that any individual test result is an intermediate outcome that relies on proper clinical interpretation and utilization in context for that specific patient.

For example, if a patient with breast cancer tests negative for specific BRCA 1/2 mutations, the physician may move forward with specific drug therapy treatment based on this information; however, the very same test may be used for someone who doesn’t have breast cancer but is being tested because there is a strong family history of breast cancer. In this case, the test is used as a screening tool before the onset of disease. It really depends on how the physician uses the information.

I currently co-chair the Association for Molecular Pathology (AMP) Framework for the Evidence Needed to Demonstrate (FEND) Clinical Utility Task Force, which was formed two years ago to address these specific challenges. The task force seeks to represent the views of the more than 2,300 AMP members, who are fully embedded in the various disciplines of molecular diagnostics, including infectious diseases, inherited conditions and oncology. AMP’s members include individuals from academic and community medical centers, government and industry, including pathologist and doctoral scientist laboratory directors, basic and translational scientists, technologists and trainees.

The FEND task force recently authored a new report published in The Journal of Molecular Diagnostics that establishes a new standard for clinical utility of molecular diagnostics for inherited diseases and cancer. One of our early goals was to have a peer-reviewed publication that could help start the next wave of discussions with all key stakeholders. In the report, we recommend a broad, patient-centered definition that takes into account the different ways that a test might be used, with an understanding that the test results may indicate follow-on activities that are not as simple as merely determining which drug to prescribe, or at what dose. Our inclusive approach utilizes a modified ACCE model and emphasizes that a clinical test result’s utility depends on the context in which it is used to classify a patient’s disease or disorder and/or guide management. We were very careful to make recommendations that can be extended to additional applications of molecular testing.

We believe our recommendations provide a reasonable and feasible path forward that puts patients and their families at the center of evaluating clinical utility for molecular testing procedures. We look forward to continued stakeholder engagement to further advance clinical genomics so that we can begin to realize the full promise of personalized medicine.

To read the full-text, free report, please visit

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Can We Assess the Value of Personalized Medicine in Treating Cancer?

Guest Blog
from Dan Leonard, M.A., President, National Pharmaceutical Council


Dan Leonard, M.A.

Although there is a bright spotlight on the field of personalized medicine thanks to the Obama administration’s Cancer Moonshot and Precision Medicine initiatives, there are real concerns about how targeted medicines will be considered in value assessment frameworks, which are geared toward evaluating treatments for a population rather than individual patients.

This week, National Pharmaceutical Council (NPC) President Dan Leonard sat down with Amy M. Miller, Ph.D., Executive Vice President, PMC, to discuss these issues.

Dan Leonard (DL): Amy, thank you for joining me to talk about personalized medicine and value frameworks. Tell us a little about personalized medicine and its impact on patient care, especially in light of ongoing debates about costs, coverage and value.

Amy Miller (AM): Thank you for this opportunity. Personalized medicine is an evolving field in which physicians use diagnostic tests to determine which medical treatments will work best for each patient. By combining the data from those tests with an individual’s medical history, circumstances and values, health care providers can develop targeted treatment and prevention plans. This concept challenges how health care products and services are discovered, developed, regulated, covered, paid for and delivered in the clinic. Therefore, it is no surprise that personalized medicine challenges how value assessments are conducted.

DL: The basis for personalized medicine is that every patient is unique and will respond to treatments differently, something NPC also has demonstrated in our research. How can a value assessment framework take that important concept into consideration?  

AM: Fortunately for value assessment framework designers, many organizations have published suggestions for them. It is important for the value assessment questions to accurately reflect available data. Furthermore, when looking at disease areas with targeted therapeutics, value assessment frameworks must look at the full complement of clinical tools, including the diagnostic test or tests and the clinical outcome differences between a targeted and non-targeted treatment approach.

DL: The Institute for Clinical and Economic Review (ICER) is currently evaluating treatments for non-small-cell lung cancer (NSCLC), a disease that is unique to each patient and requires targeted treatment. They’ll be hosting a public meeting about that evaluation on October 20. What kinds of factors should ICER be considering as part of its review of NSCLC treatments?

