President Obama announced during the recent State of the Union address that his administration would initiate an enhanced funding and policy focus on the field of precision medicine. Precision medicine is informed by the collection of genetic, proteomic, microbial and other biological data of a patient – and the end result is to more sharply define disease states and allow for treatment that is more personalized, with a higher likelihood of success. In the specific case of cancer, for example, a patient’s tumor cells can be analyzed genetically to develop a precise molecular characterization – and treatments can be customized accordingly. According to the White House release:
Launched with a $215 million investment in the President’s 2016 Budget, the Precision Medicine Initiative will pioneer a new model of patient-powered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients.
The proposed funding is directed to the National Institutes of Health (NIH), the NIH’s National Cancer Institute and the Food and Drug Administration (FDA), and the National Coordinator for Health Information Technology (ONC). The initiative will focus on oncology-related objectives as a starting point:
The cancer-focused component of this initiative will be designed to address some of the obstacles that have already been encountered in “precision oncology”: unexplained drug resistance, genomic heterogeneity of tumors, insufficient means for monitoring responses and tumor recurrence, and limited knowledge about the use of drug combinations. Precision medicine's more individualized, molecular approach to cancer will enrich and modify, but not replace, the successful staples of oncology - prevention, diagnostics, some screening methods, and effective treatments - while providing a strong framework for accelerating the adoption of precision medicine in other spheres. The most obvious of those spheres are inherited genetic disorders and infectious diseases, but there is promise for many other diseases and environmental responses.
The breakdown of this investment is as follows:
$130 million to NIH for development of a voluntary national research cohort of a million or more volunteers to propel our understanding of health and disease and set the foundation for a new way of doing research through engaged participants and open, responsible data sharing.
$70 million to the National Cancer Institute (NCI), part of NIH, to scale up efforts to identify genomic drivers in cancer and apply that knowledge in the development of more effective approaches to cancer treatment.
$10 million to FDA to acquire additional expertise and advance the development of high quality, curated databases to support the regulatory structure needed to advance innovation in precision medicine and protect public health.
$5 million to ONC to support the development of interoperability standards and requirements that address privacy and enable secure exchange of data across systems.
The proposed investment of $215 million is actually quite small, when compared to an annual NIH budget of around $30 billion, and further still when it is divided among the target agencies. Congressional approval will also be needed, but that is probably likely, given ongoing bipartisan advocacy efforts in Congress to increase funding for “21st Century Cures.” However, apart from the financial aspects, the announcement does tie various policy architects together in the federal ecosystem of personalized medicine – imagining newly developed data from the NIH research cohort that is used to identify a new genetic marker for cancer diagnosis or susceptibility, leading to a new test devised by the NCI, which then enters the marketplace under a regulatory regime supervised by the FDA, and all emerging data points accountable in a more standardized electronic environment that the ONC has helped to develop. There are several regulatory sinkholes in this announcement, of course - what will it mean to launch a volunteer-sourced bio-database under government oversight, given a current minimalist privacy regime for genetic information (e.g., GINA). What regulatory scheme will prevail at the FDA with respect to LDTs and next-generation sequencing technologies (see recent post)?
The regulation of genetic tests is uneven, with the FDA exercising enforcement discretion of this field within its general authority to regulate medical devices. To date, the FDA requires approval of genetic testing kits, considered to be in vitro diagnostics (IVD). The FDA has paid specific attention to one subset of genetic test kits, known as companion diagnostics. The FDA describes companion diagnostics:
A companion diagnostic device can be in vitro diagnostic device or an imaging tool 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 particular therapeutic product is stipulated in the instructions for use in the labeling of both the diagnostic device and the corresponding therapeutic product, as well as in the labeling of any generic equivalents and biosimilar equivalents of the therapeutic product.
Companion diagnostics illustrate the use of pharmacogenetics to refine pharmaceutical treatment of cancers or other illnesses. The FDA has just approved a new companion diagnostic test for use in the treatment of non small cell lung cancer, the cobas EGFR Mutation Test that refines the optimal use for Tarceva, a biotech drug approved by the FDA in 2004 (a monoclonal antibody). This approval scenario illustrates how the optimal treatment profile for an already approved drug is being refined by subsequent genetic research, where new understandings of the relationship between particular genes and the specific cancers is allowing for more refinement in treatment decisions. The FDA published a guidance document for the approval of companion diagnostics in 2011:
An IVD companion diagnostic device could be essential for the safe and effective use of a corresponding therapeutic product to identify patients who are most likely to benefit from a particular therapeutic product; identify patients likely to be at increased risk for serious adverse reactions as a result of treatment with a particular therapeutic product; or monitor response to treatment for the purpose of adjusting treatment (e.g., schedule, dose, discontinuation) to achieve improved safety or effectiveness.
