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1.  Improving the efficiency and relevance of evidence-based recommendations in the era of whole-genome sequencing: an EGAPP methods update 
To provide an update on recent revisions to Evaluation of Genomic Applications in Practice and Prevention (EGAPP) methods designed to improve efficiency, and an assessment of the implications of whole genome sequencing for evidence-based recommendation development. Improvements to the EGAPP approach include automated searches for horizon scanning, a quantitative ranking process for topic prioritization, and the development of a staged evidence review and evaluation process. The staged process entails (i) triaging tests with minimal evidence of clinical validity, (ii) using and updating existing reviews, (iii) evaluating clinical validity prior to analytic validity or clinical utility, (iv) using decision modeling to assess potential clinical utility when direct evidence is not available. EGAPP experience to date suggests the following approaches will be critical for the development of evidence based recommendations in the whole genome sequencing era: (i) use of triage approaches and frameworks to improve efficiency, (ii) development of evidence thresholds that consider the value of further research, (iii) incorporation of patient preferences, and (iv) engagement of diverse stakeholders. The rapid advances in genomics present a significant challenge to traditional evidence based medicine, but also an opportunity for innovative approaches to recommendation development.
doi:10.1038/gim.2012.106
PMCID: PMC3932295  PMID: 22955111
evidence-based medicine/methods; evidence-based medicine/standards; genetics; genomics/methods; genomics/standards; medical/methods
2.  Integrating Comparative Effectiveness Design Elements and Endpoints Into a Phase III, Randomized Clinical Trial (SWOG S1007) Evaluating OncotypeDX-Guided Management for Women With Breast Cancer Involving Lymph Nodes 
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.
doi:10.1016/j.cct.2012.09.003
PMCID: PMC3525786  PMID: 23000081
breast cancer; comparative effectiveness research; OncotypeDx; everolimus; stakeholder
3.  Redesigning Radiotherapy Quality Assurance: Opportunities to Develop an Efficient, Evidence-Based System to Support Clinical Trials 
Background
In the context of national calls for reorganizing cancer clinical trials, the National Cancer Institute (NCI) sponsored a two day workshop to examine the challenges and opportunities for optimizing radiotherapy quality assurance (QA) in clinical trial design.
Methods
Participants reviewed the current processes of clinical trial QA and noted the QA challenges presented by advanced technologies. Lessons learned from the radiotherapy QA programs of recent trials were discussed in detail. Four potential opportunities for optimizing radiotherapy QA were explored, including the use of normal tissue toxicity and tumor control metrics, biomarkers of radiation toxicity, new radiotherapy modalities like proton beam therapy, and the international harmonization of clinical trial QA.
Results
Four recommendations were made: 1) Develop a tiered (and more efficient) system for radiotherapy QA and tailor intensity of QA to clinical trial objectives. Tiers include (i) general credentialing, (ii) trial specific credentialing, and (iii) individual case review; 2) Establish a case QA repository; 3) Develop an evidence base for clinical trial QA and introduce innovative prospective trial designs to evaluate radiotherapy QA in clinical trials; and 4) Explore the feasibility of consolidating clinical trial QA in the United States.
Conclusion
Radiotherapy QA may impact clinical trial accrual, cost, outcomes and generalizability. To achieve maximum benefit, QA programs must become more efficient and evidence-based.
doi:10.1016/j.ijrobp.2011.12.080
PMCID: PMC3361528  PMID: 22425219
clinical trial design; credentialing; radiotherapy; quality assurance
4.  Improving the efficiency and effectiveness of pragmatic clinical trials in older adults in the United States 
Contemporary clinical trials  2012;33(6):1211-1216.
