{"paper_id":"6330a9a8-0b24-428e-a36e-7c707455a967","body_text":"R E S E A R C H Open Access\nDevelopment and content validation of a\npatient-reported endometriosis pain daily\ndiary\nFloortje E. van Nooten 1*, Jennifer Cline 2, Celeste A. Elash 3, Jean Paty 4 and Matthew Reaney 5\nAbstract\nBackground: Endometriosis is a common gynecological disorder that causes inflammation and pelvic pain.\nEndometriosis-related pain is best captured with patient-reported outcome (PRO) measures, however, assessment of\nendometriosis-related pain in clinical trials has been difficult in the absence of a reliable and valid PRO instrument.\nWe describe the development of the Endometriosis Pain Daily Diary (EPDD), an electronic PRO developed as a\nsurvey instrument to assess endometriosis-related pain and its impact on patients ’ lives.\nMethods: The EPDD was initially developed on the basis of an existing Endometriosis Pain and Bleeding Diary, a\ntargeted review of relevant literature, clinical expert interviews, and open-ended (concept elicitation) patient\ninterviews in the United States (US) and Japan which captured patients ’ experience with endometriosis. Cognitive\ninterviews of patients with endometriosis were conducted to evaluate patient comprehension of the EPDD items. A\nconceptual model of endometriosis was developed, and meetings with US and European regulatory authorities\nprovided feedback for validating the EPDD in the context of clinical trials. Translatability assessments of the EPDD\nwere conducted to confirm its appropriate interpretation and ease of completion across 17 languages.\nResults: The iterative development progressed through three versions of the instrument. The EPDDv1 included 18\nitems relating to dysmenorrhea/pelvic pain, dyspareunia and sexual activity, bleeding, hot flashes, daily activities,\nand use of rescue medication. The EPDDv2 was a larger 43-item survey tested in cognitive interviews and\nsubsequently revised to yield the current 11-item EPDDv3, consisting of five core items relating to dysmenorrhea,\nnon-menstrual pelvic pain, and dyspareunia, and six extension items relating to sexual activity, daily activities, and\nuse of rescue medication.\nConclusions: The EPDD is a PRO for the evaluation of endometriosis-related pain and its associated impacts on\npatients’ lives. The EPDD represents an important step in providing a PRO that is relevant to patients with\nendometriosis-related pain in the context of a clinical study setting (ie, fit-for-purpose), designed to evaluate pain\nassociated with endometriosis, including regulatory agency support for its further exploration in clinical trials.\nKeywords: Endometriosis, Patient-reported outcome measures, Dysmenorrhea, Pelvic pain\n* Correspondence: floortjevannooten@hotmail.com\n1Astellas Pharma, Leiden, the Netherlands\nFull list of author information is available at the end of the article\n© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0\nInternational License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and\nreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to\nthe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver\n(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 \nDOI 10.1186/s12955-017-0819-1\n\nBackground\nEndometriosis is a common gynecological disorder char-\nacterized by the presence of endometrial glands and\ntissue outside of the uterus, resulting in chronic inflam-\nmation, dysmenorrhea, dyspareunia, and chronic pelvic\npain [1]. The prevalence of endometriosis ranges from 6\nto 10% in the worldwide female population [2], and has\nbeen shown to be associated with dysmenorrhea, dys-\npareunia, and chronic pain. Women with endometriosis\nexperience absenteeism and reduced overall work pro-\nductivity as a result of their condition, and have de-\nmonstrated reduced quality of life scores on the Short\nForm-36 version 2. Additionally, among women in a\nrelationship, endometriosis can negatively impact part-\nner relationships [3, 4].