A Roadmap for Improving Medicare's Application of Coverage With Evidence Development.

The Centers for Medicare and Medicaid Services' coverage with evidence development (CED) policy allows the agency to provide coverage for an item or service through a National Coverage Determination (NCD), conditional upon an agreement to collect evidence designed to address specific questions or uncertainties. The goals of this policy are to expedite beneficiary access to new items and services and to generate additional evidence on the impact of these items or services for Medicare beneficiaries. However, these goals have not been fully realized because of several issues with the way the policy has been implemented, including (1) a lack of clear criteria for when CED will be applied, (2) examples of CED data collection activities placing unnecessary burdens on clinicians and the potential for undue inducement on beneficiaries, and (3) a lack of clarity around the process and timeline for reconsidering and ending CED requirements. Additionally, there are cases in which the application of CED has failed to improve access to services for certain Medicare beneficiaries because no data collection activity was implemented in response to the CED requirement or because the NCD only allows the technology to be provided and studied in certain centers of excellence. We describe a roadmap for addressing these issues, which includes, for example, developing a framework to guide the application of coverage constraints in NCDs with CED requirements. Once these issues are addressed, the Centers for Medicare and Medicaid Services could consider expanding the use of CED to technologies that are not subject to NCDs.

Supportive Services at End of Life can Help Reduce Acute Care Services: Observations From the Medicare Care Choices Model.

OBJECTIVES: This study identifies the mechanisms through which supportive and palliative care services at the end-of-life helped prevent unnecessary use of acute care services. BACKGROUND: From 2016 to 2021, the Medicare Care Choices Model (MCCM) tested whether offering Medicare beneficiaries the option to receive supportive and palliative care services through hospice providers, concurrently with treatments for their terminal conditions, improved patients' quality of life and care and reduced Medicare expenditures. Previous MCCM evaluation results showed that the model achieved its goals, but did not examine in depth the causal mechanisms leading to these results. METHODS: Mixed-methods evaluation based on descriptive analysis of MCCM encounter data and qualitative analysis of interviews with staff from high-performing MCCM hospices. RESULTS: MCCM hospices provided 217 156 encounters to 7263 enrollees over 6 years. Enrollees received on average 30 encounters with hospice staff while enrolled in the model, representing about 10 encounters per month enrolled. Most encounters were delivered by clinically trained staff in the patient's home. Hospice staff identified five services critical for keeping patients from seeking acute care services: early and frequent needs assessments, direct observation of patients in their homes, immediate responses to patients' medical complaints, round-the-clock telephone access to nursing staff, and communication and coordination of care with primary care physicians and specialists. CONCLUSIONS: Palliative care approaches that are high-touch, employ clinically trained staff who visit patients in their homes, routinely evaluate how to manage patient symptoms, and are available when needs arise can improve outcomes and decrease costs at the end of life.

Features of health care interventions associated with reduced services and spending.

OBJECTIVES: This study examines 14 independent and diverse health care interventions funded under the second round of Health Care Innovation Awards by CMS to determine if any organizational, model, or implementation features were strongly associated with the programs' estimated impacts on total expenditures, hospitalizations, or emergency department visits. STUDY DESIGN: We estimated program impacts using awardee-specific difference-in-differences models based on Medicare and Medicaid enrollment and claims data for treatment and matched comparison groups from 2012 to 2018. METHODS: We used 2 analytic approaches to identify program features associated with favorable impacts. The first method identified program characteristics that were common among programs that had estimated reductions in costs and service use and uncommon among those that did not. The second approach compared median impacts among awardees with a given distinguishing feature with median impacts among awardees that lacked the characteristic. RESULTS: Of the 23 program features examined, 7 were associated with favorable estimated impacts: 3 intervention components (behavioral health, telehealth, and health information technology) and 4 program design and organizational characteristics (having prior experience implementing similar programs, targeting patients with substantial nonmedical needs in addition to medical problems, being focused on individual patient care rather than transforming provider practice, and using nonclinical staff as frontline providers of the intervention). CONCLUSIONS: Innovative health care service delivery models with 2 or more of these 7 identified features were more likely than programs without them to reduce Medicare and Medicaid beneficiaries' needs for costly health care services.

