The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics, 2015
As interest in comparative effectiveness research grows, questions have emerged regarding whether... more As interest in comparative effectiveness research grows, questions have emerged regarding whether it is ever acceptable to alter informed consent requirements for research when patients are randomly assigned to widely-used therapies. This paper reports on interviews with Institutional Review Board members and researchers and on focus groups with patients from Geisinger and Johns Hopkins health systems. The objective was to elicit participants' views of the acceptability of four different disclosure and authorization models for low-risk pragmatic comparative effectiveness trials of widely-used therapies. Results suggest that although participants valued autonomous choice, many also believed that it was acceptable to streamline information disclosure and to use an opt-out process for eligible individuals who would prefer not to participate. This provides some preliminary evidence that relevant stakeholders find alternatives to traditional informed consent acceptable for low-risk p...
To successfully implement a pragmatic clinical trial, investigators need access to numerous resou... more To successfully implement a pragmatic clinical trial, investigators need access to numerous resources, including financial support, institutional infrastructure (e.g. clinics, facilities, staff), eligible patients, and patient data. Gatekeepers are people or entities who have the ability to allow or deny access to the resources required to support the conduct of clinical research. Based on this definition, gatekeepers relevant to the US clinical research enterprise include research sponsors, regulatory agencies, payers, health system and other organizational leadership, research team leadership, human research protections programs, advocacy and community groups, and clinicians. This article provides a framework to help guide gatekeepers' decision-making related to the use of resources for pragmatic clinical trials. Relevant ethical considerations for gatekeepers include (1) concern for the interests of individuals, groups, and communities affected by the gatekeepers' decisio...
Page 1. In the Field _ - by Danielle Whicher, Peter Currie, and Holly A. Taylor Factors That Infl... more Page 1. In the Field _ - by Danielle Whicher, Peter Currie, and Holly A. Taylor Factors That Influence Institutional Review Board Members' Commitment to Their Role Responsibilities % growing body of empirical research exists ...
Electronic clinical data (ECD) will increasingly serve as an important source of information for ... more 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. 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.
Comparative effectiveness research (CER), or research design to meet the needs of post-regulatory... more Comparative effectiveness research (CER), or research design to meet the needs of post-regulatory decision makers, has been brought into the spotlight with the introduction of the American Recovery and Reinvestment Act, which provided $US1.1 billion over 2 years to support CER. In the short run, the majority of this money will be invested in observational studies and building of infrastructure; however, in the long run, we will likely see an increase in the number of randomized controlled trials (RCTs), as this method is arguably the most unbiased approach for establishing causal effect between treatments and health outcomes. RCTs are an integral component of CER for generating credible evidence on the relative value of alternative interventions in order to meet the needs of post-regulatory decision makers (patients, physicians, payers and policy makers). Explanatory phase III RCTs are fit for purpose; researchers make use of guidance documents produced by the US FDA to inform the design of these clinical trials. Historically, without explicit FDA guidance, broad patient populations, including women and minorities, often were not considered in trial design. In addition, attempts to minimize cost and maximize efficiency have led to smaller sample sizes, as is clear from the increase in 'creeping phase II-ism'. To demonstrate effectiveness, RCTs must be reflective of how an intervention will be used in the healthcare market. The concept of pragmatic clinical trials has emerged to describe those trials that are designed explicitly with this need in mind. Use of pragmatic trials will be most impactful if post-regulatory decision makers are engaged in the development of recommendations for trial design features, such as indicating outcomes measures and articulating patient populations of interest, which clearly express their evidence needs.
As many as 1 in 10 patients is harmed while receiving hospital care in wealthy countries. The ris... more As many as 1 in 10 patients is harmed while receiving hospital care in wealthy countries. The risk of health care-associated infection in some developing countries is as much as 20 times higher. In response, in many global regions, increased attention has turned to the implementation of a broad program of safety research, encompassing a variety of methods. Although important international ethical guidelines for research exist, literature has been emerging in the last 20 years that begins to apply such guidelines to patient safety research specifically. This paper provides a review of the literature related to ethics, oversight, and patient safety research; identifies issues highlighted in articles as being of ethical relevance; describes areas of consensus regarding how to respond to these ethical issues; and highlights areas where additional ethical analysis and discussion are needed to provide guidance to those in the field.
