Implementation of Pharmacogenetics in Primary Care: A Multi-Stakeholder Perspective.

INTRODUCTION: Aberrant pharmacogenetic variants occur in a high proportion of people and might be relevant for the prescription of over 26 drugs in primary care. Early identification of patients who metabolize these drugs more rapidly or slowly than average could predict therapeutic effectivity and safety. Yet implementation of pharmacogenetics is progressing slowly. A high public health impact can potentially be achieved by increasing the proportion of people tested, when and where eligible according to clinical validity and utility. METHODS: In this study we defined actions, roles, and responsibilities for implementation of pharmacogenetics in primary care in consultation with stakeholder groups, by using a three-step mixed-methods approach. First, to define barriers and facilitators, public pharmacists (n = 24), primary care physicians (n = 8), and patients (n = 21) participated in focus groups and face-to-face interviews. Second, a multidisciplinary expert meeting (n = 16) was organized to define desired actions, roles, and responsibilities. Third, an online Delphi Study (n = 18) was conducted to prioritize the designated actions. RESULTS: For the integration of pharmacogenetics in primary care guidelines and practice, lack of evidence for clinical utility was mentioned as a main barrier. Furthermore, reimbursement, and facilitation of data registration and sharing were considered as key elements for future routine application of pharmacogenetic testing. Moreover, the division of roles and responsibilities, especially between general practitioners and pharmacists, is currently perceived as unclear. Sixteen actions in these four areas (clinical utility, reimbursement, data registration and sharing, and roles and responsibilities) were formulated and assigned to specific actors during the expert meeting. After ranking these 16 actions in the Delphi Study, nine actions remained pertinent, covering the four areas with at least one action. However, participants showed low agreement on the prioritization of the different actions, illustrating their different perspectives and the need to attune between them. DISCUSSION: Stakeholders together were able to formulate required actions to achieve true integration of pharmacogenetics in primary care, but no consensus could be achieved on the prioritization of the actions. Coordination of the current independent initiatives by the different stakeholders could facilitate effective and efficient implementation of useful pharmacogenetics in primary care.

Primary endpoint discrepancies were found in one in ten clinical drug trials. Results of an inception cohort study.

OBJECTIVE: To identify the occurrence and determinants of protocol-publication discrepancies in clinical drug trials. STUDY DESIGN AND SETTING: All published clinical drug trials reviewed by the Dutch institutional review boards in 2007 were analyzed. Discrepancies between trial protocols and publications were measured among key reporting aspects. We evaluated the association of trial characteristics with discrepancies in primary endpoints by calculating the risk ratio (RR) and 95% confidence interval (CI). RESULTS: Of the 334 published trials, 32 (9.6%) had a protocol/publication discrepancy in the primary endpoints. Among the subgroup of randomized controlled trials (RCTs; N = 204), 12 (5.9%) had a discrepancy in the primary endpoint. Investigator-initiated trials with and without industry (co-) funding were associated with having discrepancies in the primary endpoints compared with industry-sponsored trials (RR 3.7; 95% CI 1.4-9.9 and RR 4.4; 95% CI 2.0-9.5, respectively). Furthermore, other than phase 1-4 trials (vs. phase 1; RR 4.6; 95% CI 1.1-19.3), multicenter trials were also conducted outside the European Union (vs. single center; RR 0.2; 95% CI 0.1-0.6), not prospectively registered trials (RR 3.3; 95% CI 1.5-7.5), non-RCTs (vs. superiority RCT; RR 2.4; 95% CI 1.2-4.8) and, among the RCTs, crossover compared with a parallel group design (RR 3.7; 95% CI 1.1-12.3) were significantly associated with having discrepancies in the primary endpoints. CONCLUSIONS: Improvement in completeness of reporting is still needed, especially among investigator-initiated trials and non-RCTs. To eliminate undisclosed discrepancies, trial protocols should be available in the public domain at the same time when the trial is published.

Recruitment failure and futility were the most common reasons for discontinuation of clinical drug trials. Results of a nationwide inception cohort study in the Netherlands.