Rethinking ethical oversight in the era of the learning health system.

Opportunities to advance science increasingly arise through investigations embedded within routine clinical practice in the form of learning health systems. Such activities challenge conventional approaches to research regulation that have not caught up with those opportunities, often imposing burdens generalized from riskier research. We analyze the rules and conventions in the US, demonstrating how even those rules are compatible with a much more flexible approach to participant risk, institutional oversight, participant consent, and disclosure for low-risk learning activities in all jurisdictions.

What Should Oversight of Clinical Decision Support Systems Look Like?

A learning health system provides opportunities to leverage data generated in the course of standard clinical care to improve clinical practice. One such opportunity includes a clinical decision support structure that would allow clinicians to query electronic health records (EHRs) such that responses from the EHRs could inform treatment recommendations. We argue that though using a clinical decision support system does not necessarily constitute a research activity subject to the Common Rule, it requires more ethical and regulatory oversight than activities of clinical practice are generally subjected to. In particular, we argue that the development and use of clinical decision support systems should be governed by a framework that (1) articulates appropriate conditions for their use, (2) includes processes for monitoring data quality and developing and validating algorithms, and (3) sufficiently protects patients' data.

An overview of the impact of rare disease characteristics on research methodology.

BACKGROUND: About 30 million individuals in the United States are living with a rare disease, which by definition have a prevalence of 200,000 or fewer cases in the United States ([National Organization for Rare Disorders], [About NORD], [2016]). Disease heterogeneity and geographic dispersion add to the difficulty of completing robust studies in small populations. Improving the ability to conduct research on rare diseases would have a significant impact on population health. The purpose of this paper is to raise awareness of methodological approaches that can address the challenges to conducting robust research on rare diseases. APPROACH: We conducted a landscape review of available methodological and analytic approaches to address the challenges of rare disease research. Our objectives were to: 1. identify algorithms for matching study design to rare disease attributes and the methodological approaches applicable to these algorithms; 2. draw inferences on how research communities and infrastructure can contribute to the efficiency of research on rare diseases; and 3. to describe methodological approaches in the rare disease portfolio of the Patient-Centered Outcomes Research Institute (PCORI), a funder promoting both rare disease research and research infrastructure. RESULTS: We identified three algorithms for matching study design to rare disease or intervention characteristics (Gagne, et.al, BMJ 349:g6802, 2014); (Gupta, et.al, J Clin Epidemiol 64:1085-1094, 2011); (Cornu, et. al, Orphet J Rare Dis 8:48,2012) and summarized the applicable methodological and analytic approaches. From this literature we were also able to draw inferences on how an effective research infrastructure can set an agenda, prioritize studies, accelerate accrual, catalyze patient engagement and terminate poorly performing studies. Of the 24 rare disease projects in the PCORI portfolio, 11 are randomized controlled trials (RCTs) using standard designs. Thirteen are observational studies using case-control, prospective cohort, or natural history designs. PCORI has supported the development of 9 Patient-Powered Research Networks (PPRNs) focused on rare diseases. CONCLUSION: Matching research design to attributes of rare diseases and interventions can facilitate the completion of RCTs that are adequately powered. An effective research infrastructure can improve efficiency and avoid waste in rare disease research. Our review of the PCORI research portfolio demonstrates that it is feasible to conduct RCTs in rare disease. However, most of these studies are using standard RCT designs. This suggests that use of a broader array of methodological approaches to RCTs --such as adaptive trials, cross-over trials, and early escape designs can improve the productivity of robust research in rare diseases.

Deliberative Engagement Methods for Patient-Centered Outcomes Research.

