coreSCD: multi-stakeholder consensus on core outcomes for sickle cell disease clinical trials.

BACKGROUND: With the dramatic increase in the pipeline for new sickle cell disease (SCD) therapies in recent years, the time is ripe to ensure a robust body of evidence is available for decision making by regulators, payers, clinicians, and patients. Harmonization of the outcomes selected across interventional trials enables optimal post-trial appraisal and decision making through valid pooled analyses and indirect comparisons. We employed a structured, multi-stakeholder consensus process to develop core outcome sets (COS) for use in clinical trials of SCD interventions. METHODS: CoreSCD utilized a modified Delphi method adapted from the standards recommended by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. An initial list of candidate outcomes was developed through a targeted literature review and input from an 11-member advisory committee. A 44-member multi-stakeholder Delphi Panel was established and included patients and family members, advocates, clinicians, researchers, payers, health technology assessors, representatives from government agencies, and industry representatives. Patients/advocates comprised 25% of the Delphi Panel and orientation and training was provided prior to the consensus process to ensure all were prepared to participate meaningfully. Panelists completed three rounds of an online survey to rate the importance of candidate outcomes for inclusion in the COS. Summary data was provided between each voting round and an in-person consensus meeting was held between the second and third round of voting. Consensus rules were applied following each round of voting to eliminate outcomes that did not meet predetermined criteria for retention. RESULTS: Consensus was reached for two core outcome sets. The final COS for trials of disease-modifying therapies includes ten outcomes and the COS for trials of acute interventions includes six outcomes. Both core sets include clinical outcomes as well as outcomes related to functioning/quality of life, resource utilization, and survival/mortality. CONCLUSIONS: Use of the COS in clinical development programs for SCD will help to ensure that relevant, consistent outcomes are available for decision making across the product lifecycle.

One size does not fit all: Insights for engaging front-line clinicians in pragmatic clinical trials.

INTRODUCTION: Despite the proliferation of pragmatic clinical trials (PCTs) conducted in health care delivery settings, we know relatively little about how practicing clinicians perceive their potential roles in such research. Empirical evidence and practical guidance concerning clinician engagement in research is needed to inform the design and successful implementation of PCTs. METHODS: We conducted a two-phase qualitative study to better understand how and to what extent practicing clinicians should be involved in PCTs and to develop guidance for researchers on engaging front-line clinicians in PCTs. In phase one, clinicians who spend the majority of their time providing direct patient care participated in 90-min focus groups. In phase two, we conducted key informant interviews with PCT research teams and clinicians participating in the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness) trial. RESULTS: Thirty-four physicians, nurses, and other care providers from four health care delivery organizations participated in focus groups. Focus group participants stressed the importance of engaging clinicians early in the PCT planning process to identify clinically relevant study questions, provide input on study design, and customize study protocols to fit unique clinic workflows. We conducted 18 interviews with principal investigators, project managers, and clinicians involved in the ADAPTABLE trial across six clinical data research networks. Study team members described trying multiple approaches to optimize in-clinic recruitment and enrollment of eligible patients. Successful strategies involved several key factors related to research team interactions with eligible patients, clinicians, and clinic staff. CONCLUSIONS: More active involvement by a range of clinical stakeholders in PCT planning may help researchers avoid common barriers to trial implementation. We propose a "medium-touch" approach to involving clinicians in PCT recruitment and enrollment that focuses clinician effort where it is most critical-to reassure eligible patients that trial participation is a safe alternative for them.

Increasing the Patient-Centeredness of Health Economics and Outcomes Research Through Patient Engagement in Core Outcome Set Development.

Core outcome sets (COS) are becoming increasingly popular in clinical research and can provide important inputs for further health economics and outcomes research (HEOR) studies. Use of standard, consistently reported outcomes can demonstrate and allow differentiation of the effectiveness and value of different treatments. Incorporating patient values during COS development increases the patient centeredness of evidence available across decision-making contexts. However, the approach to meaningful patient engagement in the COS process is evolving and poses both unique challenges and opportunities. We describe an approach to patient-centered COS development and discuss challenges and adaptations to improve engagement across COS projects. We provide examples from our experience in patient engagement for COS development using three completed COS projects. This approach includes patient engagement in terms of partnering with patient organizations, orientation and training, and the consensus process. Including COS in clinical development programs and HEOR will ensure that relevant, consistent outcomes are available for healthcare decision making and should result in faster access to high-value and novel therapies for patients. Patient-centered COS development increases the likelihood that further HEOR studies and decisions made using the COS are relevant to patients.

Engaging Stakeholders in the Design and Conduct of Embedded Pragmatic Clinical Trials for Alzheimer's Disease and Alzheimer's Disease-Related Dementias.