OBJECTIVES: The objective of the study was to identify the reasons for discontinuation of clinical drug trials and to evaluate whether efficacy-related discontinuations were adequately planned in the trial protocol. STUDY DESIGN AND SETTING: All clinical drug trials in the Netherlands, reviewed by institutional review boards in 2007, were followed until December 2015. Data were obtained through the database of the Dutch competent authority (Central Committee on Research Involving Human Subjects [CCMO]) and a questionnaire to the principal investigators. Reasons for trial discontinuation were the primary outcome of the study. Three reasons for discontinuation were analyzed separately: all cause, recruitment failure, and efficacy related (when an interim analysis had demonstrated futility or superiority). Among the efficacy-related discontinuations, we examined whether the data monitoring committee, the stopping rule, and the moment of the interim analysis in the trial progress were specified in the trial protocol. RESULTS: Of the 574 trials, 102 (17.8%) were discontinued. The most common reasons were recruitment failure (33 of 574; 5.7%) and solely efficacy related (30 of 574; 5.2%). Of the efficacy-related discontinuations, 10 of 30 (33.3%) of the trial protocols reported all three aspects in the trial protocol, and 20 of 30 (66.7%) reported at least one aspect in the trial protocol. CONCLUSION: One out of five clinical drug trials is discontinued before the planned trial end, with recruitment failure and futility as the most common reasons. The target sample size of trials should be feasible, and interim analyses should be adequately described in trial protocols.

Non-Publication Is Common among Phase 1, Single-Center, Not Prospectively Registered, or Early Terminated Clinical Drug Trials.

The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands.All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non-publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials.

Research for Policy (R4P): development of a reflection tool for researchers to improve knowledge utilization.

BACKGROUND: To improve knowledge utilization in policymaking, alignment between researchers and policymakers during knowledge production is essential, but difficult to maintain. In three previously reported case studies, we extensively evaluated complex research projects commissioned by policymakers to investigate how alignment is achieved in a research process and to discover ways to enhance knowledge contributions to health policy. In the present study, we investigated how the findings of these three research projects could be integrated into a practical tool for researchers to enhance their contribution to evidence-based policy. METHODS: A cross-case analysis was conducted to integrate the findings of the evaluation of the three research projects and to identify important alignment areas in these projects. By means of an iterative process, we prepared a tool that includes reflection questions for researchers. The "Research for Policy" tool was tested with input from the project managers of three new research projects. Based on the findings, the final version of the Research for Policy tool was prepared. RESULTS: By cross-case analysis of the three case studies, the following important alignment areas were identified: the goal, quality, relevance, timing, and presentation of research, the tasks and authorities of actors, the consultative structure and vertical alignment within organizations, and the organizational environment. The project managers regarded the Research for Policy tool as a useful checklist for addressing the important alignment areas in a research project. Based on their feedback, the illustrative examples from the case studies were added to the reflection questions. The project managers suggested making the tool accessible not only to researchers but also to policymakers. The format of the Research for Policy tool was further adjusted to users' needs by adding clickable links. CONCLUSIONS: Alignment between research and policymaking requires continuous efforts and a clear understanding of process issues in the research project. The Research for Policy tool offers practical alignment guidance and facilitates reflection on process issues, which supports researchers in aligning with policymakers and in acting in a context-sensitive way.

Contributions of knowledge products to health policy: a case study on the Public Health Status and Forecasts Report 2010.

BACKGROUND: The Dutch Public Health Status and Forecasts report (PHSF Report) integrates research data and identifies future trends affecting public health in the Netherlands. To investigate how PHSF contributions to health policy can be enhanced, we analysed the development process whereby the PHSF Report for 2010 was produced (PHSF-2010). METHOD: To collect data, a case study approach was used along the lines of Contribution Mapping including analysis of documents from the PHSF-2010 process and interviews with actors involved. All interviews were recorded and transcribed ad verbatim and coded using an inductive code list. RESULTS: The PHSF-2010 process included activities aimed at alignment between researchers and policy-makers, such as informal meetings. However, we identified three issues that are easily overlooked in knowledge development, but provide suggestions for enhancing contributions: awareness of divergent; continuously changing actor scenarios; vertical alignment within organizations involved and careful timing of draft products to create early adopters. CONCLUSION: To enhance the contributions made by an established public health report, such as the PHSF Report, it is insufficient to raise the awareness of potential users. The knowledge product must be geared to policy-makers' needs and must be introduced into the scenarios of actors who may be less familiar. The demand for knowledge product adaptations has to be considered. This requires continuous alignment efforts in all directions: horizontal and vertical, external and internal. The findings of this study may be useful to researchers who aim to enhance the contributions of their knowledge products to health policy.

