{"paper_id":"8f94678c-36ff-46ea-a3bb-25b4b06cd0c8","body_text":"S T U D Y P R O T O C O L Open Access\nDeveloping consensus on core outcome\ndomains and measurement instruments for\nassessing effectiveness in perioperative\npain management after sternotomy, breast\ncancer surgery, total knee arthroplasty, and\nsurgery related to endometriosis\nThe IMI-PainCare PROMPT protocol for achieving a consensus\non core outcome domains\nUlrike Kaiser 1 , Hiltrud Liedgens 2, Winfried Meissner 3, Claudia Weinmann 3, Peter Zahn 4 and\nEsther Pogatzki-Zahn 5*\nAbstract\nIntroduction: Evidence synthesis of clinical trials requires consistent outcome assessment. For pain management after\nsurgery, inconsistency of effectiveness assessment is still observed. A subproject of IMI-PainCare (Innovative Medicine\nInitiatives, www.imi-paincare.eu) aims for identifying core outcome domains and measurement instruments for\npostoperative pain in four surgical fields (sternotomy, breast cancer surgery, total knee arthroplasty, and surgery related\nto endometriosis) in order to harmonize outcome assessment for perioperative pain management.\nMethods: A multifaceted process will be performed according to existing guidelines (Core Outcome Measures in\nEffectiveness Trials (COMET), COnsensus-based Standards for the selection of health Measurement INstruments\n(COSMIN)). In a first step, outcome domains will be identified via systematic literature review and consented on during\na 1-day consensus meeting by 10 stakeholder groups, including patient representatives, forming an IMI PROMPT\nconsensus panel. In a second step, outcome measurement instruments regarding the beforehand consented core\noutcome domains and their psychometric properties will be searched for via systematic literature review and approved\nby COSMIN checklist for study quality and scale quality separately. In a three-step online survey, the IMI PROMPT\nconsensus panel will vote for most suitable measurement instruments. The process is planned to be conducted\nbetween 11/2017 (systematic literature review on common outcome domains) and 3/2022 (final voting on core\noutcome measurement).\n© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,\nwhich permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give\nappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if\nchanges were made. The images or other third party material in this article are included in the article's Creative Commons\nlicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons\nlicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain\npermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nThe Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the\ndata made available in this article, unless otherwise stated in a credit line to the data.\n* Correspondence: pogatzki@anit.uni-muenster.de\n5Department of Anaesthesiology, Intensive Care and Pain Medicine,\nUniversity Hospital Münster, Albert-Schweitzer-Campus 1, A1, 48149 Münster,\nGermany\nFull list of author information is available at the end of the article\nKaiser et al. Trials          (2020) 21:773 \nhttps://doi.org/10.1186/s13063-020-04665-9\n\nIntroduction\nMore than 300 million patients receive surgery each year\nworldwide, where pain is one of the most common and\ndevastating symptoms thereafter [ 1]. Acute postoperative\npain does not only cause suffering in patients for several\ndays; high pain scores early after surgery are associated\nwith postoperative complications like ileus, gastroparesis,\nconstipation, atelectasis, respiratory insufficiency, urinary\nretention, and thrombosis [ 2], some with long-term con-\nsequences including prolonged, persistent pain for years\nafter surgery [ 3]. Although efforts to improve the situ-\nation of patients have been undertaken, pain manage-\nment within the first days after surgery is still\ninsufficient [ 4–7].\nPain management options need to be evaluated re-\ngarding their effectiveness in preventing and managing\nacute postoperative pain [ 8]. There are several reasons\nfor non-satisfying acute pain management; one of them\nbeing a flaw in designing RCTs by choosing study end-\npoints not displaying clinically relevant treatment effects\n[9]. Acute pain ratings at rest serve as a common pri-\nmary outcome [ 10]; yet, pain intensity at rest is usually\nless intense than, for example, pain during movement,\nand does poorly correspond to postoperative rehabilita-\ntion (physiotherapy), recovery, length of hospitalization,\nand long-term consequences including chronic postop-\nerative pain [ 3, 9]. In fact, it is unclear to date if pain in-\ntensity ratings are relevant measures after surgery [ 2,\n11]. The lack of clinically relevant and standardized\npatient-reported outcome measures (PROMs) for studies\naddressing the management of postoperative pain im-\npedes identification of effective treatments for certain\nsurgical procedures. Improving comparability of effect-\niveness research therefore requires a core set of outcome\nmeasures in clinical practice and controlled trials for\nperioperatively managing pain after surgical procedures.