Embedded pragmatic clinical trials (ePCTs) of nondrug interventions for Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) are conducted in real-world clinical settings and designed to generate an evidence base to inform clinical and policy decisions about care for this vulnerable population. The ePCTs exist within a complex ecosystem of relationships between researchers, payors, policymakers, healthcare systems, direct care staff, advocacy groups, families, caregivers, and people living with dementia (PLWD). Because the rapid increase of the number of Americans with AD/ADRD outpaces curative treatments, there is an urgent need to mobilize the power of these relationships to improve dementia care and address a mounting public health crisis. Stakeholder engagement in ePCTs is essential to generate research questions, establish the relevancy of trials to the intended end users, and understand the factors that influence dissemination and implementation in real-world clinical settings. The process of including stakeholders in ePCTs for dementia is similar to stakeholder engagement in ePCTs for other diseases and conditions; however, the unique nature of embedded research, prevalence of caregiver and provider burden, and the progressive worsening of cognitive impairment in PLWD must be approached with additional strategies. This article presents key considerations of stakeholder engagement for ePCTs in AD/ADRD and main activities of the stakeholder engagement team in the National Institute on Aging IMPACT Collaboratory to move the field forward. J Am Geriatr Soc 68:S62-S67, 2020.

Addressing heterogenous outcomes in uterine fibroid research: a call to action.

Uterine fibroid tumors are the most common benign pelvic tumors in women, with complications that include heavy menstrual bleeding, pelvic pain, reproductive complications, and bulk-related symptoms. Although the majority of uterine fibroid tumors are asymptomatic, those women who experience symptoms can experience substantial burdens on quality of life and daily functioning. Comparative effectiveness reviews of available medical, surgical, and radiologic treatments have found that a lack of high-quality data to inform treatment decisions is, in part, due to the use of heterogeneous outcomes and instruments in clinical studies. With multiple new interventions emerging, this call-to-action encourages the development and use of a core outcome set that will capture the most relevant, patient-important outcomes in late-phase and after-marketing therapeutic trials for uterine fibroid tumors. The core outcome set should be developed by a diverse, multistakeholder group comprised of key healthcare decision-makers. Development and uptake of a core outcome set ensures that a consistent, collaboratively vetted set of outcomes will be accessible across different studies and promotes transparency for innovators who seek to anticipate the evidence needs of patients, providers, payers, regulators, and other stakeholders.

Engaging patients, clinicians, and the community in a Clinical Data Research Network: Lessons learned from the CAPriCORN CDRN.

Engaging patients, clinicians, and community members in the development of a research network creates opportunities and challenges beyond engagement in discrete learning activities. This paper describes our experiences establishing and maintaining a stakeholder engagement infrastructure for the Chicago Area Patient-Centered Outcomes Research Network (CAPriCORN) and highlights important lessons learned over the first 4 years. During this time, the CAPriCORN Patient and Community Advisory Committee (PCAC) appointed patient, clinician, and community representatives to governance and advisory groups throughout the network, developed a process and criteria for patient- and clinician-centered review of research proposals, and evolved from a large, diverse group to a smaller yet still diverse, more actively engaged group with connections to the broader community. Key challenges faced by the PCAC have included determining the optimal size and composition of the group, understanding the complex structure of the network as a whole, coordinating with other network entities and functions, and integrating the patient and community voice into the research review process. Efforts to engage stakeholders in clinical data research networks should anticipate and develop solutions to address these challenges.

Practical Guidance for Involving Stakeholders in Health Research.

Stakeholder engagement is increasingly common in health research, with protocols for engaging multiple stakeholder groups becoming normative in patient-centered outcomes research. Previous work has focused on identifying relevant stakeholder groups with whom to work and on working with stakeholders in evidence implementation. This paper draws on the expertise of a team from four countries-Canada, Australia, the UK, and the USA-to provide researchers with practical guidance for carrying out multi-stakeholder-engaged projects: we present a list of questions to assist in selecting appropriate roles and modes of engagement; we introduce a matrix to help summarize engagement activities; and we provide a list of online resources. This guidance, matrix, and list of resources can assist researchers to consider more systematically which stakeholder groups to involve, in what study roles, and by what modes of engagement. By documenting how stakeholders are paired up with specific roles, the matrix also provides a potential structure for evaluating the impact of stakeholder engagement.

Paying for Cures: Perspectives on Solutions to the "Affordability Issue".

