[Show abstract][Hide abstract] ABSTRACT: The concept of adaptive licensing (AL) has met with considerable interest. Yet, some remain sceptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of on-going debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm.
A life-span approach to bringing innovation to patients is expected to help address the perceived access versus evidence trade-off, help de-risk drug development, and lead to better outcomes for patients. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Abstract The interest in Comparative Effectiveness Research (CER) in the international community is growing. A panel titled "What Can Comparative Effectiveness Research Contribute to Integrative Health in International Perspective?" took place at the 3rd International Research Congress on Integrative Medicine and Health in Portland, Oregon, in 2012. The presentations at this panel highlighted different perspectives on CER, including the funders' and the stakeholders' perspectives from the United States, as well as experiences with economic evaluations from Australia and pragmatic trials in Europe. The funders' perspective emphasized the need for innovation and controlling costs in large-scale studies. The stakeholder's perspective stressed the need to gather the input of stakeholders in shaping the framework for more informative, more decision-maker-driven research. Several examples of cost-effectiveness analyses were offered from Australia. The importance of balancing rigor and pragmatism was also discussed in a presentation of the efficacy-effectiveness continuum. A wide-ranging discussion explored additional questions concerning the translation of evidence into practice; the effect of pragmatic trials on funding or policy; evidentiary distinctions between and among pragmatic trials and traditional randomized clinical trials; and the multiple roles of stakeholders, particularly in generating new information and knowledge. The presentations and discussions showed that more development of methods is needed. This includes developments on study design and statistical approaches, as well as methods for stakeholder involvement and mechanisms to bring these results into practice.
Journal of alternative and complementary medicine (New York, N.Y.) 11/2014; 20(11). DOI:10.1089/acm.2014.0073 · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is broad agreement among healthcare stakeholders that more must be done to assure that patients have timely access to new and innovative medicines. Assuming that industry will continue to develop such medicines at a sustainable rate, regulators and payers become the gatekeepers. Regulators, starting in the late 1980s/early 1990s, and more recently, payers have implemented a variety of early access pathways or initiatives and this practice is continuing even today. This paper describes the specific approaches that have been taken in four economically developed regions, reviews their success rates, and suggests possible new directions.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 09 July 2014; doi:10.1038/clpt.2014.145.
[Show abstract][Hide abstract] ABSTRACT: Medicare is one of the largest health care payers in the United States. As a result, its decisions about coverage have profound implications for patient access to care. In this commentary, the authors describe how Medicare used evidence on heterogeneity of treatment effects to make population-based decisions on health care coverage for implantable cardiac defibrillators. This case is discussed in the context of the rapidly expanding availability of comparative effectiveness research. While there is a potential tension between population-based and patient-centered decision making, the expanded diversity of populations and settings included in comparative effectiveness research can provide useful information for making more discerning and informed policy and clinical decisions.
Journal of managed care pharmacy: JMCP 06/2014; 20(6):547-54. · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An important challenge in comparative effectiveness research is the lack of infrastructure to support pragmatic clinical trials, which compare interventions in usual practice settings and subjects. These trials present challenges that differ from those of classical efficacy trials, which are conducted under ideal circumstances, in patients selected for their suitability, and with highly controlled protocols. In 2012, we launched a 1-year learning network to identify high-priority pragmatic clinical trials and to deploy research infrastructure through the NIH Clinical and Translational Science Awards Consortium that could be used to launch and sustain them. The network and infrastructure were initiated as a learning ground and shared resource for investigators and communities interested in developing pragmatic clinical trials. We followed a three-stage process of developing the network, prioritizing proposed trials, and implementing learning exercises that culminated in a 1-day network meeting at the end of the year. The year-long project resulted in five recommendations related to developing the network, enhancing community engagement, addressing regulatory challenges, advancing information technology, and developing research methods. The recommendations can be implemented within 24 months and are designed to lead toward a sustained national infrastructure for pragmatic trials.