\nCore outcome sets (COS) are considered legitimate\napproaches to overcome irrelevant and inconsistent out-\ncome assessment in clinical trials [ 12]. They are defined\n“as minimum core sets consisting of patient relevant or\nreported outcome domains and corresponding measure-\nment instruments to be assessed in any clinical trial re-\ngarding a specific health condition and/or intervention ”\n[12]. Outcome domains are defined as concepts to be\nmeasured in terms of a further specification of an aspect\nof health [ 13], e.g., health-related quality of life. A COS\ncommonly includes patient-reported outcomes (PRO)\nand patient-reported outcome measures (PROM), the\nlatter understood as “any report of the status of a pa-\ntient’s health condition that comes directly from the pa-\ntient, without interpretation of the patient ’s response by\na clinician or anyone else ” [14] and is therefore different\nfrom other, so-called “objective” measures such as\nbiomarkers.\nThe development of such a COS, comprising of both\noutcome domains and measurement instruments, is a\nmultifaceted process, containing systematic research and\nconsensus processes. Standards for their development\nhave been set by COMET ( Core Outcome Measures in\nEffectiveness Trials [12]). Four key features are required\nin order to establish an accepted and ready to use COS\nfor the research field of concern: structured procedure\n(e.g., guided by COMET handbook), transparency of\nperformance (e.g., guided by COS Star guidelines of\nreporting COS studies), transparency of decision criteria,\nand inclusion of relevant stakeholders (including patient\nrepresentatives).\nThe a priori defined health condition acute postopera-\ntive pain has not been considered as a separate health\ncondition so far. Postoperative pain has been acknowl-\nedged as one domain (out of many) in perioperative\nmedicine [ 15] but was not further established. For total\nknee arthroplasty (and for knee replacement or joint re-\nplacement), several initiatives work on harmonizing out-\ncome assessment [ 11, 16–28], by considering effects of\nsurgery and general long-term features without focusing\non acute postoperative pain (e.g., knee injury and/or\nknee osteoarthritis, knee, hip, and hand osteoarthritis\n[16–20, 22–28] or hip or knee osteoarthritis [ 11, 21]).\nRegarding breast surgery and sternotomy, COS consider-\nations for postoperative pain have not been worked on\nyet, despite some effort to harmonize outcome assess-\nment in general for reconstructive breast surgery [ 29,\n30]. Some initiatives have worked on COS for endomet-\nriosis [ 31–34], but again, postoperative pain was not ad-\ndressed. For all surgical procedures, perioperative pain\nmanagement is characterized by a short duration of\nintervention (regularly for some days up to 1 or 2 weeks\nafter surgery), and ideally supporting quick recovery and\nregain of functioning. Therefore, perioperative pain\nmanagement aims for enabling the patient to return\nquickly to as much self-management ability and reduced\npain-related interference of wellbeing as possible, de-\npending on limitations of functioning due to the surgical\nintervention.\nPROMPT (Patient-Reported Outcome Measures in Pain\nTreatment) is one of three subprojects within the IMI-2\nJU project IMI-PainCare (Innovative Medicines Initiative\nPain Care, www.imi-paincare.eu, 30th March 2020)\nfunded by the European Union and European Federation\nof Pharmaceutical Industries and Associations (EFPIA).\nWithin PROMPT (PROMs suitable for assessing changes\nin acute postsurgical pain), one initiative (, work package\n2 of IMI-PainCare) seeks to improve postoperative pain\nby effective perioperative pain management in terms of\ndeveloping a COS of patient-reported outcome measures\nassessing efficacy and effectiveness in any clinical and ob-\nservational studies as well as in clinical practice. Due to\nKaiser et al. Trials          (2020) 21:773 Page 2 of 10\n\nthe assumable fact, that outcome domains and measure-\nment instruments might differ dependently to specific\ntreatment effects of certain surgical procedures (see for\nexample www.postoppain.org, 30th March 2020), four\nsurgical procedures are addressed: sternotomy (St), breast\ncancer surgery (BS), total knee arthroplasty (TKA), and\nsurgery for endometriosis (EM). Those surgeries were\nchosen for (1) the differences in type and extent of tissue\ninjury (soft tissue, bone/joint/ visceral), (2) the differences\nin patient populations (young versus old; cancer versus\nnon-cancer patients, preoperative pain or none), (3) the\nfrequency of practice and the concomitant moderate to\nsevere postoperative pain, thus being relevant both for\nnew treatment approaches and for many patients and\nhealth care practitioners worldwide. These procedures\nrepresent a broad spectrum of requirements of periopera-\ntive pain management, with the option to address the\nquestion of developing either separate COS for periopera-\ntive pain management after each surgical procedure or an\noverarching COS comprising all.