Curative therapies and other medicines considered "game-changing" in terms of health gain can be accompanied by high demand and high list prices that pose budget challenges to public and private payers and health systems-the so-called affordability issue. These challenges are exacerbated when longer term effectiveness, and thus value for money, is uncertain, but they can arise even when treatments are proven to be highly cost-effective at the time of launch. This commentary reviews innovative payment solutions proposed in the literature to address the affordability issue, including the use of credit markets and of staged payments linked to patient outcomes, and draws on discussions with payers in the United States and Europe on the feasibility or desirability of operationalizing any of the alternative financing and payment strategies that appear in the literature. This included a small number of semistructured interviews. We conclude that there is a mismatch between the enthusiasm in the academic literature for developing new approaches and the scepticism of payers that they can work or are necessary. For the foreseeable future, affordability pressures will continue to be handled by aggressive price bargaining, high co-pays (in systems in which this is possible), and restricting access to subgroups of patients. Of the mechanisms we explored, outcomes-based payments were of most interest to payers, but the costs associated with operating such schemes, together with implementation challenges, did not make them an attractive option for managing affordability.

Stakeholder perspectives regarding alternate approaches to informed consent for comparative effectiveness research.

INTRODUCTION: Traditional informed consent approaches, involving separate discussions and lengthy consent forms, may be an imperfect fit for comparative effectiveness research (CER) that is integrated into usual care and compares non-investigational treatments. However, systematic efforts to collect broad stakeholder perspectives about alternative streamlined approaches to disclosure and consent in this context have been limited. METHODS: We used a deliberative engagement method to solicit the views of a multi-stakeholder group regarding 3 alternative models of disclosure, consent, and authorization in CER studies: Opt-In, Opt-Out, and "General Approval". Participants considered the acceptability of these 3 models for observational and randomized CER studies of hypertension medications and for alternative treatments for spinal stenosis, all conducted in the context of a learning health care system. RESULTS: Fifty-eight stakeholders participated in the all-day deliberative engagement session. Following deliberation, a majority of stakeholders (67%) liked the General Approval model for the observational hypertension study, more than the number who reported liking Opt-Out or Opt-In (45% and 36%, respectively). Support was lower for General Approval model in the context of a randomized hypertension study, with 80% liking a traditional Opt-In approach, compared with 54% liking Opt-Out, and 11% liking General Approval. Similarly, for the spinal stenosis CER studies, while most stakeholders preferred a streamlined Opt-Out approach for the observational design, most preferred a traditional Opt-In approach for the randomized version. CONCLUSIONS: This multi-stakeholder group was more favorable towards streamlined models for disclosure and authorization for observational CER than randomized designs. These findings are consistent with arguments that informed consent requirements should be tailored to the context of the research design, rather than a standard "one size fits all" approach.

Stakeholder engagement in comparative effectiveness research: how will we measure success?

Stakeholder engagement in comparative effectiveness research continues to gain national attention. While various methods are used to gather stakeholder expertise and form recommendations, evaluation of the stakeholder experience is often missing. The lack of evaluation prohibits assessing how effective and meaningful engagement practices are for enhancing research efforts and limits the ability to identify areas for future improvement. We propose that an evaluation plan of engagement processes be developed before stakeholder involvement begins and be required as part of a request for proposal or research grant where stakeholder input is being sought. Furthermore, we recommend the inclusion of six meta-criteria that represent normative goals of multiple studies: respect, trust, legitimacy, fairness, competence and accountability. To aid in the development of future evaluations, we have developed definitions for and matched specific examples of measuring each meta-criterion to serve a guide for others in the field.

The quality of media reports on discoveries related to human genetic diseases.

OBJECTIVES: To examine (1) the quality of media reports (newspapers, television and public radio) of genetic discoveries with medical relevance and (2) factors related to the completeness and balance of the stories. METHODS: Analysis of the accuracy, balance, and completeness of 228 media stories reporting 24 genetic discoveries between 1996 and 2000 using a previously validated instrument. RESULTS: Although usually accurate, the stories contained only 45.5 +/- 13.8% (mean +/- SD) of relevant items. Stories appearing on television and stories reporting discoveries of genes for rare diseases were the least complete. Stories in non-US English-speaking newspapers included more content items per word than US stories. Less balanced stories exaggerated the benefits of discoveries, ignored possible risks, and did not present a range of expert opinion. Scientists were sometimes the source of exaggeration. CONCLUSIONS: To increase the quality of media reports about genetic discoveries, stories should include more relevant items and be written by journalists skilled in science writing. Scientists will have to resist the tendency to exaggerate. These conclusions may apply to media stories of other discoveries as well.

Informed consent for enrolling minors in genetic susceptibility research: a qualitative study of at-risk children's and parents' views about children's role in decision-making.

