Academic response to improving value and reducing waste: A comprehensive framework for INcreasing QUality In patient-oriented academic clinical REsearch (INQUIRE)

<div><p>Background</p><p>Compelling evidence has demonstrated that a large proportion of investment in biomedical research is wasted; this waste is avoidable. Academic institutions have, thus far, shown limited response to recommendations for increasing value and reducing waste. We formulated an academic response by (i) achieving consensus across a wide range of stakeholder groups on a comprehensive framework for quality of patient-oriented clinical research and (ii) highlighting first successful examples of its operationalization to facilitate waste-reducing strategies at academic institutions.</p><p>Methods and findings</p><p>Based on a systematic review of quality definitions, concepts, and criteria in the medical literature (systematic MEDLINE search up to February 15, 2015, with independent and in duplicate article selection) and on stakeholder websites from 13 countries (Australia, Austria, Canada, France, Germany, Italy, Japan, Norway, Spain, Sweden, Switzerland, United Kingdom, and United States), we systematically developed a comprehensive framework for the quality of clinical research. We identified websites through personal contacts with experts in clinical research or public health who also suggested, for each country, websites of the following 7 stakeholder groups: patient organizations; academic research infrastructures; governmental bodies; regulatory agencies; ethics committees; the pharmaceutical industry; and funding agencies. In addition, we searched websites of inter- or supranational bodies involved in clinical research until no further insights emerged. After consolidation of the identified definitions, concepts, and criteria of quality in a basic framework structure, we conducted 4 rounds of an adapted online Delphi process among the same 7 stakeholder groups from 16 countries. The Delphi process ultimately achieved consensus on structure and content. The framework addresses 5 study stages (concept, planning and feasibility, conduct, analysis and interpretation, and reporting and knowledge translation) and includes the following dimensions: (i) protection of patient safety and rights, (ii) relevance/patient centeredness and involvement, (iii) minimization of bias (internal validity), (iv) precision, (v) transparency/access to data, and (vi) generalizability (external validity) of study results. These dimensions interact with 2 promoters—infrastructure and sustainability through education—that include a set of factors that may enhance all listed quality dimensions. Each quality dimension contains specific questions and explanatory items that guide quality assessment at each research stage from conceptualization of the research question through reporting and knowledge translation of study results. In the last survey round, Delphi participants from 9 countries (Austria, Australia, Canada, Germany, Italy, the Netherlands, Switzerland, UK, and US) agreed on the structure, content, and wording of the research stages, quality dimensions, specific questions, and descriptive examples of the final framework. In Switzerland, INQUIRE has resulted in a roadmap that guides initiatives to increase value within the Swiss Clinical Trial Organization network and through affiliated researchers.</p><p>Conclusions</p><p>We present a framework based on a consensus of different stakeholder groups guiding the practical assessment of clinical research quality at all stages of a research project. Operationalization of this common structure will support the increase of value by guiding academic institutions and researchers in developing quality enhancement initiatives, from posing the right research question to the transparent publication of results.</p></div

SCTO roadmap on how to increase value in Swiss academic clinical research.

<p>¹The CTU Network and SCTO actively support the design, planning, and conduct of investigator-initiated studies that apply for the Swiss National Science Foundation’s call for investigator-initiated clinical trials (<a href="http://www.snf.ch/en/funding/programmes/iict/Pages/default.aspx" target="_blank">http://www.snf.ch/en/funding/programmes/iict/Pages/default.aspx</a>). The Swiss National Science Foundation has earmarked CHF 10 million for the 2017 funding period. Performance measures would allow assessing the SCTO network’s impact on the success of supported studies. ²SCTO platforms are excellence clusters for specific support units, e.g., data management, statistics, training, and education, located at different CTUs. CTU, Clinical Trial Unit; REWARD, Reduce Research Waste and Reward Diligence.</p

INQUIRE’s specific quality questions (and descriptive examples for Stage I) by quality dimension and research stage, and promoters.

<p>INQUIRE’s specific quality questions (and descriptive examples for Stage I) by quality dimension and research stage, and promoters.</p

Response rates by stakeholder group for Delphi rounds 1 and 2.

