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Singing a New SONG: Outcomes for Clinical Trials

Malone, Andrew F. MBBCh, MRCPI1; Brennan, Daniel C. MD1

doi: 10.1097/TP.0000000000001775
Commentaries

The Standardized Outcomes in Nephrology (SONG) initiative, formed in 2014, standardizes care in chronic kidney disease. Malone and Brennan review 2 studies that apply the SONG criteria to transplant recipients to define core outcomes.

1 Division of Nephrology, Department of Medicine, Washington University School of Medicine, St Louis, MO.

Received 16 March 2017. Revision received 27 March 2017.

Accepted 30 March 2017.

The authors declare no funding or conflicts of interest.

A.M. and D.B. participated in the interpretation and writing of the article.

Correspondence: Daniel C. Brennan, MD, Alan A. and Edith L. Wolff Professor of Renal Diseases, Washington University School of Medicine in St. Louis, Director, Transplant Nephrology, Barnes-Jewish Hospital, Campus Box 8126, 660S. Euclid Avenue, St. Louis, MO 63110. (dbrennan@dom.wustl.edu; LKIPPER@DOM.wustl.edu).

Clinical trials in transplantation report a variety of clinical, surrogate, or patient-reported outcomes that are usually short-term, and often inconsistent and incomplete. For example, the use of early acute cellular rejection to predict graft loss.1,2 Several stakeholders including regulatory bodies, physicians, surgeons, researchers, industry, and most importantly patients and their caregivers are invested in the uniform, consistent, and complete reporting of the most relevant outcomes to improve the development of clinical guidelines and provide better treatments. The Food and Drug Administration Risk Evaluation and Mitigation Strategy was designed to track adverse events after drug approval with longer-term follow-up. In our experience, however, Risk Evaluation and Mitigation Strategy is frequently ignored by practitioners and not enforced by the Food and Drug Administration. Surrogate endpoints, such as estimated glomerular filtration rate, are beginning to be reported but are not yet recognized as valid outcome measures.3,4 Even less commonly reported are patient-centered outcomes such as quality of life.

Recognizing these unmet needs, there has been a call to develop “core outcome sets”, defined as an “agreed minimum set of outcomes to be reported in all trials.”5 In the rheumatology field the “Outcome Measures in Rheumatoid Arthritis Clinical Trials” has successfully established a methodology to improve and standardize outcome measures. Outcomes of interest are determined from general outcome domains and refined using a data-driven and iterative approach.6 The Standardized Outcomes in Nephrology (SONG) initiative was formed in 2014 to develop outcome measures for the care of patients with chronic kidney disease using a similar approach.7

Two articles in this issue describe the results of the SONG initiative applied to kidney transplantation, SONG-Tx. This global initiative draws on involvement of groups of health professionals, patients and their caregivers to reach consensus on a “core set” of the most important clinical trial outcome endpoints in transplantation.8,9

The process used for this global initiative to define core outcomes through consensus was recently published.10 Once established, core outcome sets could permit reliable comparisons of the effect of interventions across and between trials, and enhance the use and uptake of trial evidence in decision-making. The results of this process are described in this issue of Transplantation.8 There are several unique features about the process, and foremost may be the use of techniques more common in the social sciences including focus groups, iterative Delphi surveys, Likert scales, and Qualitative Data Analysis (Figure 1). Focus groups bring together people of different backgrounds to discuss what is important to them. In the case of SONG-Tx, the focus group comprised international patient/caregivers, healthcare professionals, members of societies, and regulatory bodies. Thus, the SONG-Tx group of “experts” was international, multidisciplinary, and importantly, included patients. SONG-Tx used the Delphi technique is an approach for establishing consensus through iterative surveys with anonymous responses among an “expert” panel (Figure 1). Participants were recruited by site investigators at participating hospitals, from patient organizations worldwide using standardized invitation fliers, the SONG Network database by email, and via “snowball sampling” which included the use of social media. Snowball sampling involves recruited subjects recruiting other subjects. Invitations directed participants to register on the SONG website. The outcomes domains to be scored by the participants were identified from systematic review of outcomes reported in clinical trials studies and studies on patient reported outcomes.

The SONG-Tx Delphi surveys then relied on a Likert scale that ranged from 1 to 9 to rank the outcomes domains. Outcomes not scored highly by most participants were not included in round 2 or 3 of the Delphi survey. “Consensus” definition of a core outcome was based on all stakeholder groups having a median score of greater than or equal to 8, a mean score greater than or equal to 7.5, and the proportion of participants rating the outcome as ‘critically important’ being greater than or equal to 75% (Figure 1). Respondents could also provide comments after each survey. Importantly, all these comments were available for participants to review before the next round of the Delphi survey was rescored. Comments were then analyzed using Qualitative Data Analysis techniques to group text into themes that were then added to the surveys.

The results show patients/caregivers and healthcare providers have similar priorities regarding many outcomes that should be measured in studies among transplant patients. Notably, however, there are a few interesting differences (Figure 2). For example, healthcare professionals are more worried about death as an outcome than patients. Patients are more worried about skin cancer, blood pressure, surgical complications, cognition, ability to work, and depression—in short, because death is inevitable, all the things that are concerning to a patient!

After the international Delphi survey was finished and critically important outcome domains identified by consensus, 2 workshops were convened to deliberate these results.9 These workshops supported the inclusion of the core set of outcomes identified. They also emphasized the importance of patient-reported outcomes, such as life-participation. Not only are the goals laudable for the SONG-Tx initiative, the methods used for obtaining consensus are also an advance for the field.

There are limitations to the SONG initiative. There may be some bias in the selection of the participants, as the authors recognize. There are no children included, and only English speakers were eligible to participate. Computer literacy and access to the internet in some countries might also have limited participation.

There are major strengths of SONG-Tx and its process. A great strength of the Delphi technique is reliance on anonymity. Anyone who has been on a consensus panel knows the bias that can be introduced by the most outspoken or intransigent participant. SONG-Tx is a multicenter, international study that used novel approaches, a variety of healthcare-related professionals, and importantly patients and caregivers. SONG-Tx provides new insight into including patient centered outcomes. Shared-outcomes between patients and professionals is a new song for all us to sing.

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