Pragmatic clinical trials (PCTs) seek to improve the generalizability and increase the statistical power of traditional explanatory trials. They are a major tenet of comparative effectiveness research. While a powerful study design, PCTs have been limited by high cost, modest efficiency, and limited ability to fill relevant evidence gaps. Based on an American Reinvestment and Recovery Act (ARRA) supported meeting of national stakeholders, we propose several innovations and future research that could improve the efficiency and effectiveness of such studies focused in the U.S. Innovations discussed include optimizing the use of community based practices through partnership with Practice Based Research Networks (PBRNs), using information technology to simplify PCT subject recruitment, consent and randomization processes, and utilizing linkages to large administrative databases, such as Medicare, as a mechanism to capture outcomes and other important PCT variables with lower subject and research team burden. Testing and adaptation of such innovations to PCT are anticipated to improve the public health value of these increasingly important studies.
doi:10.1016/j.cct.2012.07.002
PMCID: PMC3675785  PMID: 22796098
Pragmatic clinical trials; Large simple trials; Comparative effectiveness research; Practice Based Research Network
5.  Building the Evidence Base for Decision-making in Cancer Genomic Medicine Using Comparative Effectiveness Research 
Background
The clinical utility is uncertain for many cancer genomic applications. Comparative effectiveness research (CER) can provide evidence to clarify this uncertainty.
Objectives
To identify approaches to help stakeholders make evidence-based decisions, and to describe potential challenges and opportunities using CER to produce evidence-based guidance.
Methods
We identified general CER approaches for genomic applications through literature review, the authors’ experiences, and lessons learned from a recent, seven-site CER initiative in cancer genomic medicine. Case studies illustrate the use of CER approaches.
Results
Evidence generation and synthesis approaches include comparative observational and randomized trials, patient reported outcomes, decision modeling, and economic analysis. We identified significant challenges to conducting CER in cancer genomics: the rapid pace of innovation, the lack of regulation, the limited evidence for clinical utility, and the beliefs that genomic tests could have personal utility without having clinical utility. Opportunities to capitalize on CER methods in cancer genomics include improvements in the conduct of evidence synthesis, stakeholder engagement, increasing the number of comparative studies, and developing approaches to inform clinical guidelines and research prioritization.
Conclusions
CER offers a variety of methodological approaches to address stakeholders’ needs. Innovative approaches are needed to ensure an effective translation of genomic discoveries.
doi:10.1038/gim.2012.16
PMCID: PMC3632438  PMID: 22516979
evidence synthesis; evidence generation; stakeholder; clinical utility
6.  Stakeholder participation in comparative effectiveness research: defining a framework for effective engagement 
Aims
Stakeholder engagement is fundamental to comparative effectiveness research (CER), but lacks consistent terminology. This paper aims to define stakeholder engagement and present a conceptual model for involving stakeholders in CER.
Materials & methods
The definitions and model were developed from a literature search, expert input and experience with the Center for Comparative Effectiveness Research in Cancer Genomics, a proof-of-concept platform for stakeholder involvement in priority setting and CER study design.
Results
Definitions for stakeholder and stakeholder engagement reflect the target constituencies and their role in CER. The ‘analytic-deliberative’ conceptual model for stakeholder engagement illustrates the inputs, methods and outputs relevant to CER. The model differentiates methods at each stage of the project; depicts the relationship between components; and identifies outcome measures for evaluation of the process.
Conclusion
While the definitions and model require testing before being broadly adopted, they are an important foundational step and will be useful for investigators, funders and stakeholder groups interested in contributing to CER.
doi:10.2217/cer.12.7
PMCID: PMC3371639  PMID: 22707880
cancer genomics; comparative effectiveness research; consumer participation; deliberative methods; public participation; stakeholder engagement; stakeholders
7.  Building a Strategic Framework for Comparative Effectiveness Research in Complementary and Integrative Medicine 
The increasing burden of chronic diseases presents not only challenges to the knowledge and expertise of the professional medical community, but also highlights the need to improve the quality and relevance of clinical research in this domain. Many patients now turn to complementary and integrative medicine (CIM) to treat their chronic illnesses; however, there is very little evidence to guide their decision-making in usual care. The following research recommendations were derived from a CIM Stakeholder Symposium on Comparative Effectiveness Research (CER): (1) CER studies should be made a priority in this field; (2) stakeholders should be engaged at every stage of the research; (3) CER study designs should highlight effectiveness over efficacy; (4) research questions should be well defined to enable the selection of an appropriate CER study design; (5) the CIM community should cultivate widely shared understandings, discourse, tools, and technologies to support the use and validity of CER methods; (6) Effectiveness Guidance Documents on methodological standards should be developed to shape future CER studies. CER is an emerging field and its development and impact must be reflected in future research strategies within CIM. This stakeholder symposium was a first step in providing systematic guidance for future CER in this field.