Enhancing the contribution of research to health care policy-making: a case study of the Dutch Health Care Performance Report.

OBJECTIVES: The Dutch Health Care Performance Report, issued by the National Institute of Public Health and the Environment, aims to monitor health care performance in The Netherlands. Both the National Institute and the Ministry of Health wish to increase the contribution of the Report to health care policy-making. Our aim was to identify ways to achieve that. METHOD: We used contribution mapping as a theoretical framework that recognizes alignment of research as crucial to managing contributions to policy-making. To investigate which areas need alignment efforts by researchers and/or policy-makers, we interviewed National Institute researchers and policy-makers from the Ministry of Health and assessed the process for developing the 2010 Report. RESULTS: We identified six areas where alignment is specifically relevant for enhancing the contributions of future versions of the Dutch Health Care Performance Report: well-balanced information for different ministerial directorates; backstage work; double role actors; reports of other knowledge institutes; data collection/generation and presentation forms. CONCLUSION: The contribution of health care performance reporting to policy-making is complex and requires continuous alignment efforts between researchers and policy-makers. These efforts should form an inseparable part of health care performance reporting and although this demands considerable resources, it is worth considering since it may pay back in better contributions to policy-making.

Occurrence and determinants of selective reporting of clinical drug trials: design of an inception cohort study.

INTRODUCTION: Responsible conduct of research implies that results of clinical trials should be completely and adequately reported. This article describes the design of a cohort study that aims to investigate the occurrence and the determinants of selective reporting in an inception cohort of all clinical drug trials that were reviewed by the Dutch Institutional Review Boards (IRBs) in 2007. It also describes the characteristics of the study cohort. METHODS AND ANALYSIS: In 2007, Dutch IRBs reviewed 622 clinical drug trials. For each trial, we assessed the stages of progress. We discriminated five intermediate stages and five definite stages. Intermediate stages of progress are: approved by an IRB; started inclusion; completed as planned; terminated early; published as article. The definite stages of progress are: rejected by an IRB; never started inclusion; not published as article; completely reported; selectively reported. We will use univariate and multivariate Cox regression models to identify trial characteristics associated with non-publication. We will identify seven trial-specific discrepancy items, including the objectives, inclusion and exclusion criteria, end points, sample size, additional analyses, type of population analysis and sponsor acknowledgement. The percentage of trials with discrepancies between the protocol and the publication will be scored. We will investigate the association between trial characteristics and the occurrence of discrepancies. ETHICS AND DISSEMINATION: No IRB-approval is required for this study. Access to confidential research protocols was provided by the Central Committee on Research Involving Human Subjects. We plan to finish data collection in June 2015, and expect to complete data cleaning, analysis and manuscript preparation within the next 3 months. Hence, a first draft of an article containing the results is expected before the end of October 2015.

Analyzing the contributions of a government-commissioned research project: a case study.

BACKGROUND: It often remains unclear to investigators how their research contributes to the work of the commissioner. We initiated the 'Risk Model' case study to gain insight into how a Dutch National Institute for Public Health and the Environment (RIVM) project and its knowledge products contribute to the commissioner's work, the commissioner being the Health Care Inspectorate. We aimed to identify the alignment efforts that influenced the research project contributions. Based on the literature, we expected interaction between investigators and key users to be the most determining factor for the contributions of a research project. METHODS: In this qualitative case study, we analyzed the alignment efforts and contributions in the Risk Model project by means of document analysis and interviews according to the evaluation method Contribution Mapping. Furthermore, a map of the research process was drafted and a feedback session was organized. After the feedback session with stakeholders discussing the findings, we completed the case study report. RESULTS: Both organizations had divergent views on the ownership of the research product and the relationship between RIVM and the Inspectorate, which resulted in different expectations. The RIVM considered the use of the risk models to be problematic, but the inspectors had a positive opinion about its contributions. Investigators, inspectors, and managers were not aware of these remarkably different perceptions. In this research project, we identified six relevant categories of both horizontal alignment efforts (between investigators and key users) as well as vertical alignment efforts (within own organization) that influenced the contributions to the Inspectorate's work. CONCLUSIONS: Relevant alignment efforts influencing the contributions of the project became manifest at three levels: the first level directly relates to the project, the second to the organizational environment, and the third to the formal and historical relationship between the organizations. Both external and internal alignments influence the contributions of a research project. Based on the findings, we recommend that research institutes invest in a reflective attitude towards the social aspects of research projects at all levels of the organization and develop alignment strategies to enhance the contributions of research.

