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Identifying What to Measure in Acne Clinical Trials: First Steps towards Development of a Core Outcome Set

2017; Elsevier BV; Volume: 137; Issue: 8 Linguagem: Inglês

10.1016/j.jid.2017.04.017

1523-1747

Alison Layton, E. Anne Eady, Diane Thiboutot, Jerry Tan, Flordeliz Abad‐Casintahan, Ketaki Bhate, Fiona Collier, Fiona Cowdell, Claudia M. Y. A. Donkor, Leon Kircik, Megan N. Landis, Shari Marchbein, Sandra Nijland, Falk Ochsendorf, Nanette B. Silverberg, Guy Webster, Jonathan Weiss,

Meta-analysis and systematic reviews

Outcome measures to assess the efficacy of acne treatments are heterogeneous and inconsistently applied (Lehmann et al., 2002Lehmann H.P. Robinson K.A. Andrews J.S. Holloway V. Goodman S.N. Acne therapy: a methodologic review.J Am Acad Dermatol. 2002; 47: 231-240Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). The lack of universal adoption of a minimum set of well-validated outcome measures is a major obstacle to evidence synthesis. To date, the main focus has been on physician-assessed methods such as lesion counts and global severity scales. Instruments assessing impacts of acne on patients have only been used occasionally. The goal of the Acne Core Outcomes Research Network (ACORN) is to develop a set of core outcome measures to assess acne in a clinical trial setting following the Harmonizing Outcome Measures for Eczema roadmap (Schmitt et al., 2015Schmitt J. Apfelbacher C. Spuls P.I. Thomas K.S. Simpson E.L. Furue M. et al.The Harmonizing Outcome Measures for Eczema (HOME) roadmap: a methodological framework to develop core sets of outcome measurements in dermatology.J Invest Dermatol. 2015; 135: 24-30Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar) with consultation from the Cochrane Skin Group Core Outcome Set Initiative. The goal of this study was to identify what to measure in an acne trial, in other words, the outcomes or domains of greatest importance. In advance of this exercise, it was decided to include adverse events as a core outcome domain as they are part of the overall risk/benefit assessment of any intervention as described by the Outcome Measures in Rheumatology group (Boers et al., 2014Boers M. Kirwan J.R. Wells G. Beaton D. Gossec L. d'Agostino M.A. et al.Developing core outcome measurement sets for clinical trials: OMERACT filter 2.0.J Clin Epidemiol. 2014; 67: 745-753Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar). However, ACORN will not be developing novel outcome measures to assess adverse events. A structured iterative process based on a prespecified protocol was used in the "what to measure" exercise (Supplementary Materials and Methods online). The study was registered in the COMET database. A preliminary list of candidate items was generated using acne-specific quality-of-life instruments, an acne-specific patient-reported outcome measure, a rigorous methodologic review of acne trials, and a current ACORN systematic review of acne impacts (Alexis et al., 2014Alexis A. Daniels S.R. Johnson N. Pompilus F. Burgess S.M. Harper J.C. Development of a new patient-reported outcome measure for facial acne: the Acne Symptom and Impact Scale (ASIS).J Drugs Dermatol. 2014; 13: 333-340PubMed Google Scholar, Girman et al., 1996Girman C.J. Hartmaier S. Thiboutot D. Johnson J. Barber B. DeMuro-Mercon C. et al.Evaluating health-related quality of life in patients with facial acne: development of a self-administered questionnaire for clinical trials.Qual Life Res. 1996; 5: 481-490Crossref PubMed Scopus (100) Google Scholar, Gupta et al., 1998Gupta M.A. Johnson A.M. Gupta A.K. The development of an Acne Quality of Life scale: reliability, validity, and relation to subjective acne severity in mild to moderate acne vulgaris.Acta Derm Venereol. 1998; 78: 451-456Crossref PubMed Scopus (132) Google Scholar, Layton et al., 1997Layton A.M. Seukeran D. Cunliffe W.J. Scarred for life?.Dermatology. 1997; 195: 15-21Crossref PubMed Scopus (109) Google Scholar, Lehmann et al., 2002Lehmann H.P. Robinson K.A. Andrews J.S. Holloway V. Goodman S.N. Acne therapy: a methodologic review.J Am Acad Dermatol. 2002; 47: 231-240Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, Motley and Finlay, 1989Motley R.J. Finlay A.Y. How much disability is caused by acne?.Clin Exp Dermatol. 1989; 14: 194-198Crossref PubMed Scopus (195) Google Scholar, Rapp et al., 2006Rapp S.R. Feldman S.R. Graham G. Fleischer A.B. Brenes G. Dailey M. The Acne Quality of Life Index (Acne-QOLI): development and validation of a brief instrument.Am J Clin Dermatol. 