\nMethods\nGeneral considerations\nRationale and design for the consensus process within\nthe PROMPT project are guided by the COMET recom-\nmendations ([ 12], see Fig. 1) referring to postoperative\npain in adult patients undergoing breast surgery, sternot-\nomy, total knee arthroplasty, and surgery for endometri-\nosis and receiving perioperative pain management\ninvestigated in any clinical and observational trial as well\nas in clinical practice (scope), consisting of two parts —\none for identifying core outcome domains and one for\nthe corresponding core outcome measurement instru-\nments. Both arms start with systematic literature re-\nsearch (SLR) and lead into different forms of consensus\nprocesses. Reporting of the processes will be basing on\nCOS Star guidelines [ 35] (Fig. 1).\nEnsuring comprehensiveness of a future COS in spe-\ncific health conditions, theoretical frameworks should\nguide decision making about the systematization and the\nimportance of core outcome domains ([ 12] Fig. 1, I COS\nDomains, steps 1 and 2). The framework recommended\nby OMERACT is matching purpose and need of\nPROMPT, providing a frame for medically oriented clin-\nical trials and will be applied in order to arrange and\nstructure relevant outcome domains to relevant core\nareas during the consensus meeting [ 36].\nThe focus on therapy aims as a prerequisite for deriv-\ning relevant outcome domains shall facilitate discussion\nand enable participants to be focused (Fig. 1, I COS\nDomains, step 2). Therapy aims of perioperative man-\nagement after surgery (including BS, TKA, ST, and EM)\ncontain restoration of impaired function (for example\nphysical and/or psychological), the reduction of suffering\ndue to postoperative pain considering a patient-centered\napproach, and the risks and benefits associated with the\nintervention within the first weeks after surgery (lay def-\ninition by the authors). According to the definition, an\noutcome domain (as a further specification of an aspect\nof health) and outcome (as any identified result in a do-\nmain arising from exposure to a causal factor or health\nintervention, modified from [ 36]) correspond closely to\ntherapy intention or aim. Only aspects of health, chan-\nged by a specific intervention, seem to reasonably be\nconsidered as outcomes, because this change is intended\nand supposed to be investigated by comparative re-\nsearch. The close relationship between therapy aims and\noutcome domains will be consistently guided throughout\nthe consensus process on outcome domains. An over-\nview of the planned process for identifying COS of do-\nmains and measurement instruments for perioperative\npain management after surgery in clinical trials and clin-\nical practice is presented in Fig. 1.\nFor estimating and evaluating psychometric properties\nfor future measurement instruments (Fig. 1, II COS\nMeasurement, steps 3 and 4), standards have been estab-\nlished by the COSMIN working group. They advise to\nsystematically search for evidence of psychometric prop-\nerties of certain measurement instruments, defining\nclear criteria for good quality of study conduction and\nquality of scales. Psychometric properties of highest im-\nportance are validity (especially content validity as the\nprerequisite for further evaluation of other issues of scale\nquality), reliability, and sensitivity to change [ 37]. The\nCOSMIN checklist also provides guidance on how to\nevaluate validity, reliability, and sensitivity to change in\nmeasurement instruments [ 38, 39].\nParticipants of the IMI PROMPT consensus panel\nFor perioperative pain management, a considerable var-\niety of stakeholders can be assumed, especially regarding\nthe latest acceleration in treatment development and\nmulti-professionality in this field. Ten different stake-\nholders have found to be relevant by the steering com-\nmittee (see Table 1).\nEligible for the IMI PROMPT consensus panel are in-\ndividuals experienced in perioperative pain management\n(clinicians, researchers) after breast surgery, thoracot-\nomy/sternotomy, total knee arthroplasty, and endometri-\noses or having experienced such procedure or other\npainful surgeries themselves (patient representatives).\nFor endometriosis, inclusion was extended to individuals\nexperienced in unspecified treatment of endometriosis.\nFurther, pharma representatives, representatives of\nhealth technology assessment agencies, and regulators\n(experienced in drug development) have been identified\nas important stakeholders in the field of perioperative\npain management. Since PROMPT is embedded into the\nKaiser et al. Trials          (2020) 21:773 Page 3 of 10\n\nlarge EU-funded project (please compare www.IMI-pain-\ncare.eu, 30th March 2020) and other processes will be bas-\ning on PROMPT future results, the IMI PROMPT\nconsensus panel was extended by corresponding working\ngroup members of the IMI-PainCare project (comprising\nfunctional pain biomarkers (BioPain) and Translational\nResearch in Pelvic Pain (TriPP)), announced by the IMI-\nPainCare leaders. In preparation of the process, inter-\nnational scientific organizations associated with pain\nresearch and management (EFIC) or anesthesia and post-\noperative pain management (ESA) have been approached\nand were invited to nominate at least 4 relevant experts\nfrom their field of interest. In Table 1,s t a k e h o l d e rg r o u p s\nare provided along with addressed scientific and patient\nself-help organizations nominating representatives for\ntheir participation as well.