The FDA also recognizes a scenario of co-development between a drug manufacturer and a test developer, such that both products are approved simultaneously, as illustrated by the FDA's co-approval of Xalkori and the Vysis ALK Break Apart FISH Probe Kit in 2011. The list of approved companion diagnostics continues to grow. As a general matter, the FDA regulates genetic tests sold as kits to laboratories or consumers. In the general genetic testing market, however, most genetic tests are offered as laboratory-derived tests (LDTs), available as services, rather than products. The FDA does not regulate LDTs, although it has stated that some LDTs are considered medical devices, subject to its oversight. However, despite issuing a statement of intention for possible oversight in 2010, the FDA to date has not taken on LDTs in general, or even the genetic LDTs. Laboratories providing LDTs are regulated under the Clinical Laboratory Improvement Amendments (CLIA), administered by the Centers for Medicare and Medicaid Services (CMS), which requires that laboratories meet specified standards, and that individual tests are scientifically accurate, but which does not evaluate the clinical validity or clinical utility of LDTs. Calls for the FDA to increase its involvement in the regulation of LDTs have come from many sources, including the Secretary's Advisory Committee for Genetics, Health and Society in 2008. More recently, the American College of Medical Genetics published a risk-classification framework for the regulation of LDT genetic tests, calling for FDA pre-market approval of high-risk LDTs, where "the consequence of an incorrect result or interpretation could lead to serious mortality or morbidity."
Pharmacogenomics (abbreviated PGx) is the use of genetic information in tailoring or predicting drug response – examples include whether a patient has a particularly favorable genetic profile that indicates that a drug will likely work, or whether the tumor from a cancer patient appears to be genetically vulnerable to chemotherapeutic drugs. In general, the FDA does not regulate the vast field of genetic testing (see here for more background). However, the FDA has been involved in regulating some coupling of genetic testing with the use of FDA-approved drugs (resulting in a companion diagnostic). This paradigm of approving drugs for specific genetically typed populations began with the approval of Herceptin and an accompanying genetic test in 1998. Herceptin is a monoclonal antibody that targets a particular protein on breast cancer cells. The subset of cancer patients who tested for HER-2 positive cancer cells became the target group for the use of this drug. This drug was developed through the detailed molecular study of cancer cells and so the genetic profile for the drug was known at the start. The trend toward the approval of companion diagnostic continues. The FDA definition: "An in vitro companion diagnostic device 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 particular therapeutic product is stipulated in the instructions for use in the labeling of both the diagnostic device and the corresponding therapeutic product, as well as in the labeling of any generic equivalents and biosimilar equivalents of the therapeutic product." Here is the current FDA list of approvals. The FDA has approved another companion diagnostic for use in the treatment of colon cancer. In this case, the TheraScreen test for mutations in the K-ras gene will be used to evaluate the likelihood that the already approved Erbitux will be effective in the treatment of colon cancer. The infilitration of PGx into drug prescribing does not stop there. Fast forward and we now have dozens of drugs (not all of which are newly developed) which include PGx information on their FDA-approved labels. This reflects the FDA’s increasing embrace of genomic information as a component of the therapeutic information climate, and it continues to advise drug companies who wish to include such information by issuing guidance on how to incorporate a genomic dimension into clinical trials. A number of PGx correlates for drug use have come to light after drug approval, as researchers attempt to identify successes and failures as the drug is used in the general population (see here for earlier story on Plavix and PGx). The PGx field is distinctive in genetic testing as the FDA is taking affirmative steps to manage the use of genetic information in drug prescribing, while it continues to exercise what it describes as “enforcement discretion” with respect to other applications of genetic testing.
The American Heart Association (AHA), a leading professional organization focused on cardiovascular (disease) medicine (CVD) has published an interesting and comprehensive overview of many relevant issues at the intersection of genetics, law and medicine that is worth looking at (published in the AHA journal, Circulation). The professional medical organizations (e.g., American Medical Association and others) have lent their expertise and engaged in advocacy on genetic legal issues over the last decade. They have been visible in the gene patent litigation, Association for Molecular Pathology v. U.S. Patent and Trademark Office (AMP v. USPTO) (headed back to court this summer), where they have largely opposed the granting of gene patents and filed amicus briefs in this ongoing litigation. Now, the AHA has provided its professional analysis and policy recommendations on the central legal/political debates in genetic medicine: gene patents (oppose the granting of gene patents); the possible use of genetic information to discriminate in employment and health care (supports the federal Genetic Information Nondiscrimination Act (GINA), and recommends its expansion to life and long-term insurance policies); the very critical issue of regulatory oversight of genetic tests in the marketplace (recommends that the FDA exercise its enforcement discretion to review and advise on the clinical validity of the laboratory-derived tests in genetic testing); further attention to the establishment of solid pharmacogenetic correlations before genetic information is used to guide drug prescribing and to solid research before genetic risk classifications become routine; further work on a consensus patient consent mechanism that would allow study participants to clearly understand the limits and benefits to participation in large-scale genetic studies; some standardization for insurance payment schemes for genetic tests, and, lastly, the AHA calls attention to the need for deeper practitioner training in genetics. Here are links to some earlier stories here on these issues: FDA regulation; pharmacogenomics, genetic discrimination. Some of the issues discussed in the AHA article require legal resolution (gene patents? FDA oversight?) while others are challenges and overtures to the professional field itself (the AHA calls for increasing development of the specialization of CVD and genetics). In sum, this article is a useful cataloging of the issues confronting all practitioners who increasingly make genetically-informed medical decisions (e.g. oncologists, neurologists, etc.) and provides a template and scorecard to monitor these issues.