AM: NSCLC is a disease where personalized medicine has transformed care over the last decade, and patients have seen tremendous improvements in morbidity, mortality and quality of life as a result. We’ve seen evolution in treatments targeting many driver mutations in the tumor. We’ve seen evolution in the types of diagnostics used to select those treatments. I think ICER needs to carefully consider all that we’ve learned over the last decade using EGFR-mutation therapeutics, value those therapeutics from a patient’s perspective, and consider how we incentivize investments in PD-1 therapeutics so we can capitalize on their tremendous potential in a similar way. PD-1 inhibitors work quite well for a subset of patients, but we do not know how best to use them yet. We will figure it out, and when we do, it will likely have tremendous implications for patients, giving them longer, better lives than comparators like chemotherapy.

DL:  What have you heard from your member companies about ICER’s review of NSCLC treatments? Are there ways that ICER could better integrate those comments, as well as patient input?

AM: ICER concurrently opened a public comment period where stakeholders could suggest process changes.  One example of a process change that ICER could make now is to include a more representative group of stakeholders on its advisory council. Furthermore, historically, ICER has discussed the implications of its decision after a vote on the value assessment. Simply listening to the public before voting would reassure stakeholders that ICER values their input.

DL: You had asked ICER to provide a longer comment period for NSCLC, which they granted. Do you think that was enough time? How could they improve the comment process in the future?

AM: PMC is a coalition representing pharmaceutical manufacturers, diagnostic companies, patients, providers, payers and other stakeholders, and the perspectives that these groups have together are often valuable to those who seek input on their work. However, for a coalition to engage a group like ICER requires that our members consider the issues from their perspective before joining a conversation about how to support a concept. ICER’s comment period (30 days and, in this case, including holidays) did not allow for us to engage.  For a document of this magnitude and import, we suggested allowing for a 60 – 90 day comment period, which conforms to other organizations’ timelines. We hope ICER will consider that.

DL: These are exciting times for personalized medicine, with rapid developments in understanding this science and finding new cures. With these developments, how could — or should — ICER update its reports to remain current?

AM: In the case of NSCLC, new clinical evidence was published during ICER’s comment period, and for PD-1 inhibitors, I think we’ll see new data coming in more than once a year going forward. Because ICER is not alone in the value assessment trade, I’d suggest that the field of value assessment coordinate and come up with best practices for updating their findings. That way, innovators, patients and providers will have a timetable to engage with the update.

DL: Thanks so much for speaking with me.

For more about value framework assessments, check out NPC’s Guiding Practices for Patient-Centered Value Assessment and Current Landscape: Value Assessment Frameworks and watch the video from the organization’s conference, Assessing Value: Promise and Pitfalls.

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Beyond the Barriers: Deconstructing the Regulatory and Reimbursement Hurdles for Companion Diagnostics

Guest Blog
by Alessandra Cesano, M.D., Ph.D., Chief Medical Officer, NanoString Technologies


Alessandra Cesano, M.D., Ph.D.

On November 16, a group of diagnostic industry representatives will convene to discuss the regulatory and reimbursement hurdles for personalized medicine diagnostics during the 12th Annual Personalized Medicine Conference at Harvard Medical School. These kinds of discussions have never been more important.

The push for personalized medicine came to the national forefront in January when President Obama announced the National Cancer Moonshot. This bold initiative aims to accelerate the discovery of personalized treatments tailored to an individual’s genetic profile and/or the tumor’s biology. Companion diagnostics (CDx) play an important role in precision medicine, as they are designed to enrich care for patients who will benefit from a “companion” drug, by helping to characterize the disease’s biology and matching it with the mechanism of action of a specific drug.

Because many of the new drugs in the pipeline work on a specific genetic or biological target that is present in some, but not all, patients with a certain kind of cancer, there is a need for an accompanying test to determine if the drug will or will not have a benefit for a specific patient. These tests may also point to which patients are at immediate risk for harmful side effects.

The promise of companion diagnostics is not under debate, but there are regulatory and reimbursement hurdles that need to be overcome before these tests achieve widespread acceptance and deliver on the promise. First is the cost. The development of a companion diagnostic requires a significant investment, along the lines of tens of millions of dollars. However, presently, the value that companion diagnostics bring to the health care system, specifically in terms of improving patient outcomes and effectiveness of the care delivered, is not appropriately recognized by the reimbursement system.