Metabolic profile of the hippocampus of Zucker Diabetic Fatty rats assessed by in vivo 1H magnetic resonance spectroscopy.

Localized in vivo 1H magnetic resonance spectroscopy (MRS) was used to investigate metabolite levels in the brain of adult Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes mellitus. This study focussed on the hippocampus, assumed to be one of the main brain areas affected by this disease. Together with an almost 5-fold increase in blood glucose concentration measured by glucose oxidation, significant increases were found in the hippocampal concentrations of glucose (4.93 vs 1.66 mM p < 0.001), myo-inositol (6.52 vs 4.30 mM; p < 0.05), and total creatine (12.71 vs 10.50 mM; p < 0.05) in ZDF rats (n = 5) compared with littermates (n = 5). Although no obvious alterations were detected in the hippocampal levels of other metabolites, including NAA + NAAG and choline-containing compounds in the ZDF rats, the increase in Glc and Ins levels is in line with elevated brain tissue contents of these metabolites in patients with diabetes mellitus.

Exploring levels of hexosamine biosynthesis pathway intermediates and protein kinase C isoforms in muscle and fat tissue of Zucker Diabetic Fatty rats.

Many studies suggest that insulin resistance develops and/or is maintained by an increased flux of glucose through the hexosamine biosynthesis pathway. This pathway may attenuate insulin-stimulated glucose uptake by activating protein kinase C (PKC). Therefore, we investigated whether the concentrations of the major hexosamine metabolites, uridine diphosphate- N-acetyl-glucosamine (UDP-GlcNAc) and uridine diphosphate- N-acetyl-galactosamine (UDP-GalNAc), and the expression levels of PKC isoforms were affected in Zucker Diabetic Fatty (ZDF) rats, an animal model widely used to study type 2 diabetes mellitus. At the age of 6 wk, control and ZDF rats were normoglycemic. Whereas control rats remained normoglycemic, the ZDF rats became hyperglycemic. The amount of UDP-GlcNAc and UDP-GalNAc in muscle tissue of ZDF rats was similar at 6, 12, 18, and 24 wk of age. Moreover, the concentration of both hexosamines did not differ among ZDF, phlorizin-treated ZDF, and control rats. Western blot analysis revealed that PKCalpha, delta, epsilon, andzeta, but not PKCbeta and gamma, were expressed in muscle and fat tissues from 6- and 24-wk-old control and ZDF rats. In addition, we did not observe changes in the expression levels of the PKC isoforms following prolonged hyperglycemia. Taken together, these findings indicate that the amounts of several metabolites from the hexosamine biosynthesis pathway and PKC isoforms, both hypothesized to be important in the development and/or maintenance of the insulin-resistant state of muscle and fat tissue, are not different in ZDF compared with nondiabetic rats.

Expression of the novel epithelial Ca2+ channel ECaC1 in rat pancreatic islets.

The epithelial Ca2+ channel, ECaC1, is primarily expressed in the apical membrane of vitamin D-responsive tissues. This study characterizes for the first time the presence of this novel channel in pancreatic tissue by reverse transcriptase-polymerase chain reaction and immunohistochemistry. In addition, the expression of ECaC1 was investigated in an animal model for Type 2 diabetes mellitus, the Zucker diabetic fatty (ZDF) rat. Identical staining patterns for ECaC1 and insulin were observed, whereas no co-localization of ECaC1 with glucagon was found. ECaC1, insulin, and prohormone convertase 1 (a neuroendocrine endoprotease expressed in secretory granules) showed a similar punctate staining. ECaC1 co-localized with the Ca2+ binding protein calbindin-D(28K) in the beta-cells. Furthermore, in contrast to wild-type rats, in ZDF rats aging led to a progressive decrease in both insulin and ECaC1 staining. Plasma 1,25-dihydroxyvitamin D3 levels were similar in both control and ZDF rats and decreased with aging. Taken together, our findings indicate that this novel Ca2+ channel may play a role in the regulation of endocrine Ca2+ homeostasis.