\nEndometriosis-related pain and its impact on patients ’\nlives are best captured through the use of direct reports\nfrom patients regarding their experience, that is, patient-\nreported outcome (PRO) measures. PROs are widely\nused in evaluating pain; three PROs are commonly used\nin studies of endometriosis. The Composite Pelvic Signs\nand Symptoms Score (CPSSS) is a modified version of\nthe Biberoglu and Behrman Scale [5] and measures\ndysmenorrhea, dyspareunia, non-menstrual pelvic pain\n(NMPP), pelvic tenderness, and pelvic induration. This\nscale was developed on the basis of physician opinion,\nwithout specific input from patients, and has a 28-day\nrecall period [6]. Given that responses to PRO items are\nlikely to be influenced by the patient ’s state at the time\nof recall, the United States (US) Food and Drug Admin-\nistration (FDA) PRO Guidance for Industry recom-\nmends, in alignment with good measurement practices\n[7, 8], that PROs have a recall period that is appropriate\nto capture the patient ’s current or recent state [9].\nAdditionally, patient data are recorded by the physician\nand thus the CPSSS is not a direct PRO. The Endometri-\nosis Health Profile (EHP) is a PRO instrument that\nmeasures the impact of endometriosis on patients ’ lives;\nspecifically, the EHP measures pain, control and power-\nlessness, social support, emotional well-being, and self-\nimage [10 –13]. The EHP was designed to measure the\nimpact of endometriosis rather than specific symptoms\nand has a 4-week recall period. The Endometriosis Pain\nand Bleeding Diary (EPBD) [14] was developed to meas-\nure endometriosis symptoms. Although the EPBD was\ndeveloped on the basis of both patient and physician\ninput, and designed to collect information daily, the\ninstrument’s development was discontinued prior to\nestablishing that it was fit-for-purpose.\nThus, the CPSSS, EHP , and EPBD have their limitations\nas a fit-for-purpose tool for evaluating endometriosis-\nrelated pain in the context of supporting labeling claims of\na treatment benefit, as outlined in the US FDA PRO Gui-\ndance for Industry [9]. Therefore, we have developed the\nEndometriosis Pain Daily Diary (EPDD) as a fit-for-\npurpose PRO instrument to assess pain and its impact\non patients ’ lives in clinical trials for women with\nendometriosis-related pain.\nGiven its development process, the EPBD was an\nappropriate starting place for the EPDD. The FDA\nguidance emphasizes the importance of demonstrating\nevidence of the relevance (ie, content validity) of the\nPRO instrument to the target patient population, and\nensuring that the population studied in the PRO instru-\nment development and documentation process is com-\nparable with that in the clinical study setting in which\nthe instrument is to be used (ie, that the instrument is\nfit-for-purpose).\nThis paper describes the initial steps of the develop-\nment of the EPDD. Specifically, this paper describes the\nprocess undertaken for establishing content validity of\nthe EPDD, providing evidence that it measures relevant\nconcepts and experiences relating to pain associated\nwith endometriosis, is homogenously interpretable, and\nis easily comprehendible. The processes described herein\nrepresent the first steps of development of an instrument\nthat is ‘fit-for-purpose’.\nMethods\nThe EPDD was developed through a series of proce-\ndures, including the development of an evidence-\nsupported conceptual model of disease, all of which\nfollowed regulatory guidance set forth by the European\nMedicines Agency ’s (EMA) Committee for Medicinal\nProducts for Human Use (CHMP) reflection paper on\nthe use of health-related quality of life measures in the\nevaluation of medicinal products [15] and the FDA PRO\nGuidance for Industry [9]. The recommendations in\nthese regulatory guidelines are aligned with good instru-\nment development practices [7, 8]. The development\nprocess described herein encompasses all procedures\nthat took place in the development of the EPDD as a\ncontent-valid PRO designed for the purpose of assessing\ntreatment response in clinical trials (Fig. 1).