There is growing emphasis on eliciting and incorporating stakeholder perspectives into health research and public policy development. The deliberative engagement session (DES) method provides one approach to elicit informed preferences from patients and other stakeholders on policy issues. DES involves day-long interaction with participants, including short plenary presentations followed by small group discussion. While interest in DES methods is expanding, practical guidance for researchers on this method remains limited. In this paper, we describe the DES method and its contemporary relevance for health policy research, illustrate how to conduct a DES using an example of a recent patient-centered outcomes research (PCOR) study with which we were involved, and discuss strengths and challenges of using this approach. DES methods generate rich data, reduce the risk of eliciting uniformed preferences or non-attitudes, and increase the likelihood of eliciting informed, reflective preferences. However, they are resource-intensive, and thus generally require trading away a larger, more representative sample. Despite these limitations, the DES method, when carefully designed, is well-suited for engaging stakeholders in research on complex health policy issues.

Gatekeepers for pragmatic clinical trials.

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' decisions, including protection from harm and maximization of benefits; (2) advancement of organizational mission and values; and (3) stewardship of financial, human, and other organizational resources. Separate from these ethical considerations, gatekeepers' actions will be guided by relevant federal, state, and local regulations. This framework also suggests that to further enhance the legitimacy of their decision-making, gatekeepers should adopt transparent processes that engage relevant stakeholders when feasible and appropriate. We apply this framework to the set of gatekeepers responsible for making decisions about resources necessary for pragmatic clinical trials in the United States, describing the relevance of the criteria in different situations and pointing out where conflicts among the criteria and relevant regulations may affect decision-making. Recognition of the complex set of considerations that should inform decision-making will guide gatekeepers in making justifiable choices regarding the use of limited and valuable resources.

Ethics Review of Survey Research: A Mandatory Requirement for Publication?

National regulations governing human subjects research differ with regard to whether they require survey research to be overseen by institutional ethics boards or committees. In cases where ethical review has been waived, or was provided by an individual or group other than an institutional ethics board, journals may question the appropriateness of the waiver or alternative review when making determinations about whether to accept the manuscript for publication. The purpose of this article is to provide guidance for journals to consider when making determinations about the necessity of ethical review for survey research projects. We review the functions of ethics oversight and consider the importance of those functions within the context of survey research. In survey research, no intervention is delivered to research participants. As a result, there is no risk of physical harm to individuals who participate. However, there can be a risk of informational or psychological harms. In situations where there is greater than minimal risk of informational or psychological harms, the survey research should have received institutional ethics oversight. Additionally, survey research projects that enroll vulnerable individuals with diminished autonomy should receive institutional ethics oversight. We hope that this article leads to further guidance on this subject by authoritative group such as the International Committee of Medical Journal Editors.

Stakeholders' Views of Alternatives to Prospective Informed Consent for Minimal-Risk Pragmatic Comparative Effectiveness Trials.

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 pragmatic comparative effectiveness trials of widely-used therapies as long as a sufficient amount of choice is preserved.

The views of quality improvement professionals and comparative effectiveness researchers on ethics, IRBs, and oversight.

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.

Ethical Issues in Patient Safety Research: A Systematic Review of the Literature.

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.

A general method for making peptide therapeutics resistant to serine protease degradation: application to dipeptidyl peptidase IV substrates.

Bioactive peptides have evolved to optimally fulfill specific biological functions, a fact which has long attracted attention for their use as therapeutic agents. While there have been some recent commercial successes fostered in part by advances in large-scale peptide synthesis, development of peptides as therapeutic agents has been significantly impeded by their inherent susceptibility to protease degradation in the bloodstream. Here we report that incorporation of specially designed amino acid analogues at the P1' position, directly C-terminal of the enzyme cleavage site, renders peptides, including glucagon-like peptide-1 (7-36) amide (GLP-1) and six other examples, highly resistant to serine protease degradation without significant alteration of their biological activity. We demonstrate the applicability of the method to a variety of proteases, including dipeptidyl peptidase IV (DPP IV), dipeptidyl peptidase 8 (DPP8), fibroblast activation protein α (FAPα), α-lytic protease (αLP), trypsin, and chymotrypsin. In summary, the "P1' modification" represents a simple, general, and highly adaptable method of generating enzymatically stable peptide-based therapeutics.