2006; 7: 185-192Crossref PubMed Scopus (41) Google Scholar). Two authors (EAE, AML) and one patient appraised the list of items for omissions or ambiguity. Wording was edited to optimize understanding by all participants and definitions were provided (Supplementary Materials and Methods). Potential participants were contacted using email lists for the Acne Priority Setting Partnership, ACORN membership, the Acne Global Alliance, the American Acne and Rosacea Society, and also via the American Acne and Rosacea Society website. At least one editor of each of the top 30 dermatology journals was invited. Although consensus-based methods typically involve less than 50 participants, this number was considered too few to obtain unbiased international representation of multiple stakeholder groups. Although our target was a minimum of 200 participants in round 1, 500 participants from 54 countries responded to email requests to select the 12 most important items to measure from among a list of 24 items (Figure 1 and see Supplementary Materials and Methods for survey). Responses were monitored and efforts made to increase numbers for any stakeholder group that appeared to be under-represented. Two hundred and sixty participants left email addresses indicating that they wished to take part in round 2. The top 12 items of importance (Figure 1c) were taken forward. Sixty-nine people added suggestions for other items, but when appraised, most were covered by an existing item (Supplementary Materials and Methods). Two suggestions that required further consideration were acne scars/dark marks and skin texture/quality. Concern was raised that two widely used outcomes in acne trials, global acne severity assessed by a physician and health-related quality of life ranked 13 and 16, respectively. To resolve these ambiguities, the ACORN Steering Committee consulted the Outcomes Identification Group and Cochrane Skin Group Core Outcome Set Initiative. Their recommendation was to also take forward global acne severity assessed by a physician, health-related quality of life, and acne scars/dark marks into round 2 where participants were invited to score 15 items on a Likert-like scale where 1 = not at all important and 9 = extremely important (see Supplementary Materials and Methods for survey). For data analysis, scores of 1–3 were considered unimportant, 4–6 equivocal, and 7–9 important. To be included in the core domain set, consensus was defined a priori as being achieved when at least 70% of patients and 70% of professionals scored the item ≥7 and ≤15% scored the same item ≤3. Any items for which more than 70% of patients and professionals gave a score ≤3 would be dropped. Response rate, summary scores for each item, and items selected for inclusion as a core domain from round 2 are shown in Table 1. "Satisfaction with treatment received" reached consensus among professionals but was 0.2% short of consensus among patients. The Outcomes Identification Group and Cochrane Skin Group Core Outcome Set Initiative agreed that this item should be included as a core domain. They were also consulted regarding the disagreement between patients and professionals regarding who should assess the clinical features of acne. The recommendation was to move signs and symptoms forward as a core domain recognizing that who and how they should be assessed would need to be resolved in the next phase to develop outcome measures. No items met the criterion for exclusion in this round (Table 1).Table 1Summary of scoring by participants in rounds 2 and 3Signs by physSigns/Sx by ptSpeed of improveSatisf with appearPhys glob severSelf-esteemHR QoLLong-term controlSatisf with RxValue of Rx to ptPhys global improvPt global improveLong-term conseqScars/dark marksNo flareRound 2: 15 items. Scores 7–9 important; 1–3 not important. Overall response rate = 63%Patients, n = 52Median score7 [3]8 [2]8 [2.5]8 [2]6 [5]8 [2]7 [3]8 [1]8 [3]7 [3]7 [4]7 [3.5]8 [2]8 [2]8 [2.5]Percentage scores 7–964.277.475.58347.279.254.788.769.860.450.967.977.477.475.5Percentage scores 1–315.13.87.59.426.49.49.45.75.79.41711.31.95.75.7Professionals, n = 112Median score8 [3]7 [4]7 [3]8 [2]7 [4]8 [3]7 [4]7 [1]7 [3]7 [3]7 [3]8 [3]7 [4]8 [3]7 [2]Percentage scores 7–971.260.451.476.659.567.657.775.771.25063.170.359.57365.8Percentage scores 1–39.913.596.37.25.47.24.56.310.87.23.611.76.36.3Consensus