\nThe EPDD was designed to be administered using an\nelectronic platform, asking patients to record their\nendometriosis-related pain experiences over the previous\n24 h. To date, the EPDD has been administered using a\nsmall hand-held electronic device that queries the\npatient each evening for a recording. The device allows\npatient compliance to be tracked and is designed to\nminimize incomplete records, as the programming does\nnot allow patients to skip questions.\nDevelopment of the EPDDv1\nThe initial version of the EPDD (EPDDv1) was devel-\noped on the basis of the conceptual framework of the\nexisting Endometriosis Pain and Bleeding Diary (EPBD)\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 2 of 13\n\n[14], available literature on endometriosis, and input\nfrom outcomes research scientists and a clinical expert\nfrom Europe (Fig. 1). In order for the EPDD to be imple-\nmented in a phase 2 clinical trial of endometriosis\n(TERRA; NCT01767090), cognitive interviews were\nconducted to test for patient comprehension of the draft\nitems, language, instructions, and response options.\nSpecifically, the cognitive interviews were designed to\ngain the patient ’s perception of the survey items (ie,\nwhat the patient believes the question is asking) and\ncomprehension of terms (ie, what specific words and\nphrases mean to the patient) [16]. Semi-structured, indi-\nvidual, face-to-face interviews were conducted with 14\nwomen from the US with surgically confirmed endomet-\nriosis and consisted of patients completing the EPDDv1\nand answering questions relating to the intent of the\nquestions and the interpretation of specific terms. Inter-\nviewers were research scientists with training and exten-\nsive experience conducting qualitative interviews with\npatients across a number of therapeutic indications\nincluding endometriosis and other areas of women ’s\nhealth. In preparation for these studies, the interviewers\nreviewed the content and purpose of semi-structured\ninterview guide questions with the authors and con-\nducted practice interviews with each other to become\nfamiliar with interview content and flow. Near the end\nof the interview, the patient ’s acceptance of the elec-\ntronic platform was assessed with a brief series of ques-\ntions assessing ease of use, ease of response selection,\nacceptability of the electronic platform and any\nproblems using the electronic platform. The information\nobtained from these exercises was used to inform the\nfinalization of the EPDDv1. The EPDDv1 was then\ntranslated and linguistically validated in 12 languages\n(including English) to ensure conceptual equivalency of\nthe survey items in the 10 countries that enrolled\npatients for the global phase 2 TERRA study. Prior to\ntranslation, all language was reviewed for any potential\nmodification that would be required to ensure that the\nconceptual basis of each question would be retained.\nThe translation and linguistic validation followed\ninternationally accepted standards set forth by the Inter-\nnational Society for Pharmacoeconomics and Outcomes\nResearch and consisted of seven processes: 1) a dual\nforward translation was performed by two independent\nnative-speaking translators; 2) a third native-speaking\nlinguist assessed the translations and reconciled any\ndiscrepancies between the two translations; 3) a native\nspeaker with proficiency in English performed a back\ntranslation to ensure that the forward translation was\nconceptually equivalent to the original; 4) a medical\nreview was conducted to ensure that the survey items\nwere appropriate for a clinical setting; 5) cognitive test-\ning of the EPDDv1 was conducted on a small group of\nrelevant patients with endometriosis in order to test\nalternative wording and to check understandability,\ninterpretation, and cultural relevance of the translation;\n6) a review of cognitive testing results