Did the FDA jump the gun when it recommended genetic testing to accompany the use of Plavix (clopidogrel), a widely prescribed blood thinner drug? In March, 2010, the FDA issued a post-marketing black box warning for Plavix, suggesting that prescribers consider CYP2C19 genotyping (a genetic test for mutations in the gene) to identify “slow metabolizer” patients who remained at risk for heart attack, stroke, and other cardiovascular events. The theory was that a subset of patients with a particular genetic profile in the CYP2C19 gene for whom the drug was prescribed because of cardiovascular risk could not properly metabolize the drug; thus they were not protected by the drug against possible heart attacks. This warning followed reports and lawsuits over the use of Plavix (adverse side effects and ineffectiveness). A black box warning is the strictest warning that can be added to a drug label, short of recalling the drug. Such a warning may decrease use of the drug, sometimes without need. Therefore, its use (e.g., adverse reactions to drugs, contraindications for use) is optimally reserved for instances where the level of risk, as supported by data, warrants the elevated monitoring. The FDA recommendation for the genetic test was not supported by leading medical associations, specifically the American Medical Association and the American College of Cardiology, which stated that the evidence was insufficient to support a sweeping recommendation, but did issue guidelines for practitioners who prescribed Plavix. Now, research reports in the British Medical Journal and the Journal of the American Medical Association (JAMA) show that the data does not support the conclusion that the CYP2C19 genetic test results correlate with a population with increased cardiovascular events, as the underlying theory would predict. A JAMA editorial criticized the “irrational exuberance” of the FDA in its recommendation of the genetic testing and noted that “the pharmacogenomics approach to drug therapy must undergo the same rigorous testing for efficacy and cost-effectiveness that is required for other therapies. Overzealous adoption based on limited biochemical data does not serve the public interest.” Any recommendation for genetic testing immediately presents issues of cost and insurance coverage, so that patients may face a more complicated access scenario (and delay). So far, the FDA has not responded to the new research with any revisions in its recommendations. However, the episode is certainly a cautionary tale for the agency, which must balance its growing accommodation of the phamacogenetic dimension of drug prescribing with thorough attention to scientific rigor.
The field of pharmacogenomics, in which pharmaceutical treatments are informed by genetic analysis, allows for more individualized therapeutic regimens. This field is also described as personalized medicine. The Public Library of Science hosts an online repository, Evidence on Genomic Tests, that publishes peer-reviewed reports of genomic tests used in clinical practice. These are short, summary reports, which, interestingly, attend to the key attributes that need to be studied in genetic testing: analytic validity, clinical validity, and clinical utility. For more information on these parameters, see the 2008 Report by the HHS Advisory Committee on Genetics, Health and Society on the U.S. oversight of genetic tests. One such report recently studied the Oncotype DX, which is a genetic test that aims to predict the possibility of recurrence for breast cancer patients by analyzing the variations in a discrete 21-gene set which correlate to either lower or higher recurrence risk. The clinical import is that women with lower risks of recurrence, as identified by Oncoptype DX, could receive less aggressive followup treatment, such as adjuvant chemotherapy. The report concluded that, as yet, there is some analytic validity, some clinical validity, but concluded: "There is currently no data clearly demonstrating clinical utility of Oncotype DX in women with lymph node-positive breast cancer." While these phamacogenomic tests have received critical attention, leading to some FDA oversight, it is important to simultaneously monitor how these tests are actually faring in practice. This is key for patients who could be spared unnecessary treatment, but also for patients who might unduly be denied treatment, either conclusions might be drawn from these tests. In addition to frank medical concerns, insurance coverage for these tests varies and presents additional complications. This report reminds us that, as the debates over a proper regulatory framework for genetic testing continue, the scientific evaluation of proposed pharmagenomic modalities is relatively recent, currently ongoing, and far from completed.
The use of genetic information to inform pharmaceutical treatments is known as pharmacogenetics/pharcogenomics. The FDA has argued for its authority to approve such tests, despite the fact that it does not approve most commercially offered genetic tests in the U.S. Now the FDA has approved another genetic test, the Dual ISH test manufactured by Ventana Systems, which will determine which women could benefit from the use of the monoclonal antibody treatment, Herceptin, which will be particularly helpful to patients whose cancer cells exhibit the HER-2 protein. The FDA notes: "HER-2 overexpression and gene amplification should be determined using FDA-approved tests with an indication for the specific tumor type being tested." Other HER-2 tests are available, including one offered by Genentech, which produces Herceptin.