\nGroup size considerations referred to the consensus\nmeeting because of financial, timely, and administrative\nFig. 1 Schedule and Steps of the IMI PROMPT Consensus on a Core Outcome PROM Set for surgery after TKA, BS, ST and EM\nKaiser et al. Trials          (2020) 21:773 Page 4 of 10\n\nresources on one side and requirements for equal distri-\nbution of stakeholder representatives on the other. Dur-\ning the consensus, four separate breakout groups have\nbeen planned (TKA, BS, St, and EM) with at least one\nstakeholder representative from each group ( n = 10). It\nwas therefore intended that each stakeholder group\nshould consists of 4 representatives, in sum a number of\nn = 40 was expected to participate.\nThe same panel will be invited to the online Delphi sur-\nvey on measurement instruments (Fig. 1, steps 2 and 4).\nInformation sources\nAccording to the COMET data source ( http://www.\ncomet-initiative.org/, 30th March 2020) and to the best\nof our knowledge, no COS initiative is engaged in peri-\noperative pain management in general or for the chosen\nprocedures total knee arthroplasty, breast surgery, and\nsternotomy so far.\nEndometriosis is being worked on by several initiatives\nwith different scopes, either published as report or study\nprotocol [ 31, 33, 34, 40] or not published yet but pro-\nvided to authors of this manuscript [personal communi-\ncation with Katy Vincent, Email during June 2018].\nConsidering this work is required, thus, following\nCOMET recommendation of careful consideration of\nprevious work in the field of interest [ 12], it was there-\nfore necessary to break down this consensus process into\ntwo different arms, at least referring to COS domains.\nInitial list of outcome domains (Fig. 1, step 1)\nAn initial list of outcome domains for effectiveness as-\nsessment of perioperative pain management after TKA,\nBS, and St will be gathered via separate SLRs, all regis-\ntered at PROSPERO database [CRD42018093838;\nCRD42018095142; CRD42018095137], where compre-\nhensive details can be found. The searches will be con-\nducted in Embase, MEDLINE, and CENTRAL (without\ntimely or quantity restriction of publication) until 2018,\nsearching for all forms of clinical prospective observa-\ntional and randomized controlled trials regarding effect-\niveness of perioperative pain management after TKA,\nBS, and St. No quality assessment (e.g., by GRADE) is\nintended since the sole frequency of outcomes or out-\ncome domains will be of interest. Screening of title/ab-\nstract and full text will be performed by two\nindependent reviewers. Extraction will contain, besides\nstudy characteristics, types and frequencies of the ap-\nplied outcomes or outcome domains forming a descrip-\ntive synthesis.\nFor endometriosis, previous results [ 31–34, 40] of ini-\ntiatives specifically dedicated to study and improve treat-\nment of endometriosis will be provided to the IMI\nPROMPT consensus panel after deciding about main\naims of perioperative pain management in patients with\nendometriosis. This will be used in order to subse-\nquently decide whether these recommended domains\nserve the purpose of capturing effectiveness in peri-\noperative pain management in endometriosis or if modi-\nfications are needed. Key issues of discussion will be\ndocumented and reported in the future meeting report.\nInitial list of measurement instruments (Fig. 1, step 3)\nBased on the a priori defined and recommended out-\ncome domains for perioperative pain management after\nsurgery (BS, TKA, St, and EM), relevant measurement\ninstruments will be identified via systematic review in\ntwo steps following the COSMIN guidance. The first\nstep will comprise a scoping review and hand search for\nmeasurement instruments mapping outcome domains\nand definitions. Search will be performed in Embase,\nMEDLINE, and CENTRAL, in case of psychological do-\nmains additionally in PsychINFO and PsychArticle and,\nif needed, in common data bases for PROMs. Two inde-\npendent reviewers will screen the results for title and ab-\nstract and for full text. Extraction will contain, besides\nstudy characteristics, definition of construct, description\nof the developmental process (in terms of identifying\npatient-reported outcome measures), scale construction,\ndescription of scale, and preliminary results in case of\nfirst validation. Primary search terms will refer to inaug-\nuration articles (articles describing the development of a\nscale or measurement instrument) and the specific do-\nmain (including synonyms or related terms).\nCOSMIN and COMET suggest searching also in their\ndatabase of SLRs regarding measurement instruments.\nIn case of old or low-quality SLRs, they advise to\nTable 1 PROMPT consensus panel\nStakeholder groups Nominated by\nAnesthesiologists ESA\nESRA\nPain specialists IMI Group\nEFIC\nIMI Group IMI Group\nSurgeons EFIC\nIMI Group\nPsychologists EFIC\nIMI Group\nPhysiotherapists EFIC\nIMI Group\nHTA/PRO experts and regulatory experts IMI Group\nPain nurses EFIC\nIMI Group\nPatient representatives EFIC\nIMI Group\nIMI-EFPIA IMI Group\nESA European Society of Anaesthesiologists, EFIC European Pain Federation,\nESRA European Society of Regional Anesthesia and Pain Therapy, IMI\nGroupIMI-PainCare Consortium\nKaiser et al. Trials          (2020) 21:773 Page 5 of 10\n\nconduct an update or to perform a new SLR; otherwise,\nit is considered sufficient to rely on existing results.