Supporting the development of CDx tests will require significant investment up front, but once adopted they will help the health care system realize considerable cost and time savings. Currently, the health care system favors the “one-size-fits-all” approach to drug delivery, despite the fact that the subgroup of patients benefiting from treatment is on average only 20 – 30 percent. By using CDx, we can enrich the patient population for which a specific drug is effective, resulting in better outcomes and significantly reduced costs for the health care system. Designing and executing appropriate clinical trials to demonstrate the “clinical utility” and cost-effectiveness of selection biomarkers in each particular clinical setting will be an important part of the evidence needed to obtain test reimbursement.

Another obstacle involves how CDx and personalized medicine have impacted the regulatory landscape. While the regulatory path to a CDx is relatively well defined by regulatory guidelines, a gray area remains on when/how a  “generic” version of those tests (aka laboratory-developed tests or LDTs, which are analytically developed by a single laboratory without a clinical validation requirement) will be regulated by the FDA. This uncertainty has negatively affected the investor community’s appetite for diagnostic companies.

In light of these hurdles, a promising solution to driving CDx adoption is partnership among diagnostic manufacturers and the pharmaceutical industry. Biopharmaceutical companies are developing many therapies and as a result need to enroll patients in many hundreds of clinical trials. The clinical development of their drugs is going to demand enrichment strategies based on biomarkers. In fact, I can see a future in which it is the exception, rather than the rule, that drugs don’t have biomarkers when they come to market.

The biopharmaceutical industry is going to work with in vitro diagnostic companies that have the technology and the capabilities to both analyze the tumor’s biology and build an in vitro diagnostic product that can win clearance from the FDA. Ideally, these tests will be able to cut across whole drug classes (targets). Because of a limited supply of biotissue, the tests will need to be as holistic as possible. Thus, multi-plexed assays that allow for investigation of multiple aspects of biology in a single sample would be preferred.

Because of their unique ability to “match-make” a tumor’s biology with the right therapeutic choice, companion diagnostics are important for the efficient and effective treatment of patients. If the National Cancer Moonshot and other initiatives are going to be successful, there needs to be an alignment among all the stakeholders — including regulators, payers, pharmaceutical companies, physicians, patients and advocacy groups — recognizing the value of companion diagnostics in making “precision medicine” not just a promise but finally a reality.


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Think the Diagnostics Community Doesn’t Agree on Anything When It Comes to LDT Regulation? Think Again.

by Amy M. Miller, Ph.D., Executive Vice President, Personalized Medicine Coalition


Amy M. Miller, Ph.D.

As we enter a new round of discussions about laboratory-developed test (LDT) regulation, it is helpful to review where we’ve been. Many stakeholders have weighed in on the topic, and GenomeWeb’s comprehensive summary of the different proposals offers a useful comparison of them. At first glance, there appears to be little or no consensus. But listening to the community reveals more.

At the beginning of this year, I moderated a series of discussions on potential legislative solutions with representatives from the entire LDT community, including but not limited to those with an interest in personalized medicine. In short, the community agrees that a legislative solution to LDT regulation should take a risk-based approach and:

  1. Protect public health labs. Public health labs should be protected by any regulatory paradigm, which means that sentinel labs must be able to develop, deploy and use rapidly developed diagnostics to address critical public health needs.
  2. Allow flexibility and efficiency when managing modifications. As diagnostic device developers have long argued, the way modifications are managed by a regulatory system should be flexible and efficient to allow diagnostic tests to evolve with the clinical science that underpins them.
  3. Mitigate regulatory burdens for government and industry. To reduce regulatory burdens on government and industry, regulatory agencies should, when appropriate, recognize when certain safeguards are already in place. These mitigation strategies can help regulatory bodies keep pace with the rapidly evolving pace of personalized medicine diagnostic testing.
  4. Design a grandfathering system for tests already on the market. When FDA published its draft framework for regulating LDTs, we had no clear appreciation of the number of tests that might be captured by it. While we still do not have an exact count, tech firm NextGxDx estimates that there are nearly 70,000 personalized medicine diagnostics offered by about 300 labs with another eight to 10 coming to market each business day. To manage such an enormous workload, a regulatory agency must design a grandfathering system that will allow most tests to remain on the market unless there is a compelling reason to remove them.
  5. Ensure regulatory burdens reflect testing volumes. Regulatory burden must be reflective of testing volume.  For example, diagnostics designed for rare and un-met needs should be given careful and different consideration by any regulatory agency to ensure that tests are developed for micro-markets.
  6. Accept valid scientific evidence for regulatory purposes — even if that evidence does not include data from a randomized control trial. Personalized medicine has challenged how health care products and services are conceived, developed, regulated, covered, paid for and used by physicians.  Evidentiary requirements for regulatory review must also evolve. The community agrees that for diagnostics, valid scientific evidence should be acceptable for regulatory review, even when that evidence does not include data from randomized control trials.