<p>Response rates by stakeholder group for Delphi rounds 1 and 2.</p

PRISMA flow diagram.

<p>PRISMA flow diagram.</p

Network meta-analysis results for serum calcium.

<p>Forest plot of effectiveness outcome for mean calcium reduction at the end of the study period; MD: Mean difference; Crl: Credible interval; PrI: predictive intervals.</p

Patient reported outcomes.

<p>Individual trials’ outcomes expressed on a 0 to 100 scale. RTW coord. = return to work coordination. MID = minimal important difference.</p

Effects of different phosphate lowering strategies in patients with CKD on laboratory outcomes: A systematic review and NMA

<div><p>Background</p><p>Chronic kidney disease-mineral and bone disorder (CKD-MBD), a complication of chronic kidney disease, has been linked to reduced quality and length of life. High serum phosphate levels that result from CKD-MBD require phosphate-lowering agents, also known as phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on laboratory outcomes in patients with CKD-MBD.</p><p>Methods</p><p>Data sources included MEDLINE and EMBASE from January 1996 to April 2016, and the Cochrane Register of Controlled Trials up to April 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible randomized controlled trials (RCTs). Eligible trials enrolled patients with CKD-MBD and randomized them to receive calcium-based phosphate binders (delivered as calcium acetate, calcium citrate or calcium carbonate), non-calcium-based phosphate binders (NCBPB) (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate), phosphorus restricted diet (diet), placebo or no treatment and reported effects on serum levels of phosphate, calcium and parathyroid hormone.</p><p>We performed Bayesian network meta-analyses (NMA) to calculate the effect estimates (mean differences) and 95% credible intervals for serum levels of phosphate, calcium and parathyroid hormone. We calculated direct, indirect and network meta-analysis estimates using random-effects models. We applied the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for each pairwise comparison.</p><p>Results</p><p>Our search yielded 1108 citations; 71 RCTs were retrieved for full review and 16 proved eligible. Including an additional 13 studies from a previous review, 29 studies that enrolled 8335 participants proved eligible; 26 trials provided data for quantitative synthesis. Sevelamer, lanthanum, calcium, iron, diet and combinations of active treatments (calcium or sevelamer or lanthanum and combination of calcium and sevelamer) resulted in significantly lower serum phosphate as compared to placebo (moderate to very low quality of evidence). We found no statistically significant differences between active treatment categories in lowering serum phosphate. Sevelamer, lanthanum and diet resulted in lower serum calcium compared to calcium (moderate quality evidence for lanthanum and diet; low quality evidence for Sevelamer). Iron, sevelamer and calcium yielded lower parathyroid hormone levels as compared to lanthanum. Meta-regression analyses did not yield a statistically significant association between treatment effect and trial duration.</p><p>Discussion/Conclusions</p><p>We found few differences between treatments in impact on phosphate and differences in parathyroid hormone. Relative to calcium, sevelamer, lanthanum and diet showed significant reduction in serum calcium from baseline. Treatment recommendations should be based on impact on patient-important outcomes rather than on surrogate outcomes.</p><p>Systematic review registration: PROSPERO CRD-42016032945</p></div

Network of clinical trials of phosphate binders in patients with chronic kidney disease: outcome mean change from baseline in serum calcium concentration.

<p>Netplot of effectiveness outcome for mean calcium reduction at the end of the study period. Network of randomized controlled trials comparing different phosphate binders for mean change in serum calcium. Lines connect different phosphate binder categories with direct evidence. The width of lines correlates the number of RCTs for each direct comparison while the size of the nodes correlates with the total sample size. Abbreviations: cal: calcium; calmag: calcium and magnesium; calsev: calcium and Sevelamer; Lant: lanthanum; seve: Sevelamer.</p

Status of participants and their outcome data at both the trial and systematic review levels.

<p> † It is possible that the investigators collected but did not report the data. * Data analysis might have included assumptions about missing participant data. ITT =  intention to treat; CCA =  complete case analysis. § Refers to ineligible participants mistakenly randomized and meeting the conditions for appropriate exclusion (see text), and to participants with other reasons for appropriate exclusion (e.g., subsequently found not to have condition of interest, or never underwent a procedure for which the intervention is intended).</p