\nMeasurement instruments corresponding to IMI\nPROMPT outcome domain definitions, developed as\npatient-reported outcome and with a similar target\npopulation (postoperative, acute pain; similar character-\nistics as observed in TKA, BS, St, and EM) will be\nchosen for further investigation of psychometric proper-\nties regarding the COSMIN quality criteria for creating a\nlist of potential PROMs.\nCOSMIN search strings will be applied [ 41] for subse-\nquent systematic literature reviews in the abovemen-\ntioned data sources, concerning at least one of the\npsychometric properties regarding content validity, con-\nstruct validity, reliability, and sensitivity to change. For\nboth validities, studies will be included when presenting\nresults for construct and/or content validity. For reliabil-\nity and sensitivity to change, studies will be included\nwhen providing information to the a priori defined tar-\nget population (adult patients undergoing surgery for\nBS, TKA, St, and EM). Quality approval includes quality\nof study conduction and reporting and, in a second step,\nquality of the scale, performed by COSMIN checklist\n[38, 39, 42, 43]. All information for each scale will be fi-\nnally summarized in a table providing the definition of\nthe construct, the identified results regarding validity\n(content and construct), reliability, and sensitivity to\nchange, including quality ratings of study quality and\nquality of the psychometric property separately. The\nfinal tables will then be provided to the IMI PROMPT\nconsensus panel during the online Delphi survey for fur-\nther decision about relevant measurement instruments.\nConsensus process\nOutcome domains- consensus meeting\nThe consensus process (a 1-day face to face consensus\nmeeting) will be facilitated by two members of the steer-\ning committee (EPZ, UK). A structured schedule (pro-\nvided as a handout), consisting of plenary discussions,\nbreakout groups (stakeholder groups, groups working on\nthe specific health conditions) shall support consistent\nand transparent discussion and approaching a stable\nconsensus.\nEnhancing respectful discussion, the IMI PROMPT\nconsensus panel will be advised to discuss from the per-\nspective of their stakeholder group, not as unique per-\nson, wherefore a basic understanding of representative\nof a stakeholder group will be formed by a specific,\nintroductory part. Brainstorming and aligning on therapy\naims and finally choosing relevant corresponding out-\ncome domains for perioperative pain management will\nbe performed within breakout groups referring to each\nsurgery separately. All results of the breakout groups will\nbe discussed subsequently after completing each step\n(aligning on therapy aims, aligning on corresponding\noutcome domains) and overarching results, comprising\nperioperative pain management in all surgery groups in\ngeneral, are appreciated. Members of the steering com-\nmittee (HL, WM, PZ, and CW) will facilitate the break-\nout groups. The variety of steps and groups enables\nequal chances to contribute for each participant.\nThe first section of the meeting aims for the aligning\non relevant and most critical therapy aims of periopera-\ntive pain management. Starting with a brainstorming on\nrelevant therapy aims for each surgery (via world café, 4\nrounds), all participants will be invited to leave as much\ninformation to the breakout groups as they feel is rele-\nvant. A prioritization within the breakout groups on\nmost critical therapy aims will complete this section.\nThe breakout groups prioritize therapy aims according\nto the OMERACT 2.0 filter ([ 36], four core areas: death,\nlife impact, resource use/economical impact, patho-\nphysiological manifestations, adverse events) and also ac-\ncording to their relevance on a 1 –9 scale (Likert scale,\n1–3 not important, 4 –7 important but not critical, 7 –9\ncritical). Presenting the breakout group results to the\nplenary group will invite comprehensive feedback of\nother participants. The IMI PROMPT consensus panel\nwill also be encouraged to structure therapy aims either\ninto general therapy aims of perioperative pain manage-\nment or into more specific therapy aims regarding sur-\ngery in the four regions.\nDuring a subsequent section, outcome domains from\nsystematic literature review (initial list of outcomes) will\nbe matched to the a priori aligned most critical therapy\naims (rated as critical (7 –9)), added by official definitions\nof those outcome domains if available. Regarding align-\nment on relevant and important therapy aims, existing\nand via SLR-identified outcome domains can be in-\ncluded, excluded, or merged into each other, always en-\nsuring transparent documentation of the process.