PURPOSE: To better understand the process by which families at increased risk of disease would decide to enroll their children in genetic susceptibility research in order to develop recommendations regarding the informed consent process by which at-risk children are enrolled in such research in the future [corrected]. METHODS: Parents and children (ages 10-17 years) from families at increased risk for heart disease (n = 21 dyads) or breast cancer (n = 16 dyads) participated in two face-to-face, audio-taped, semi-structured interviews: Initial interviews were conducted with parents and children separately, and follow-up family interviews were conducted 1 year later. Interview transcripts were coded based on common themes. RESULTS: Families vary in the stage at which, and degree to which, children would be involved in decision-making about research participation. In general, the older/more mature the child, the less risky the research and the more open the communication style, the greater the likelihood that decisions would be made jointly. Most children wanted some parental input, but still thought the final decision should be theirs. Most parents would want to make the initial decision about whether it would be reasonable to consider enrolling their child in the research being proposed, but none opposed the child having some time alone with the researcher. All parents and children in our study placed extreme importance on not forcing children to participate in nontherapeutic research if they do not want to. CONCLUSIONS: Decision-making about enrolling children in genetic susceptibility research should be based on an informed consent process that (a) gives parents and children sufficient opportunity to ask questions of the researcher(s) and to communicate with one another, and (b) gives children the opportunity to exercise their right to refuse participation without parental influence. This process should be tailored to the child's maturity level and style of communication in the family.

Houseofficers' reactions to media coverage about the sequencing of the human genome.

After the announcement that sequencing of the human genome was nearly complete, media coverage was extensive. In light of ample evidence that the media are a primary source of health and science information, even for health professionals, media portrayals are often inaccurate or misleading, and discoveries that emanate from sequencing the human genome are likely to influence future health care, it is important to assess physicians' interpretations of media coverage about the human genome announcement. This paper describes the reactions of a sample of new physicians in the United States to this announcement, as well as the content of the stories they read or heard. Semi-structured surveys were distributed to all incoming houseofficers during Orientation at one major academic medical center. Eighty-one percent of 190 houseofficers returned a survey; 123 completed surveys were analyzed. Fifty-four percent of respondents thought the media message was only positive and 21% thought it was negative or mixed. Participants who reported radio as their media source were less likely to recall positive messages (p<0.05). Sixty-five percent and 76%, respectively, had positive perceptions of the impact of the accomplishment on people and on the medical profession. Overall, 48% were enthusiastic and 52% were guarded about the accomplishment. Enthusiasm was related to being an adult primary care houseofficer (p=0.07) or to having heard about it on television or in the newspaper (p<0.05). Of the 36 stories analyzed, newspaper and television reports focused more on medical implications and radio reports focused more on ethical issues. The degree of enthusiasm about the accomplishment reflects the content of the media coverage, and, at least for adult primary care houseofficers, probably reflects the increasing relevance of genetic discoveries to medical practice. Since physicians obtain much of their health and science information from the media, they can play an instrumental role in helping their patients interpret media coverage of advances in genetics and their impact on health care. However, this will require that physicians develop an appreciation of the newsmaking process, and how subtle interactions between politics, the media and science influence the "framing" of media coverage.

Parents' and children's attitudes toward the enrollment of minors in genetic susceptibility research: implications for informed consent.

PURPOSE: Children at high risk of future disease may be recruited for participation in disease susceptibility research involving genetic testing. This study was aimed at assessing parents' and children's reactions to such research, and their perceptions of risks and benefits of participating. METHODS: Parents and children (ages 10-17) from families at increased risk for breast cancer (n = 16 dyads) and heart disease (n = 21 dyads) participated in separate audiotaped interviews and a follow-up family interview one year later. We asked about reactions, risks and benefits, and informational needs regarding participation in hypothetical research involving genetic testing on a saliva sample. Audiotape transcripts were analyzed qualitatively. RESULTS: All children would initially participate because they viewed the research as low risk. When thinking about learning their test result and sharing it with others, or the uncertainties of testing, many children became hesitant about participating. Many parents thought their child might worry about a positive result, making them unlikely to enroll their child, or to choose not to tell the child test results. Both children and parents thought the benefits of participating included early detection or treatment (breast cancer families), prevention (heart disease families) and helping others. Children's questions about research participation centered on details of the study design and purpose, while parents' questions related to the genetic test itself. CONCLUSIONS: Children's first reaction to participating in research involving genetic susceptibility testing research may not indicate an adequate appreciation of risks and benefits; if encouraged to personalize the impact of genetic testing, children are able to engage in a more informed decision-making process.

Mapping the human genome: an assessment of media coverage and public reaction.

PURPOSE: To assess public reactions to the June 26, 2000, announcement that scientists had nearly finished mapping the human genome. METHODS: We conducted a random-digit telephone survey of 407 Maryland residents as well as a content analysis of 55 relevant media reports. RESULTS: African Americans were more likely than Caucasians to report a negative reaction (P < 0.001) to the genome announcement. Overall, privacy/discrimination (16%) and human cloning (14%) were the most commonly mentioned concerns regarding the impact of the genome mapping. CONCLUSIONS: These findings highlight the need for continued public discourse, including through the media, to address concerns regarding the Human Genome Project.