Journal of the American College of Radiology, 2009
The National Oncologic PET Registry (NOPR) was one of the first attempts of the Centers for Medic... more The National Oncologic PET Registry (NOPR) was one of the first attempts of the Centers for Medicare & Medicaid Services (CMS) at coverage with evidence development. Under this coverage policy, the agency will provide payment for a technology only if patients and providers agree to enroll in a prospective study or registry. The NOPR was designed to determine if the results of positron emission tomography scans influence physicians' intended plans of patient management while imposing minimal restrictions on the use of such scans in the clinical setting. The experience of policymakers, methodologists, physicians, and patients with the NOPR provides some useful insights into the utility and challenges of implementing, financing, and creating a robust methodology for coverage with evidence development in the future. Moving to a system of evidence-based medical technology diffusion will require all health care decision makers to become involved in evidence generation and reach an agreement about the type of evidence required to make informed medical decisions.
International Journal of Technology Assessment in Health Care, 2009
In the debate on improving the quality and efficiency of the United States healthcare system, com... more In the debate on improving the quality and efficiency of the United States healthcare system, comparative effectiveness research is increasingly seen as a tool for reducing costs without compromising outcomes. Furthermore, the recent American Recovery and Reinvestment Act explicitly describes a prioritization function for establishing a comparative effectiveness research agenda. However, how such a function, in terms of methods and process, would go about identifying the most important priorities warranting further research has received little attention. This study describes an Agency for Healthcare Research and Quality-funded pilot project to translate one current comparative effectiveness review into a prioritized list of evidence gaps and research questions reflecting the views of the healthcare decision makers involved in the pilot. To create a prioritized research agenda, we developed an interactive nominal group process that relied on a multistakeholder workgroup scoring a list of research questions on the management of coronary artery disease. According to the group, the areas of greatest uncertainty regarding the management of coronary artery disease are the comparative effectiveness of medical therapy versus percutaneous coronary interventions versus coronary artery bypass grafting for different patient subgroups; the impact of diagnostic testing; and the most effective method of developing performance measures for providers. By applying our nominal group process, we were able to create a list of research priorities for healthcare decision makers. Future research should focus on refining this process because determining research priorities is essential to the success of developing an infrastructure for comparative effectiveness research.
Pharmaceutical pragmatic clinical trials (PCTs) are designed to provide the type of evidence that... more 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. 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 the more pragmatic design of Phase 3 trials is desirable.
There is a growing appreciation that our current approach to clinical research leaves important g... more There is a growing appreciation that our current approach to clinical research leaves important gaps in evidence from the perspective of patients, clinicians, and payers wishing to make evidence-based clinical and health policy decisions. This has been a major driver in the rapid increase in interest in comparative effectiveness research (CER), which aims to compare the benefits, risks, and sometimes costs of alternative health-care interventions in 'the real world'. While a broad range of experimental and nonexperimental methods will be used in conducting CER studies, many important questions are likely to require experimental approaches - that is, randomized controlled trials (RCTs). Concerns about the generalizability, feasibility, and cost of RCTs have been frequently articulated in CER method discussions. Pragmatic RCTs (or 'pRCTs') are intended to maintain the internal validity of RCTs while being designed and implemented in ways that would better address the demand for evidence about real-world risks and benefits for informing clinical and health policy decisions. While the level of interest and activity in conducting pRCTs is increasing, many challenges remain for their routine use. This article discusses those challenges and offers some potential ways forward.