\nReasons for excluding, merging, or otherwise amending\noutcome domains will be reported in the future meeting\nreport. The group also will have the opportunity to de-\ncide either to choose generic (for perioperative pain\nmanagement in general) or specific (for perioperative\npain management after the specific surgery) outcome\ndomains. In case of competing outcome domains within\none therapy aim, the panel will approve the outcome do-\nmain matching most and drop the less important out-\ncome domain regarding the therapy aim.\nIt will be suggested to recommend at least one domain\nfor each core area; otherwise, it will be explicitly ex-\nplained why a core area has not been considered for\nCOS [ 12].\nIn a final plenary section (complete IMI PROMPT\nconsensus panel), all breakout groups present and dis-\ncuss their results. When discussion is completed, the\nKaiser et al. Trials          (2020) 21:773 Page 6 of 10\n\nvoting will be performed for all outcome domains ran-\nging from 7 to 9 as most critical, starting with generic\nsuggestions. Four outcome domains are expected. The\noutcome domain with the highest rating will be pre-\nferred in case of competing outcome domains.\nPatient representatives are able to veto in case of\ncomplete disagreement with a single outcome domain.\nPatient representatives need to be unanimously against a\ndecision of other stakeholder groups to set a veto. If an-\nother stakeholder group consistently disagrees with a\npanel decision, it is able to advice the panel to discuss\nthe issue again, but the panel needs to approve the ne-\ncessity of that action. In case of disapproval to discuss\nan outcome domain again, further discussion will be dis-\nmissed and the group will move forward to the next out-\ncome domain.\nOutcome measurement instruments-Delphi online exercise\nConsensus on measurement instruments shall be\nachieved via a final online Delphi survey (Surveymon-\nkey), planned as a 3-step online survey. Information\nresulting from a second set of systematic literature re-\nviews, now on psychometric properties of corresponding\nmeasurement instruments (PROMs) and search for con-\nstruct definition of the relevant measurement instru-\nments will be provided to the IMI PROMPT consensus\npanel (see “Participants of the IMI PROMPT consensus\npanel”), alongside with quality grading by COSMIN\nchecklist for both study and scale quality. Each member\nof the IMI PROMPT consensus panel participants will\nbe invited to comment and to preliminarily vote for each\npresented instrument on 1 –9 scales as described above,\nadvised to focus on highest available quality. Summariz-\ning results from this first round regarding all presented\nmeasurement instruments, added by summarized feed-\nback by panel participants, the preliminary vote of the\ncomplete IMI PROMPT consensus panel and of the in-\ndividuals will be presented during a second round, also\ninviting comments and feedback to each instrument.\nThe final vote in the third round will only include those\nmeasurement instruments which have been rated to be\nsufficient for inclusion (rating of 7 –9 on the 1 –9 scale)\ninto future COS by at least 50% of participants in at least\n2/3 of stakeholder groups.\nScoring of outcome domains and measurement\ninstruments\nConsidering the quality of reporting outcome domains\nin intervention and effectiveness studies in terms of peri-\noperative pain management after BS, TKA, St, and EM,\nonly few studies have reported outcome domains expli-\ncitly and clearly defined. During the consensus meeting,\noutcome domains will be classified into 1 –3 not import-\nant, 4 –6 important but not critical, 7 –9 critical, as\nrecommended by COMET [ 12]. Inclusion of outcome\ndomains requires an outcome domain to be rated as at\nleast 7 on the 1 –9 rating scale.\nThe same scoring will be applied for measurement in-\nstruments during an online Delphi survey. In case of\ncompeting measurement instruments for a single out-\ncome domain, the measurement instrument with the\nhighest rating will be included into future COS.\nConsensus definition\nConsensus on outcome domains (consensus face to face\nmeeting) and measurement instruments (online Delphi\nexercise) will be defined as at least ≥70% voting for 7 –9\nand ≤ 20% voting for 1 –3 rating (means that most of the\npanel feels that the specific outcome domain is import-\nant to include) by the IMI PROMPT consensus panel in\norder to include an outcome domain and a measure-\nment instrument into future COS (see Table 2), adapted\nby COMET recommendation of 70% vs 15% [ 12] for rea-\nsons of feasibility. Exclusion is defined as 70% of voting\nfor 1 –3 and 20% voting for 7 –9 for a certain outcome\ndomain or measurement instrument. All other cases will\nbe considered no consensus, which means that there is\nuncertainty about the importance of the specific out-\ncome domain or measurement instrument to be in-\ncluded into future COS.\nProject schedule\n/C15Systematic reviews on outcome domains 11/2017 –\n06/2018 (completed, publication of results is in\npreparation or submission, DATE OF\nSUBMISSION)\n/C15Consensus meeting on outcome domains 06/2018\n(completed, publication of results in in preparation)\n/C15Systematic reviews and research between 08/2018\nand 08/2020 (SLRs are submitted to PROSPERO,\nsearch strategy is completed, screening of title/\nabstract and full text is completed for scoping\nreview on corresponding measurement instruments,\nSLR for psychometric properties is in preparation).