compared the\npatients’ interpretation of the translation with the\noriginal version to highlight and amend discrepancies\nDevelopment of the EPDDv1\n Clinical expertise, expert knowledge of endometriosis\nliterature, input from outcomes research scientists\nand a clinical expert from Europe \n Conceptual framework of the Endometriosis Pain and\nBleeding Diary\n Cognitive interviews with patients from the US (n = 14)\n Translation and linguistic validation (12 languages)\nEPDDv1 Launched in \nPhase 2 Trial\nItem Refinement and Generation Meeting\n Targeted literature review\n Telephone interviews with clinical experts\nin endometriosis (n = 5) \n Concept elicitation interviews with patients\nfrom the US (n = 17) and Japan (n = 17) \nRevision of the EPDDv1 and \nDevelopment of the EPDDv2\n Cognitive interviews with patients from the US (n = 16) and Japan (n = 15) \n Translatability assessment (17 languages)\n Item refinement and generation meeting\nCognitive Testing of the EPDDv2 and \nDevelopment of EPDDv3\nEPDDv3\nConceptual Disease \nModel of Endometriosis\nFig. 1 Development Process of the EPDD\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 3 of 13\n\nand finalize the translation; 7) the final step was proof-\nreading and final review of the translation [17].\nRevision of the EPDDv1 and development of the EPDDv2\nFollowing the launch of the phase 2 TERRA study\nthat employed the EPDDv1, the tool was further\nevaluated for content validity using updated literature\nreviews, clinician interviews, and additional, semi-\nstructured patient interviews. This three-step process\nwas designed to evaluate whether items needed to be\nmodified or deleted, or if additional items should be\nadded to the EPDDv1. The following three steps\n(Fig. 1) were:\n/C15A targeted literature review to identify the most\nimportant and relevant symptoms and impacts\nrelated to endometriosis. The MEDLINE database\nwas searched for human studies published in\nEnglish; search terms included targeted phrases such\nas ‘endometriosis sign’, ‘endometriosis symptom’,\n‘endometriosis impact ’, ‘endometriosis’ and ‘quality\nof life ’, ‘Activities of Daily Living (ADL) ’, ‘interview’,\nand ‘focus group ’.\n/C15Individual interviews with five clinical experts in\nendometriosis to collect further input regarding\nimportant and relevant health concepts (ie, signs,\nsymptoms, side-effects, impacts) for women with\nendometriosis.\n/C15Concept elicitation interviews with adult women in\nthe US and Japan to identify and confirm the\nsymptom and impact concepts from the EPDDv1\nthat were the most important and relevant to\nwomen with endometriosis-related pain. Patients\nfrom the US ( n = 17) were recruited if they were\naged 18 –45 years and had surgically confirmed\ndiagnosis of endometriosis within 5 years. Patients\nfrom Japan ( n = 17) were recruited if they were aged\n20–45 years with a diagnosis of endometriosis;\nbecause surgical diagnosis is uncommon in Japan,\nsurgical diagnosis was not required if diagnosis was\nconfirmed by a blood test, internal examination, or a\nmagnetic resonance imaging or computed\ntomography scan. During the interviews, patients\nwere first asked to spontaneously report any\nsymptoms they experienced as a result of\nendometriosis, and thereafter were asked if they\nexperienced any specific symptoms from a predefined\nlist of symptoms known to be associated with\nendometriosis (based on literature and expert input).\nThe digital audio files from the patient concept elicit-\nation interviews were transcribed into document files\nand loaded into the ATLAS.ti (version 5.0) software pro-\ngram for coding [18]. Data coding methodology followed\na three-step process. First, the coder identified each inci-\ndence of a concept expression in the transcript text.