Recently, there have been increasing numbers of activities labeled as either quality improvement ... more Recently, there have been increasing numbers of activities labeled as either quality improvement (QI) or comparative effectiveness research (CER), both of which are designed to learn what works and what does not in routine clinical care settings. These activities can create confusion for researchers, Institutional Review Board members, and other stakeholders as they try to determine which activities or components of activities constitute clinical practices and which constitute clinical research requiring ethical oversight and informed consent. We conducted a series of semi-structured focus groups with QI and CER professionals to understand their experiences and views of the ethical and regulatory challenges that exist as well as the formal or informal practices and criteria they and their institutions use to address these issues. We found that most participants have experienced challenges related to the ethical oversight of QI and CER activities, and many believe that current regulatory criteria for distinguishing clinical practice from clinical research requiring ethical oversight are confusing. Instead, many participants described other criteria that they believe are more ethically appropriate. Many also described developing formal or informal practices at their institutions to navigate which activities require ethical oversight. However, these local solutions do not completely resolve the issues caused by the blurring of clinical practice and clinical research, raising the question of whether more foundational regulatory changes are needed.
The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics, 2015
As interest in comparative effectiveness research grows, questions have emerged regarding whether... more As interest in comparative effectiveness research grows, questions have emerged regarding whether it is ever acceptable to alter informed consent requirements for research when patients are randomly assigned to widely-used therapies. This paper reports on interviews with Institutional Review Board members and researchers and on focus groups with patients from Geisinger and Johns Hopkins health systems. The objective was to elicit participants' views of the acceptability of four different disclosure and authorization models for low-risk pragmatic comparative effectiveness trials of widely-used therapies. Results suggest that although participants valued autonomous choice, many also believed that it was acceptable to streamline information disclosure and to use an opt-out process for eligible individuals who would prefer not to participate. This provides some preliminary evidence that relevant stakeholders find alternatives to traditional informed consent acceptable for low-risk p...
To successfully implement a pragmatic clinical trial, investigators need access to numerous resou... more To successfully implement a pragmatic clinical trial, investigators need access to numerous resources, including financial support, institutional infrastructure (e.g. clinics, facilities, staff), eligible patients, and patient data. Gatekeepers are people or entities who have the ability to allow or deny access to the resources required to support the conduct of clinical research. Based on this definition, gatekeepers relevant to the US clinical research enterprise include research sponsors, regulatory agencies, payers, health system and other organizational leadership, research team leadership, human research protections programs, advocacy and community groups, and clinicians. This article provides a framework to help guide gatekeepers' decision-making related to the use of resources for pragmatic clinical trials. Relevant ethical considerations for gatekeepers include (1) concern for the interests of individuals, groups, and communities affected by the gatekeepers' decisio...
Page 1. In the Field _ - by Danielle Whicher, Peter Currie, and Holly A. Taylor Factors That Infl... more Page 1. In the Field _ - by Danielle Whicher, Peter Currie, and Holly A. Taylor Factors That Influence Institutional Review Board Members' Commitment to Their Role Responsibilities % growing body of empirical research exists ...
Electronic clinical data (ECD) will increasingly serve as an important source of information for ... more 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. 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.
Comparative effectiveness research (CER), or research design to meet the needs of post-regulatory... more Comparative effectiveness research (CER), or research design to meet the needs of post-regulatory decision makers, has been brought into the spotlight with the introduction of the American Recovery and Reinvestment Act, which provided $US1.1 billion over 2 years to support CER. In the short run, the majority of this money will be invested in observational studies and building of infrastructure; however, in the long run, we will likely see an increase in the number of randomized controlled trials (RCTs), as this method is arguably the most unbiased approach for establishing causal effect between treatments and health outcomes. RCTs are an integral component of CER for generating credible evidence on the relative value of alternative interventions in order to meet the needs of post-regulatory decision makers (patients, physicians, payers and policy makers). Explanatory phase III RCTs are fit for purpose; researchers make use of guidance documents produced by the US FDA to inform the design of these clinical trials. Historically, without explicit FDA guidance, broad patient populations, including women and minorities, often were not considered in trial design. In addition, attempts to minimize cost and maximize efficiency have led to smaller sample sizes, as is clear from the increase in 'creeping phase II-ism'. To demonstrate effectiveness, RCTs must be reflective of how an intervention will be used in the healthcare market. The concept of pragmatic clinical trials has emerged to describe those trials that are designed explicitly with this need in mind. Use of pragmatic trials will be most impactful if post-regulatory decision makers are engaged in the development of recommendations for trial design features, such as indicating outcomes measures and articulating patient populations of interest, which clearly express their evidence needs.