\n/C15Preparation of results of systematic reviews for\npsychometric properties of corresponding\nmeasurement instruments and preparation of the\nonline Delphi exercise between 09/2020 and 09/2021\n/C15Final consensus on outcome measurement\ninstruments between 09/2021 and 03/2022\nDiscussion\nAs summarized in previous publications [ 44], there are\nmany ways for establishing a COS on domains so far.\nYet, the Delphi method is one of the most accepted.\nThis method is characterized by the opportunity to avoid\nbiases in response, decision, or opinion building, easily\nKaiser et al. Trials          (2020) 21:773 Page 7 of 10\n\nrestricting dominant stakeholder representatives [ 45]\nand supporting to include individuals worldwide [ 12].\nConsensus methods have been used as well, but there is\nno clear evidence of superiority of specific methods [ 12].\nBoth ways are recommended, and sometimes they are\napplied together in mixed method approaches.\nMajor limitations of both approaches as forms of\nqualitative processes comprise the affection of the final\nresults by types of stakeholders involved, the existing\nknowledge of the participants [ 46], the questions asked,\nthe provision of information (or false information [ 46]),\nand the manner of interaction [ 45]. A careful consider-\nation of the planned rationale is therefore necessary, bal-\nancing field of future COS, financial and timely\nresources, the amount of stakeholder groups necessary,\nand the complexity of the scope, aim, and domains to be\nconsidered of the future COS [ 12]. Since a\nstandardization of methods cannot be recommended to\ndate for COS development, detailed and precise report-\ning of conduction is demanded [ 12, 35].\nFor Delphi methods, additionally attrition during the\niterative process is highly relevant, challenging process\ncompletion and interpretation of results, especially when\nmissing specific stakeholder groups [ 46]. The complexity\nof the questions addressed might be strained by the for-\nmat of repeating exposure to similar looking question-\nnaires and produces effects of tiredness and motivation\nloss [ 46]. All those aspects endanger reliability and rep-\nresentativity of Delphi processes, even though when con-\nducted in large samples internationally. As discussed by\nother authors [ 47], psychometric soundness of consen-\nsus processes (e.g., Delphi) containing estimates for reli-\nability, validity, and generalizability might not serve\nproperly. They suggest rather estimating quality of such\nprocesses, considering the qualitative field of research,\nby other criteria such as transferability, credibility, ap-\nplicability, or confirmability of results. They explicitly\nstate that such process do not aim for finding the right\nanswer but support orientation and create impulses in\nresearch and health care provision.\nBased on these experiences and the situation of het-\nerogeneity in designing COS developmental studies, the\nsteering committee of IMI PROMPT decided to apply a\nmixed method approach for establishing the COS for\nperioperative pain management in four surgeries for\nclinical trials. One main consideration started with the\nobservation that bringing together different stakeholders\nwith different backgrounds in an online survey does not\nsupport understanding and acceptance since back-\ngrounds and opinions cannot be exchanged easily. There\nis a considerable risk that results of such consensus re-\npeat what has been there already, not assuming or critic-\nally reflecting on still missing aspects. Solely relying on\noutcome domains already published also creates biases,\nbased on individual routines or preferences. Besides the\nlimits of face to face meetings in timely and financial re-\nsources, it indeed provides all participants with much\nmore information by discussion and exchange. The ap-\nplication of a facilitating schedule (guided discussion,\nbreakout groups, plenary sessions) was intended to re-\nduce the danger of potential biases due to opinion lead-\ning by single individuals or strong stakeholder groups\nenhancing acceptance, transparency, and presence of\nmultiple perspectives. Since developing COS domains\nrefers much to personal backgrounds, needs, and prefer-\nences, a face to face meeting was considered most ap-\npropriate and, at the end, time saving. For defining COS\non measurement instruments, performing an online\nbased Delphi survey will suffice, since there are several\ndistinct criteria (quality of study conduction, quality of\nscale-related psychometric properties), facilitating prep-\naration of online Delphi survey and decision by the\npanel.\nThere are possible limitations to our schedule and de-\nsign. One refers to the representativeness of the panel.\nThe announcement by organizations might help to re-\nduce the selection bias induced by possible preferences\nof the steering committee, but which representatives will\nbe chosen depends much on the organization. The steer-\ning committee has no control of real expertise, motiv-\nation, and background of the participants. Patients will\nbe announced also by an international patient advocacy\norganization in order to send patients experienced in\nconsensus processes and sufficiently speaking English.