\nSecond, the coder highlighted the actual patient quote\nas the assigned code name and then matched the tagged\ntext to a code stem from the coding framework, allowing\nit to be grouped with other codes of similar content\nrelated to the project ’s objectives. If a code stem did not\nexist in the coding framework, a new one was developed\nand the coding framework was expanded; any code\nstems not used were removed when the coding diction-\nary was finalized. Third, the final coding dictionary was\nthe result of the full set of concept codes identified in\nthe patient transcripts, organized by the overall structure\nof the coding framework so the results could be related\nto the project objectives. All descriptive data from the\nscreening form were entered into SPSS (version 11.5) to\ngenerate tables of descriptive statistics.\nInformation obtained from these exercises resulted in\nthe development of a conceptual disease model of endo-\nmetriosis. This conceptual disease model served to facili-\ntate an item refinement and generation meeting, during\nwhich the EPDDv1 was updated to include relevant fin-\ndings from the literature review and patient and expert\ninterviews. The outcome of the item refinement and\ngeneration meeting was the EPDDv2.\nCognitive testing of the EPDDv2 and development of the\nEPDDv3\nThe EPDDv2 was tested in additional cognitive inter-\nviews with patients. Patients with endometriosis from\nthe US ( n = 16) and Japan ( n = 15) were identified via\nclinical record review (US) and patient self-reporting\n(Japan), and subsequently recruited and screened at\nthree US centers (Spokane, WA; Seattle, WA; New\nOrleans, LA) and one market research firm in Tokyo,\nJapan, to participate in the cognitive interviews. Patients\ncompleted the EPDDv2 and participated in face-to-face\nindividual semi-structured interviews.\nFollowing minor refinements made during and follow-\ning the cognitive interviews, a translatability assessment\nwas conducted to identify and rectify any major concep-\ntual issues to ensure appropriate interpretation of the\nEPDDv3 and address any potential concerns regarding\ncross-cultural adaptation before its potential use in pi-\nvotal trials. Independent translators assessed the trans-\nlatability of the 11-item EPDDv3 in 17 languages\n(Bulgarian, Dutch, English, French, German, Hungarian,\nItalian, Korean, Polish, Portuguese, Romanian, Russian,\nSimplified Chinese, Traditional Chinese, and Spanish\n[for Spain, US, and Argentina]) among 19 countries.\nWhen countries/languages are selected for the pivotal\ntrials, the full translation and linguistic validation\nprocess would be conducted for each language. Overall,\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 4 of 13\n\nresults from the translatability assessment demonstrated\nthat the EPDDv3 is a robust tool and has utility among\nall translated languages. No significant issues were\nidentified. Furthermore, additional regulatory feedback was\nobtained from the FDA and the EMA and a second item\nrefinement and generation meeting was held during which\nthe current version of the EPDD (EPDDv3) was developed.\nResults\nDevelopment of the EPDDv1\nThe EPDDv1 included 18 items in six categories: pelvic\npain (including dysmenorrhea and NMPP), dyspareunia\nand sexual activity, bleeding, hot flashes, daily activities,\nand rescue medication/protection. The EPDDv1 was\ndeveloped to be administered electronically with a 24-h\nrecall period. In the phase 2 TERRA trial, it was imple-\nmented with a small hand-held device.\nSemi-structured cognitive interviews for EPDDv1\nA total of 14 patients from the US participated in\nthe face-to-face, semi-structured cognitive interviews\nin three waves, with 4 –5 patients in each wave.\nDuring the first wave, wording modifications were\nmade to two instructions and 7 items of the\nEPDDv1. During the second wave, wording modifica-\ntions were made to one item. No modifications were\nmade during the third wave. Demographic data are\npresented in Table 1. Results from the Technology\nEase of Use Questionnaire indicated that the partici-\npating patients found the electronic hand-held device\nd i s p l a y i n gt h eE P D D v 1t ob ee a s yt ou s ea n dw e l l\nunderstood (T able 2).