As many as 1 in 10 patients is harmed while receiving hospital care in wealthy countries. The ris... more As many as 1 in 10 patients is harmed while receiving hospital care in wealthy countries. The risk of health care-associated infection in some developing countries is as much as 20 times higher. In response, in many global regions, increased attention has turned to the implementation of a broad program of safety research, encompassing a variety of methods. Although important international ethical guidelines for research exist, literature has been emerging in the last 20 years that begins to apply such guidelines to patient safety research specifically. This paper provides a review of the literature related to ethics, oversight, and patient safety research; identifies issues highlighted in articles as being of ethical relevance; describes areas of consensus regarding how to respond to these ethical issues; and highlights areas where additional ethical analysis and discussion are needed to provide guidance to those in the field.
Journal of the American College of Radiology, 2009
The National Oncologic PET Registry (NOPR) was one of the first attempts of the Centers for Medic... more The National Oncologic PET Registry (NOPR) was one of the first attempts of the Centers for Medicare & Medicaid Services (CMS) at coverage with evidence development. Under this coverage policy, the agency will provide payment for a technology only if patients and providers agree to enroll in a prospective study or registry. The NOPR was designed to determine if the results of positron emission tomography scans influence physicians' intended plans of patient management while imposing minimal restrictions on the use of such scans in the clinical setting. The experience of policymakers, methodologists, physicians, and patients with the NOPR provides some useful insights into the utility and challenges of implementing, financing, and creating a robust methodology for coverage with evidence development in the future. Moving to a system of evidence-based medical technology diffusion will require all health care decision makers to become involved in evidence generation and reach an agreement about the type of evidence required to make informed medical decisions.
International Journal of Technology Assessment in Health Care, 2009
In the debate on improving the quality and efficiency of the United States healthcare system, com... more In the debate on improving the quality and efficiency of the United States healthcare system, comparative effectiveness research is increasingly seen as a tool for reducing costs without compromising outcomes. Furthermore, the recent American Recovery and Reinvestment Act explicitly describes a prioritization function for establishing a comparative effectiveness research agenda. However, how such a function, in terms of methods and process, would go about identifying the most important priorities warranting further research has received little attention. This study describes an Agency for Healthcare Research and Quality-funded pilot project to translate one current comparative effectiveness review into a prioritized list of evidence gaps and research questions reflecting the views of the healthcare decision makers involved in the pilot. To create a prioritized research agenda, we developed an interactive nominal group process that relied on a multistakeholder workgroup scoring a list of research questions on the management of coronary artery disease. According to the group, the areas of greatest uncertainty regarding the management of coronary artery disease are the comparative effectiveness of medical therapy versus percutaneous coronary interventions versus coronary artery bypass grafting for different patient subgroups; the impact of diagnostic testing; and the most effective method of developing performance measures for providers. By applying our nominal group process, we were able to create a list of research priorities for healthcare decision makers. Future research should focus on refining this process because determining research priorities is essential to the success of developing an infrastructure for comparative effectiveness research.
Pharmaceutical pragmatic clinical trials (PCTs) are designed to provide the type of evidence that... more 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. 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 the more pragmatic design of Phase 3 trials is desirable.