[Show abstract][Hide abstract] ABSTRACT: Sean R Tunis is the founder, President and Chief Executive Officer of the Center for Medical Technology Policy in Baltimore (MD, USA). The Center for Medical Technology Policy's main objective is to improve the quality, relevance and efficiency of clinical research by providing a neutral forum for collaboration among experts, stakeholders and decision-makers. Tunis was a member of the Institute of Medicine Committee on Initial National Priorities for Comparative Effectiveness Research. He advises a wide range of domestic and international public and private healthcare organizations on issues of comparative effectiveness, evidence-based medicine, clinical research, reimbursement and health technology policy. In September of 2005, Tunis was the Chief Medical Officer at the Centers for Medicare and Medicaid Services, where he had lead responsibility for clinical policy for the Medicare and Medicaid programs. Previously, he served as the Director of the Health Program at the Congressional Office of Technology Assessment and as a health policy advisor to the US Senate, where he worked on pharmaceutical and device policy issues. Tunis trained at the University of California in Los Angeles (CA, USA) and the University of Maryland in Internal Medicine and Emergency Medicine (MD, USA) and holds adjunct faculty positions at the Tufts University School of Medicine (MA, USA), the Department of Internal Medicine at the Johns Hopkins School of Medicine (MD, USA), and the Department of Surgery at the University of California at San Francisco (CA, USA).
Journal of Comparative Effectiveness Research 01/2014; 3(1):11-16. DOI:10.2217/cer.13.88 · 0.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is estimated that 6.5 million people in the United States (US) suffer from chronic, non-healing wounds and that this number will grow coincident with an ageing population and increasing rates of obesity and diabetes.
Journal of Wound Care 09/2013; 22(9):470-80. DOI:10.12968/jowc.2013.22.9.470 · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pharmaceutical Pragmatic Clinical Trials (PCTs) are designed to provide the type of evidence that is desired by patients, clinicians and payers but too often missing from traditional regulatory trials.
This paper presents framework for designing pragmatic trials incorporating evidence desired by post-regulatory decision makers while remaining within acceptable standards for regulatory approval.
Following a stakeholder meeting convened in May of 2009 to identify gaps in information collected in Phase 3 trials, CMTP staff and the authors drafted recommendations for Pragmatic Phase 3 Pharmaceutical Trials. This draft was circulated first to technical working group members for their comments. After revising the document based on these comments, it was distributed electronically to other select experts and then made available for public comment. The final version of the EGD appears on the CMTP website.
The process resulted in a set of 10 recommendations for conducting Phase 3 trials that met regulatory needs while addressing information important to physicians, patients, payers, and policy-makers. These recommendations encompassed three primary areas: generalizability from the trial participants to the clinical population of interest; effectiveness relative to active comparators; and consistently measured relevant outcomes for coverage and treatment decisions. Limitations While stakeholders were involved throughout the process, not all recommendations will meet the needs of all stakeholders.
Pragmatic trial design need not be deferred until a product is in widespread use. Incremental movement toward more the more pragmatic design of Phase 3 trials is desirable.
[Show abstract][Hide abstract] ABSTRACT: Background:
Electronic clinical data (ECD) will increasingly serve as an important source of information for comparative effectiveness research (CER). Although many retrospective studies have relied on ECD, new study designs propose using ECD for prospective CER. These designs have great potential but they also raise important ethics questions.
Drawing on an ethics framework for learning health care systems, we identify morally relevant features of prospective CER-ECD studies by examining 1 case of an observational study and a second of a pragmatic, randomized trial. We focus only on questions of consent and assume research has been subject to appropriate ethics review and oversight.
Results and conclusions:
We conclude that a CER-ECD observational study that imposes no or minimal additional risk to or burden on patients may proceed ethically without express informed consent from participants in settings where: (a) patients are regularly informed of the health care institution's commitment to learning through the integration of research and practice; and (b) there are appropriate protections for patients' rights and interests. In addition, where (a) and (b) apply, some pragmatic, randomized trials that similarly impose no or minimal additional risk to or burden on patients may also proceed ethically without express consent, when certain additional conditions are satisfied, including: (c) the trial does not negatively affect patients' prospects for good clinical outcomes; (d) physicians have the option of using an intervention other than the one assigned if they believe doing so is important for a particular patient; and (e) the trial does not engage preferences or values that are meaningful to patients.