\nRevision of the EPDDv1; development of EPDDv2\nTargeted literature review\nA total of 30 peer-reviewed articles were retrieved from\nthe search; seven articles contained qualitative data. Five\ntypes of pain were identified, and bleeding and gastro-\nintestinal disturbance were also highlighted as being\nrelated to endometriosis.\nClinical expert interviews\nFive clinical experts were recruited from Europe\n(United Kingdom, n =1 ; G e r m a n y ,n = 2) and Japan\n(n = 2) and completed a semi-structured interview.\nInterviews with the Japanese experts were conducted\nin English via typed text to minimize language misin-\nterpretation. All five clinical experts highlighted the\nkey symptom of endometriosis as pain; specifically,\npain during menstruation, NMPP , pain during and\nafter sexual intercourse, and pain during defecation.\nPain during or after sexual intercourse was more\nassociated with ‘deep’ pain rather than ‘superficial ’\nTable 1 Demographics for US Patient Cognitive Interviews for\nthe EPDDv1\nCharacteristic US (N = 14)\nAge, years Mean (SD) 34.1 (6.8)\nHighest level of\neducation completed\nHigh school 3 (21.4)\nSome college 6 (42.9)\nBachelor’s degree 2 (14.3)\nGraduate or\nprofessional school\n3 (21.4)\nEthnicity White/Caucasian\n(non-Hispanic)\n13 (92.9)\nWhite/Caucasian\n(Hispanic)\n0\nBlack/African\nAmerican\n1 (7.1)\nHispanic or Latino 0\nGeneral health Excellent 1 (7.1)\nVery good 6 (42.9)\nGood 5 (35.7)\nFair 2 (14.3)\nPoor 0\nOver past month,\nendometriosis-related\npain severity during menstruation\n(0 = no pain to\n10 = worst pain imaginable)\nMean (SD) 7.2 (1.7)\nOver past month,\nendometriosis-related\npain severity not during menstruation\n(0 = no pain to\n10 = worst pain imaginable)\nMean (SD) 5.8 (1.6)\nAll data are presented as n (%) unless otherwise noted\nTable 2 Technology Ease of Use Questionnaire – Results from\nUS Patient Cognitive Interviews for the EPDDv1\nQuestionnaire Item Response Item n (%)\nHow easy/difficult did you\nfind using the electronic\nquestionnaire?\nVery easy 6 (42.9)\nQuite easy 3 (21.4)\nVery difficult –\nMissinga 5 (35.7)\nThe choices that were there\nto use when I answered\nthe questions were:\nEasy to read on the screen,\nno problem choosing\nmy response\n8 (57.1)\nA little difficult to read on\nthe screen, and I had some\ndifficulty in choosing\nmy response\n1 (7.1)\nMissinga 5 (35.7)\nOverall, did you find the\nelectronic questionnaire\nacceptable to use?\nYes 9 (64.3)\nNo –\nMissinga 5 (35.7)\naThe Technology Ease of Use Questionnaire was inadvertently not\nadministered to one wave of cognitive interviews (5 patients)\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 5 of 13\n\npain. A less common symptom not related to pain\nwas bleeding. All clinical experts stated that a primary\nconcern related to endometriosis is infertility. The\nmost common impacts on patients ’ daily lives, as\nperceived by clinical experts, were role functioning,\nespecially attendance at work and school, performance\nof daily activities, sexual function, and partner rela-\ntionships; missed work/school was consistently re-\nported as having the greatest impact.\nConcept elicitation interviews\nA total of 34 female patients were recruited from six US\nclinical sites and one Japanese market research firm;\ndemographic data are presented in Table 3.\nConcepts that are spontaneously expressed during the\nopen-ended portions of the interview can be considered\nto be of higher importance or relevance to the patient\nthan those expressed as a result of probing by the inter-\nviewer. Among US patients, the most common symp-\ntoms associated with endometriosis were ‘pain during\nmenstruation’ and ‘NMPP’, both spontaneously reported\nby 82.4% (14 of 17) of patients who reported these\nsymptoms (Table 4). Among Japanese patients, the most\ncommon symptoms associated with endometriosis were\nthe same, with ‘pain during menstruation ’ and ‘NMPP’\nspontaneously reported by 100% (17 of 17) and 76.5%\n(13 of 17) of patients who reported these symptoms,\nrespectively (Table 4).