Understanding these points and the logic behind them is essential to progress on this topic. Fortunately, we are not starting from scratch.

While there is no consensus about which regulatory agency should manage LDT regulation, the House Energy and Commerce Committee has released a draft legislative solution designed to address the community concerns outlined above. That proposal builds on a rich dialogue that began when the first genetic tests entered the market and continued in 2007 when Senators Ted Kennedy (D-MA) and Gordon Smith (R-OR) released a bi-partisan proposal for FDA to actively regulate lab tests. Soon after, then-Senator Obama and Senator Richard Burr (R-NC) released a draft legislative proposal that was not quite as burdensome. Finally, in 2010, Senator Hatch outlined a novel path at FDA for diagnostics, which opened up the conversation about the true difference between diagnostics and the medical devices that their regulatory structure mirrored.

These historical efforts stimulated conversation, and what was learned has influenced how we consider the topic. The Committee’s next draft will have been improved by stakeholder input, and we can expect the Senate to continue improving on the next draft.

Addressing this duel path to market and the difficulties inherent in such a regulatory paradigm is essential to the field.  Once this debate is settled, we can all concentrate on the biggest issue in personalized medicine: coverage, payment and use of personalized medicine diagnostics to dramatically improve the care patients receive. Guided by these areas of agreement and rich historical dialogue, we may be able to focus on those conversations sooner than we think.

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What ICER is Missing

by Amy M. Miller, Ph.D., PMC Executive Vice President


Amy M. Miller, Ph.D.

Personalized medicine challenges all aspects of health care, from the way discoveries are made to how they are regulated, covered, paid for and delivered in the clinic.

Since the mapping of the human genome 13 years ago, we have seen many efforts to alter, update and improve these processes to accommodate personalized medicines, innovative and novel diagnostic tests, and new approaches to care.  Excitement is palpable throughout the world, and personalized medicine’s proponents are no longer being accused of hyping a future that does not exist.

FDA’s new drug approvals demonstrate that about one in four new drugs (28 percent) are now targeted, a ratio likely to remain the same or increase in coming years.  As tech company NextGxDx’s count of genetic tests shows, there has also been an explosion of personalized medicine diagnostic tests on the market. Encouraged by the incredibly fast work of the National Institutes of Health (NIH) and FDA, U.S. policymakers in both chambers of the Republican-controlled Congress and the Democratic-controlled White House have expressed enthusiasm for the field’s potential.

Yet, some groups question the value of these advances.28-percent-of-fda-approvals-are-PMs

Take non-small cell lung cancer (NSCLC) for example. This disease exemplifies how a personalized approach can provide more for patients than the standard of care. Over a few short years, several new drugs and diagnostic tests for NSCLC have come to market, changing the trajectory of treatment for the disease. The first-generation ALK-targeted drug, for example, did not cross the blood-brain barrier; the second-generation therapy does. Diagnostics for NSCLC began with one-mutation tests, moved to panel tests for multiple mutations and are now moving into the realm of next-generation sequencing tests that reveal an even more comprehensive array of valuable information about the tumor. Thanks to immuno-oncology, we now have a new class of drugs to fight the disease.

Based on discoveries in clinical medicine, FDA regularly updates labels to move drugs from the second or third line to the front-line when paired with a diagnostic test. Teams of practitioners are learning about these new tools and putting them into practice.

The Institute for Clinical and Economic Review (ICER), which has released its evaluation of two classes of NSCLC drugs, may not share my excitement about these recent advances. The organization’s value assessment process has, by design or perhaps inadvertently, no mechanism for capturing the value of targeted medicines, since its model is built on population averages.

We strongly encourage advocates for personalized medicine to engage the organization and, as a first step, suggest that ICER evolve, like so much of the health care system already has, by treating personalized medicines and companion diagnostics differently than traditional therapeutics.

Comments on ICER’s draft evidence report are due September 16, 2016.