Medical Care 08/2013; 51(8 Suppl 3):S53-S57. DOI:10.1097/MLR.0b013e31829b1e4b · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found insufficient evidence to recommend testing for predictive variants in 28 variants (listed in Table 1) to assess risk for type 2 diabetes in the general population, on the basis of studies in populations of northern European descent. The EWG found that the magnitude of net health benefit from the use of any of these tests alone or in combination is close to zero. The EWG discourages clinical use unless further evidence supports improved clinical outcomes. The EWG found insufficient evidence to recommend testing for the TCF7L2 gene to assess risk for type 2 diabetes in high-risk individuals. The EWG found that the magnitude of net health benefit from the use of this test is close to zero. The EWG discourages clinical use unless further evidence supports improved clinical outcomes. On the basis of the available evidence for both the scenarios, the overall certainty of net health benefit is deemed "low." Rationale: It has been suggested that genomic profiling in the general population or in high-risk populations for type 2 diabetes might lead to management changes (e.g., earlier initiation or higher rates of medical interventions, or targeted recommendations for behavioral change) that improve type 2 diabetes outcomes or prevent type 2 diabetes. The EWG found no direct evidence to support this possibility; therefore, this review sought indirect evidence aimed at documenting the extent to which genomic profiling alters type 2 diabetes risk estimation, alone and in combination with traditional risk factors, and the extent to which risk classification improves health outcomes. Analytic validity: Assay-related evidence on available genomic profiling tests was deemed inadequate. However, on the basis of existing technologies that have been or may be used, the analytic sensitivity and specificity of tests for individual gene variants might be at least satisfactory. Clinical validity: Twenty-eight candidate markers were evaluated in the general population. Evidence on clinical validity was rated inadequate for 24 of these associations (86%) and adequate for 4 (14%). Inadequate grades were based on limited evidence, poor replication, existence of possible biases, or combinations of these factors. Type 2 diabetes genomic profiling provided areas under the receiver operator characteristics curve of 55%-57%, with 4, 8, and 28 genes. Only TCF7L2 had convincing evidence of an association with type 2 diabetes with an odds ratio of 1.39 (95% confidence interval: 1.33-1.46). TCF7L2 was evaluated for high-risk populations, and the overall odds ratio was 1.66 (95% confidence interval: 1.22-2.27) for association with progression to type 2 diabetes. Clinical utility: No studies were available to provide direct evidence on the balance of benefits and harms for genetic profiling for type 2 diabetes alone or in addition to traditional risk factors in the general population. Evidence for high-risk populations and TCF7L2 was inadequate on the basis of two identified studies. These studies found close to zero additional benefit with the addition of genomic markers to traditional risk factors (diet, body mass index, and glucose tolerance). Contextual issues: Prevention of type 2 diabetes is a public health priority. Improvements in the outcomes associated with genomic profiling could have important impacts. Traditional risk factors (e.g., body mass index, weight, fat mass, and exercise) have an advantage in clinical screening and risk assessment strategies because they measure the actual targets for therapy (e.g., fasting plasma glucose and medical interventions). To be useful in predicting disease risk, genomic testing should improve the predictive value of these traditional risk factors. Some issues important for clinical utility remain unknown, such as the level of risk that changes intervention, whether long-term disease outcomes will improve, how individuals being tested will understand/respond to test results and interact with the health-care system, and whether testing will motivate behavior change or amplify potential harms.
Genetics in Medicine 08/2013; 15(8):612-617. DOI:10.1038/gim.2013.9 · 7.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite prodigious advances in tumor biology research, few tumor-biomarker tests have been adopted as standard clinical practice. This lack of reliable tests stems from a vicious cycle of undervaluation, resulting from inconsistent regulatory standards and reimbursement, as well as insufficient investment in research and development, scrutiny of biomarker publications by journals, and evidence of analytical validity and clinical utility. We offer recommendations designed to serve as a roadmap to break this vicious cycle and call for a national dialogue, as changes in regulation, reimbursement, investment, peer review, and guidelines development require the participation of all stakeholders.
Science translational medicine 07/2013; 5(196):196cm6. DOI:10.1126/scitranslmed.3005950 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pharmaceutical companies have a good understanding of the needs and requirements of regulatory bodies, but the evidence expectations of health technology assessment (HTA) and coverage/payer bodies are less well understood and addressed. This paper seeks to improve this understanding by providing an overview of the expectations of HTA and coverage/payer bodies, explaining how and why these differ from those of regulators, and describing the extent and limitations of work on harmonization. The article goes on to describe ways in which HTA and coverage/payer bodies' expectations can be addressed, and to encourage industry to interact with HTA and coverage/payer bodies to increase mutual understanding and hence promote more efficient development of and access to innovative medicines.