\nThe most common impacts associated with endomet-\nriosis were ‘problems doing physical activities ’, spontan-\neously reported by 70.6% of US patients ( n = 17) and\n64.7% of Japanese patients ( n =1 7 ) , a n d‘having prob-\nlems at work ’, spontaneously reported by 58.8% of US\npatients and 41.2% of Japanese patients. Japanese\npatients also commonly reported ‘dropping other daily\nactivities’ (41.2%) (Table 5).\nIntegrated findings\nTable 6 summarizes the findings from all three sources\nof evidence, the literature review, and the clinician and\npatient interviews. The findings show that there was\nconsistency from all three sources with regard to types\nof pain, but less overlap with other symptoms and their\nimpact on patients ’ lives.\nConceptual model of disease\nAnalysis of data obtained from the concept evaluation\nexercises (ie, literature review, expert interviews, and\npatient interviews) informed a conceptual model of\ndisease (Fig. 2), which served to facilitate the item\nrefinement and generation meeting. The conceptual\nmodel of endometriosis includes symptom concepts\nrelated to pain and vaginal bleeding during defecation\nand gastrointestinal disturbances, and expands on\nimpacts relating to sleep disturbances, physical func-\ntioning limitations, and social functioning limitations.\nDuring the item refinemen ta n dg e n e r a t i o nm e e t i n g ,\nthe EPDDv2 was developed based on this conceptual\nmodel to be fully comprehensive. The EPDDv2 con-\nsisted of 43 items comprising revised iterations of the\noriginal 18 items of the EPDDv1 and an additional 24\nitems related to pain/bleeding during defecation,\ngastrointestinal disturbance, and difficulties with func-\ntioning and/or sleep.\nCognitive testing of the EPDDv2; development of the\nEPDDv3\nPatients were recruited and screened at three US centers\n(Spokane, WA; Seattle, WA; New Orleans, LA) and\nthrough a market research firm in Tokyo, Japan. The\ncognitive interviews were conducted in four waves in the\nUS and three waves in Japan. Patient demographics are\npresented in Table 7.\nThe EPDDv2 items were tested in three waves of\ncognitive interviews in the US, and wording modifica-\ntions were made to items after each wave. During\nWave 1 (US), wording modifications were made to\nthree items pertaining to pain, sexual intercourse and\npain, and bleeding; no items were added or removed.\nDuring Wave 2 (US), wording modifications were\nmade to one item, and alternate questions for nine\nitems were proposed and tested in Wave 3. During\nWave 3 (US), one item was removed from the survey,\nand an alternate question was proposed for one other\nitem for further testing.\nThe EPDDv2 was then translated to Japanese and\ntested in two waves of interviews in Japan. The\nJapanese translation was slightly modified after each\nwave to ensure the accuracy and understandability of\nthe language used. Based on Japanese patient feed-\nback, translation modifications were necessary for the\nphrases ‘deep pain or penetration ’, ‘spotting’, ‘social\nactivities ’,s e x u a l ‘interest’,a n d ‘during the past 24 h ’,\nwhich are not common terminology in Japan. Four\nitems were evaluated and found to be better under-\nstood by patients and subsequently replaced the\noriginal items.\nFollowing the two waves of interviews in Japan, and\nbased on feedback from the FDA and EMA regarding\nthe length of the survey, the EPDDv2 was reduced from\n43 to 11 items consisting of five core items relating to\ndysmenorrhea, NMPP , and dyspareunia, and six ex-\ntended items relating to sexual activity, daily activities,\nand use of rescue medication, yielding the EPDDv3. This\n11-item EPDDv3 was evaluated in a third wave of inter-\nviews in Japan and the fourth wave of interviews in the\nUS. During Wave 3 of the Japanese interviews,\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 6 of 13\n\nTable 3 Demographics for US and Japanese Patient