\nTable 2 Definition of consensus for PROMPT consensus on outcome domains and measurement instruments regarding\nperioperative pain management in patients after surgery (BS, TKA, St, and EM) [REF HARMAN 2013]\nConsensus\nclassification\nDescription Definition\nConsensus “in” Consensus that either outcome domain or measurement instrument should be included\ninto COS for perioperative pain management after surgery (BS, TKA, St, and EM)\n70% or more participants scoring 7 –9\nAND 20% or less participants scoring\n1–3\nConsensus\n“out”\nConsensus that either outcome domain or measurement instrument should NOT be\nincluded into COS for perioperative pain management after surgery (BS, TKA, St, and EM)\n70% or more participants scoring 1 –3\nAND 20% or less participants scoring\n7–9\nNo consensus Uncertain about importance of outcome Anything else\nKaiser et al. Trials          (2020) 21:773 Page 8 of 10\n\nSince international networking of patient advocacy orga-\nnizations is still a work in progress, selection bias for pa-\ntients cannot be ruled out, such as coming from\ncountries with a high amount of well-educated inhabi-\ntants, culturally open and experienced in scientific\ndiscussions.\nComplexity of consensus processes and the prepar-\nation of such time- and resource-consuming multifa-\nceted approaches for developing COS might be a\ndiscouragement. Yet, there is no alternative referring to\nthe major aim of finding best ways for improved care for\nour patients.\nAcknowledgements\nNone.\nFunding information\nThe PROMPT IMI Group is funded by the Innovative Medicines Initiative 2\nJoint Undertaking under grant agreement No [777500]. This Joint\nUndertaking receives support from the European Union ’s Horizon 2020\nresearch and innovation programme and EFPIA. ( www.imi.europa.eu; www.\nimi-paincare.eu, 30th March 2020). Open access funding provided by Projekt\nDEAL.\nDisclaimer\nThe statements and opinions presented here reflect the author ’s view and\nneither IMI nor the European Union, EFPIA, or any Associated Partners are\nresponsible for any use that may be made of the information contained\ntherein.\nAuthors’ contributions\nEPZ (last author) and HL are lead of the project presented here. They\ntogether with UK (first author) have developed rationale of the whole\nprocess leading to the core outcome set and the manuscript. PZ, EPZ, HL,\nand UK have developed the protocol of the systematic reviews. UK and EPZ\nhave developed the concrete rationale for the consensus and the Delphi\nprocess. UK and EPZ have drafted, coordinated, and mainly contributed to\nthe writing of the manuscript. WM, PZ, and CW have contributed to the\ndevelopment and organization of the process and have contributed\nsubstantially to the manuscript. The author(s) read and approved the final\nmanuscript.\nAvailability of data and materials\nData will be available on request of authors.\nEthics approval and consent to participate\nThe methods and procedure of the study are developed in compliance with\nthe ethical principles of the Helsinki Declaration and Good Epidemiologic\nPractice and have been approved by Ethical committee of TU Dresden (EK\n261052019). The process is described as a consensus process including\npatients who are announced by official organizations (self-help\norganizations) and therefore represent the interests of those organizations.\nNo treatment is offered and patients will not be harmed. All data of all\nparticipants will be gathered and analyzed completely anonymously and on\na group level. No personal data will be gathered. Consent forms will be filled\nin by each participant in order to comply with consent and data security\nstandards.\nCompeting interests\nEPZ: During the last 5 years, EPZ received financial support from\nMundipharma and Grünenthal for research activities, advisory and/or lecture\nfees and travel support from Grünenthal, MSD Sharp & DOHME GmbH,\nMundipharma GmbH; Mundipharma International; Janssen-Cilag GmbH; Fre-\nsenius Kabi and AcelRx.\nHL: Hiltrud Liedgens is an employee of Gruenenthal GmbH\nWM: Research: Pfizer, Grünenthal, Mundipharma. Advisory: Grünenthal, Tilray,\nSanofi. Lecture fees: Grünenthal, Northern Swan, TAD, Kyowa, Bionorica.\nCW: None\nPZ: None\nUK: Travel and accommodation refunds by Mundipharma and Gruenenthal\nAuthor details\n1Comprehensive Pain Center, University Hospital Carl Gustav Carus Dresden,\nDresden, Germany. 2Market Access, Grünenthal GmbH, Aachen, Germany.\n3Department of Anaesthesiology and Intensive Care Medicine, Jena\nUniversity Hospital, Jena, Germany. 4Department of Anaesthesiology and\nIntensive Care Medicine, Palliative Care Medicine and Pain Management,\nBerufsgenossenschaftliches Universitätsklinikum Bergmannsheil GmbH\nBochum, Ruhr University Bochum, Bochum, Germany. 5Department of\nAnaesthesiology, Intensive Care and Pain Medicine, University Hospital\nMünster, Albert-Schweitzer-Campus 1, A1, 48149 Münster, Germany.\nReceived: 1 August 2019 Accepted: 9 August 2020\nReferences\n1. 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