to includeNONONOYESNONONOYESYES1As the patient vote was 0.2% short of the 70% required for consensus, this item was included in the core set after consultation with the Outcomes Identification Group.NONONONOYESNORound 3: 9 items. Vote "Yes" or "No" for inclusion. Overall response rate = 70.7%Patients, n = 34Percentage Yes76.544.181.673.531.220.661.873.567.6Professionals, n = 82Percentage Yes53.782.943.979.330.559.869.537.839Consensus to includeNONONOYESNONONONONOKey to Items: 1. Physical signs of acne assessed by a physician; 2. Signs and symptoms of acne assessed by the patient; 3. Speed of improvement in acne; 4. Satisfaction with appearance; 5. Global acne severity assessed by a physician; 6. Self-esteem; 7. Health-related quality of life; 8. Long-term control of acne; 9. Satisfaction with treatment received; 10. Value of treatment to the patient; 11. Global improvement in acne assessed by a physician; 12. Global improvement in acne assessed by the patient; 13. Long-term consequences of treatment received; 14. Extent of scars and dark marks; 15. Absence of acne flares.Abbreviations: HRQoL, health-related quality of life; Rx, treatment; Sx, symptoms.1 As the patient vote was 0.2% short of the 70% required for consensus, this item was included in the core set after consultation with the Outcomes Identification Group. Open table in a new tab Key to Items: 1. Physical signs of acne assessed by a physician; 2. Signs and symptoms of acne assessed by the patient; 3. Speed of improvement in acne; 4. Satisfaction with appearance; 5. Global acne severity assessed by a physician; 6. Self-esteem; 7. Health-related quality of life; 8. Long-term control of acne; 9. Satisfaction with treatment received; 10. Value of treatment to the patient; 11. Global improvement in acne assessed by a physician; 12. Global improvement in acne assessed by the patient; 13. Long-term consequences of treatment received; 14. Extent of scars and dark marks; 15. Absence of acne flares. Abbreviations: HRQoL, health-related quality of life; Rx, treatment; Sx, symptoms. Concern was raised that feedback of high median scores (Table 1) to participants in round 3 would likely encourage the minority who gave low scores in round 2 to increase them. This could result in lack of discrimination with far more items being retained than is practicable for a core outcome set. The study protocol provided an option to ask a simple Yes/No question as to whether an item should be included in the core domain set if consensus was not achieved. The decision to proceed with the Yes/No option was supported by the Outcomes Identification Group. The criterion for consensus in round 3 was 70% of patients and 70% of professionals voting yes. Items on which consensus had already been reached in round 2 were not taken forward into this round. Participant information, response rates, and the responses obtained for round 3 are shown in Table 1 (see Supplementary Materials and Methods for survey). Consensus for inclusion was achieved for one item, health-related quality of life. There was considerable disagreement between patients and professionals on several remaining items, one of which, global acne severity assessed by a physician, is very widely used in acne trials and is recommended in the US Food and Drug Administration (Food and Drug Administration (FDA), 2005Food and Drug Administration (FDA), Center for Drug Evaluation and ResearchGuidance for Industry. Acne vulgaris: developing drugs for treatment, September 2005Google Scholar). A summary of the core outcome domains resulting from this study is presented in Figure 1d. Next steps involve identification or development of measures to assess each of the core outcomes. Alison M. Layton: http://orcid.org/0000-0003-0473-3319 E. Anne Eady: http://orcid.org/0000-0001-6975-5557 Diane M. Thiboutot: http://orcid.org/0000-0002-7342-2357 Jerry Tan: http://orcid.org/0000-0002-9624-4530 The authors state no conflict of interest. We thank Elizabeth Oldham for her help in administrating the questionnaires and sending out email invitations and reminders to participants. We are grateful to Jochen Schmitt of Cochrane Skin Group Core Outcome Set Initiative for ongoing help and advice during the setup and data collection phases of the study. This work was funded by the US National Institute of Health, award number 1U01AR065109-01. Download .pdf (49.31 MB) Help with pdf files Supplementary Materials and Methods