[Show abstract][Hide abstract] ABSTRACT: Summary of recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found that, for patients with metastatic colorectal cancer (mCRC) who are being considered for treatment with cetuximab or panitumumab, there is convincing evidence to recommend clinical use of KRAS mutation analysis to determine which patients are KRAS mutation positive and therefore unlikely to benefit from these agents before initiation of therapy. The level of certainty of the evidence was deemed high, and the magnitude of net health benefit from avoiding potentially ineffective and harmful treatment, along with promoting more immediate access to what could be the next most effective treatment, is at least moderate.
Genetics in medicine: official journal of the American College of Medical Genetics 02/2013; 15(7). DOI:10.1038/gim.2012.184 · 7.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Calls are increasing for American health care to be organized as a learning health care system, defined by the Institute of Medicine as a health care system “in which knowledge generation is so embedded into the core of the practice of medicine that it is a natural outgrowth and product of the healthcare delivery process and leads to continual improvement in care.” We applaud this conception, and in this paper, we put forward a new ethics framework for it. No such framework has previously been articulated. The goals of our framework are twofold: to support the transformation to a learning health care system and to help ensure that learning activities carried out within such a system are conducted in an ethically acceptable fashion.
Hastings Center Report 02/2013; 43(s1). DOI:10.1002/hast.134 · 1.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The rise of quality improvement research and comparative effectiveness research in health care settings constitutes progress toward the goal of what the Institute of Medicine has called a “learning healthcare system,” in which we are “drawing research closer to clinical practice by building knowledge development and application into each stage of the healthcare delivery process.” As clinical research and clinical practice move closer to a deliberately integrated system, the distinction between the two is increasingly blurred, although the sharp distinction in U.S. regulations and research ethics literature remains in place. In the 1970s and for two decades thereafter, this distinction was helpful: for some forms of research, it sheds light on which activities require ethical oversight. Research that is closely integrated with health care—notably, health delivery research—was then uncommon, however. That is no longer the case, and regulations and research ethics need to change to accommodate the new landscape. In this paper, we argue that conceptual, moral, and empirical problems surround the received view that we can and should draw sharp distinctions between clinical research and clinical practice. We start with the history of the research-practice distinction in the reports of a U.S. national commission and in U.S. federal regulations, and then offer a critical assessment of five characterizations of research that have been used in policy documents and the scholarly literature to try to make a sharp distinction between research and practice. We challenge the clarity and the tenability of these characterizations as a way of distinguishing research from practice. We argue that the received view of the research-practice distinction leads to overprotection of the rights and interests of patients in some cases and to underprotection in others. We contend that a new ethical foundation needs to be developed that facilitates both care and research likely to benefit patients, and that provides oversight that, rather than being based on a distinction between research and practice, is commensurate with risk and burden in both realms.
Hastings Center Report 02/2013; 43(s1). DOI:10.1002/hast.133 · 1.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Women with breast cancer involving the lymph nodes are typically treated with cytotoxic chemotherapy. Retrospective evaluations of prior studies suggest that the 21-gene test (OncotypeDX®), may allow identification of those who can safely avoid chemotherapy. To better understand the performance of the 21-gene test, the RxPONDER (Rx for Positive Node, Endocrine Responsive breast cancer) study was designed, a multicenter Phase III trial randomizing women with hormone receptor-positive and HER2-negative breast cancer involving 1–3 lymph nodes and a 21-gene assay recurrence score (RS) of 25 or less to endocrine therapy alone versus chemotherapy followed by endocrine therapy. As one of the first large-scale comparative-effectiveness studies in oncology, RxPONDER utilized an external stakeholder group to help inform the design of the trial. Stakeholders met with representatives of SWOG over several months through a structured discussion process. The stakeholder engagement process resulted in several changes being made to the trial design. In addition, stakeholder representatives from the health insurance industry provided guidance regarding a mechanism whereby the costs of OncotypeDX® would be paid by the majority of health insurers as part of the trial. The process may serve as a template for future studies evaluating the comparative effectiveness of genomic tests in oncology, particularly those that are conducted within cooperative clinical trials groups.