There is a growing appreciation that our current approach to clinical research leaves important g... more There is a growing appreciation that our current approach to clinical research leaves important gaps in evidence from the perspective of patients, clinicians, and payers wishing to make evidence-based clinical and health policy decisions. This has been a major driver in the rapid increase in interest in comparative effectiveness research (CER), which aims to compare the benefits, risks, and sometimes costs of alternative health-care interventions in 'the real world'. While a broad range of experimental and nonexperimental methods will be used in conducting CER studies, many important questions are likely to require experimental approaches - that is, randomized controlled trials (RCTs). Concerns about the generalizability, feasibility, and cost of RCTs have been frequently articulated in CER method discussions. Pragmatic RCTs (or 'pRCTs') are intended to maintain the internal validity of RCTs while being designed and implemented in ways that would better address the demand for evidence about real-world risks and benefits for informing clinical and health policy decisions. While the level of interest and activity in conducting pRCTs is increasing, many challenges remain for their routine use. This article discusses those challenges and offers some potential ways forward.
Recently, there have been increasing numbers of activities labeled as either quality improvement ... more Recently, there have been increasing numbers of activities labeled as either quality improvement (QI) or comparative effectiveness research (CER), both of which are designed to learn what works and what does not in routine clinical care settings. These activities can create confusion for researchers, Institutional Review Board members, and other stakeholders as they try to determine which activities or components of activities constitute clinical practices and which constitute clinical research requiring ethical oversight and informed consent. We conducted a series of semi-structured focus groups with QI and CER professionals to understand their experiences and views of the ethical and regulatory challenges that exist as well as the formal or informal practices and criteria they and their institutions use to address these issues. We found that most participants have experienced challenges related to the ethical oversight of QI and CER activities, and many believe that current regulatory criteria for distinguishing clinical practice from clinical research requiring ethical oversight are confusing. Instead, many participants described other criteria that they believe are more ethically appropriate. Many also described developing formal or informal practices at their institutions to navigate which activities require ethical oversight. However, these local solutions do not completely resolve the issues caused by the blurring of clinical practice and clinical research, raising the question of whether more foundational regulatory changes are needed.
Uploads
Papers by Danielle Whicher
effectiveness research (CER), both of which are designed to learn what works and what does not in routine clinical care
settings. These activities can create confusion for researchers, Institutional Review Board members, and other stakeholders
as they try to determine which activities or components of activities constitute clinical practices and which constitute
clinical research requiring ethical oversight and informed consent. We conducted a series of semi-structured focus groups
with QI and CER professionals to understand their experiences and views of the ethical and regulatory challenges that exist
as well as the formal or informal practices and criteria they and their institutions use to address these issues. We found
that most participants have experienced challenges related to the ethical oversight of QI and CER activities, and many
believe that current regulatory criteria for distinguishing clinical practice from clinical research requiring ethical oversight
are confusing. Instead, many participants described other criteria that they believe are more ethically appropriate. Many
also described developing formal or informal practices at their institutions to navigate which activities require ethical
oversight. However, these local solutions do not completely resolve the issues caused by the blurring of clinical practice
and clinical research, raising the question of whether more foundational regulatory changes are needed.
effectiveness research (CER), both of which are designed to learn what works and what does not in routine clinical care
settings. These activities can create confusion for researchers, Institutional Review Board members, and other stakeholders
as they try to determine which activities or components of activities constitute clinical practices and which constitute
clinical research requiring ethical oversight and informed consent. We conducted a series of semi-structured focus groups
with QI and CER professionals to understand their experiences and views of the ethical and regulatory challenges that exist
as well as the formal or informal practices and criteria they and their institutions use to address these issues. We found
that most participants have experienced challenges related to the ethical oversight of QI and CER activities, and many
believe that current regulatory criteria for distinguishing clinical practice from clinical research requiring ethical oversight
are confusing. Instead, many participants described other criteria that they believe are more ethically appropriate. Many
also described developing formal or informal practices at their institutions to navigate which activities require ethical
oversight. However, these local solutions do not completely resolve the issues caused by the blurring of clinical practice
and clinical research, raising the question of whether more foundational regulatory changes are needed.