doi:10.1155/2012/531096
PMCID: PMC3544532  PMID: 23346206
8.  How Comparative Effectiveness Research Can Help To Advance ‘Personalized Medicine’ In Cancer Treatment 
Health affairs (Project Hope)  2011;30(12):2259-2268.
The use of biomarkers to “personalize” cancer treatment —identifying discrete genes, proteins, or other indicators that can differentiate one type of cancer from another and enable the use of highly tailored therapies -- offers tremendous potential for improved outcomes and lower treatment costs. However, the rapid development of cancer biomarker, or genomic, tests— combined with a paucity of evidence to support the effectiveness of the tests—presents a challenge for patients, clinicians and other stakeholders. In this article, we propose that comparative effectiveness research be used to strengthen what is now a haphazard process for developing and marketing cancer biomarker tests. We suggest novel funding approaches and a systematic process for moving from regulatory approval to the generation of evidence that meets the needs of stakeholders and, ultimately, patients.
doi:10.1377/hlthaff.2010.0637
PMCID: PMC3477796  PMID: 22147853
personalized medicine; comparative effectiveness; genomics; cancer
9.  Effectiveness guidance document (EGD) for acupuncture research - a consensus document for conducting trials 
Background
There is a need for more Comparative Effectiveness Research (CER) to strengthen the evidence base for clinical and policy decision-making. Effectiveness Guidance Documents (EGD) are targeted to clinical researchers. The aim of this EGD is to provide specific recommendations for the design of prospective acupuncture studies to support optimal use of resources for generating evidence that will inform stakeholder decision-making.
Methods
Document development based on multiple systematic consensus procedures (written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders including patients, clinicians and payers were involved.
Results
Recommendations focused mainly on randomized studies and were developed for the following areas: overall research strategy, treatment protocol, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication.
Conclusion
The present EGD, based on an international consensus developed with multiple stakeholder involvement, provides the first systematic methodological guidance for future CER on acupuncture.
doi:10.1186/1472-6882-12-148
PMCID: PMC3495216  PMID: 22953730
Comparative effectiveness research; Effectiveness guidance document; Acupuncture
10.  How Well Do Randomized Trials Inform Decision Making: Systematic Review Using Comparative Effectiveness Research Measures on Acupuncture for Back Pain 
PLoS ONE  2012;7(2):e32399.
Background
For Comparative Effectiveness Research (CER) there is a need to develop scales for appraisal of available clinical research. Aims were to 1) test the feasibility of applying the pragmatic-explanatory continuum indicator summary tool and the six CER defining characteristics of the Institute of Medicine to RCTs of acupuncture for treatment of low back pain, and 2) evaluate the extent to which the evidence from these RCTs is relevant to clinical and health policy decision making.
Methods
We searched Medline, the AcuTrials™ Database to February 2011 and reference lists and included full-report randomized trials in English that compared needle acupuncture with a conventional treatment in adults with non-specific acute and/or chronic low back pain and restricted to those with ≥30 patients in the acupuncture group. Papers were evaluated by 5 raters.
Principal Findings
From 119 abstracts, 44 full-text publications were screened and 10 trials (4,901 patients) were evaluated. Due to missing information and initial difficulties in operationalizing the scoring items, the first scoring revealed inter-rater and inter-item variance (intraclass correlations 0.02–0.60), which improved after consensus discussions to 0.20–1.00. The 10 trials were found to cover the efficacy-effectiveness continuum; those with more flexible acupuncture and no placebo control scored closer to effectiveness.
Conclusion
Both instruments proved useful, but need further development. In addition, CONSORT guidelines for reporting pragmatic trials should be expanded. Most studies in this review already reflect the movement towards CER and similar approaches can be taken to evaluate comparative effectiveness relevance of RCTs for other treatments.
doi:10.1371/journal.pone.0032399
PMCID: PMC3289651  PMID: 22389699
12.  Challenges in Australian policy processes for disinvestment from existing, ineffective health care practices 
Background
Internationally, many health care interventions were diffused prior to the standard use of assessments of safety, effectiveness and cost-effectiveness. Disinvestment from ineffective or inappropriately applied practices is a growing priority for health care systems for reasons of improved quality of care and sustainability of resource allocation. In this paper we examine key challenges for disinvestment from these interventions and explore potential policy-related avenues to advance a disinvestment agenda.
Results
We examine five key challenges in the area of policy driven disinvestment: 1) lack of resources to support disinvestment policy mechanisms; 2) lack of reliable administrative mechanisms to identify and prioritise technologies and/or practices with uncertain clinical and cost-effectiveness; 3) political, clinical and social challenges to removing an established technology or practice; 4) lack of published studies with evidence demonstrating that existing technologies/practices provide little or no benefit (highlighting complexity of design) and; 5) inadequate resources to support a research agenda to advance disinvestment methods. Partnerships are required to involve government, professional colleges and relevant stakeholder groups to put disinvestment on the agenda. Such partnerships could foster awareness raising, collaboration and improved health outcome data generation and reporting. Dedicated funds and distinct processes could be established within the Medical Services Advisory Committee and Pharmaceutical Benefits Advisory Committee to, a) identify technologies and practices for which there is relative uncertainty that could be the basis for disinvestment analysis, and b) conduct disinvestment assessments of selected item(s) to address existing practices in an analogous manner to the current focus on new and emerging technology. Finally, dedicated funding and cross-disciplinary collaboration is necessary to build health services and policy research capacity, with a focus on advancing disinvestment research methodologies and decision support tools.
Conclusion
The potential over-utilisation of less than effective clinical practices and the potential under-utilisation of effective clinical practices not only result in less than optimal care but also fragmented, inefficient and unsustainable resource allocation. Systematic policy approaches to disinvestment will improve equity, efficiency, quality and safety of care, as well as sustainability of resource allocation.
doi:10.1186/1743-8462-4-23
PMCID: PMC2174492  PMID: 17973993
13.  Improving the reporting of pragmatic trials: an extension of the CONSORT statement 
Background The CONSORT statement is intended to improve reporting of randomised controlled trials and focuses on minimising the risk of bias (internal validity). The applicability of a trial’s results (generalisability or external validity) is also important, particularly for pragmatic trials. A pragmatic trial (a term first used in 1967 by Schwartz and Lellouch) can be broadly defined as a randomised controlled trial whose purpose is to inform decisions about practice. This extension of the CONSORT statement is intended to improve the reporting of such trials and focuses on applicability.
Methods At two, two-day meetings held in Toronto in 2005 and 2008, we reviewed the CONSORT statement and its extensions, the literature on pragmatic trials and applicability, and our experiences in conducting pragmatic trials.
Recommendations We recommend extending eight CONSORT checklist items for reporting of pragmatic trials: the background, participants, interventions, outcomes, sample size, blinding, participant flow, and generalisability of the findings. These extensions are presented, along with illustrative examples of reporting, and an explanation of each extension. Adherence to these reporting criteria will make it easier for decision makers to judge how applicable the results of randomised controlled trials are to their own conditions. Empirical studies are needed to ascertain the usefulness and comprehensiveness of these CONSORT checklist item extensions. In the meantime we recommend that those who support, conduct, and report pragmatic trials should use this extension of the CONSORT statement to facilitate the use of trial results in decisions about health care.
Pragmatic trials are designed to inform decisions about practice, but poor reporting can reduce their usefulness. The CONSORT and Practihc groups describe modifications to the CONSORT guidelines to help readers assess the applicability of the results
doi:10.1136/bmj.a2390
PMCID: PMC3266844  PMID: 19001484

Results 1-13 (13)