Concept Elicitation Interviews\nCharacteristic US (N = 17) Japan ( N = 17)\nAge, years Mean (SD) 30.5 (6.6) 41.1 (5.0)\nMarital status Married 5 (29.4) 13 (76.5)\nLiving with partner 4 (23.5) 0\nDivorced 2 (11.7) 2 (11.8)\nNever married 6 (35.2) 2 (11.8)\nHighest level of education completed High school 1 (5.9) 1 (5.9)\nSome college 8 (47.1) 8 (47.1)\nBachelor’s degree 3 (17.6) 7 (41.2)\nGraduate or professional school 5 (29.4) 1 (5.9)\nCurrent employment status Not employed outside of home 2 (11.8) 2 (11.8)\nEmployed full-time 8 (47.1) 6 (35.3)\nEmployed part-time 3 (17.6) 1 (5.9)\nRetired 0 1 (5.9)\nNot employed 4 (23.5) 7 (41.2)\nEthnicity White/Caucasian (non-Hispanic) 14 (82.4) –\nWhite/Caucasian (Hispanic) 2 (11.7) –\nHispanic or Latino 1 (5.9) –\nGeneral health Excellent 0 1 (5.9)\nVery good 6 (35.2) 4 (23.5)\nGood 8 (47.0) 8 (47.1)\nFair 3 (17.6) 4 (23.5)\nOver past month, endometriosis-related pain\nseverity during menstruation\n(0 = no pain to 10 = worst pain imaginable)\nMean (SD) 7.3 (1.5) 6.9 (1.9)\nMedian 7.0 7.0\nRange 4 –10 5 –10\nOver past month, endometriosis-related pain\nseverity not during menstruation\n(0 = no pain to 10 = worst pain imaginable)\nMean (SD) 5.9 (1.4) 3.2 (2.3)\nMedian 5.0 3.0\nRange 4 –90 –7\nAll data are presented as n (%) unless otherwise noted\nTable 4 Symptoms Associated With Endometriosis\nSymptom Spontaneous Probed Not Affected Not reported\nUS Japan US Japan US Japan US Japan\nPain during menstruation 14 (82.4) 17 (100) 2 (11.7) –– – 1 (5.9) –\nNMPP 14 (82.4) 13 (76.5) 2 (11.7) 2 (11.8) – 1 (5.9) 1 (5.9) 1 (5.9)\nSuperficial vaginal pain during sexual intercourse 1 (5.9) 1 (5.9) –– 15 (88.2) 16 (94.1) 1 (5.9)\nDeep vaginal pain during sexual intercourse 1 (5.9) – 2 (11.7) 9 (52.9) 10 (58.8) 7 (41.2) 4 (23.5) 1 (5.9)\nSuperficial vaginal pain after sexual intercourse 1 (5.9) – 1 (5.9) 1 (5.9) – 15 (88.2) 15 (88.2) 1 (5.9)\nDeep vaginal pain after sexual intercourse 3 (17.6) 1 (5.9) 7 (41.2) 4 (23.5) 3 (17.6) 10 (58.8) 4 (23.5) 2 (11.8)\nOther symptomsa 10 (58.8) 3 (17.6) NA –– – 7 (41.2) 14 (82.4)\nAll data are presented as n (%)\nNMPP, non-menstrual pelvic pain\naOther symptoms spontaneously offered by US patients: ache in lower back; back aches; bloating; bowel; dull achy; exhaustion; headache; heavy menstrual flow;\nheavy periods; hot flashes/night sweats; lower back ache; nausea; ovary in pain before sex; pain after sexual intercourse in pelvic area; painful bowel movements;\nrectal bleeding; sharp stabbing pain left lower abdomen; stabbing pain around right ovary; vomiting; and warming sensation\nOther symptoms spontaneously offered by Japanese patients: watching TV suddenly have pain (pain at all times); heaviness lie on side lower back (stomach);\nheavy bleeding/anemia/dizzy/squeezing pain in stomach-used to be around back feel that uterus being pulled down (clots)\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 7 of 13\n\ntranslation modifications were made to 12 items and\nwording modifications were made to two items. During\nWave 4 of the US interviews, all patients confirmed\ncomprehension of all items. After the final wave of inter-\nviews, the EPDDv3 was sent for translation and linguis-\ntic validation into 17 languages (including Japanese).\nThe EPDDv3 is displayed in Table 8, and a comparison\nof the items included in the EPDDv1 and EPDDv2 is\ndisplayed in Table 9.\nDiscussion\nIn the absence of a fit-for-purpose PRO for the measure-\nment of endometriosis-related pain, we developed an\ninstrument to support evaluation of biopharmaceutical\nproducts and to measure key signs and symptoms associ-\nated with endometriosis. To accomplish this, a conceptual\nmodel of endometriosis and the EPDD was developed on\nthe basis of three sources of evidence: a structured litera-\nture review, clinical expert opinion, and qualitative patient\nconcept elicitation interviews. In addition, translation and\nlinguistic validation and patient cognitive interviews facili-\ntated the refinement of the items to ensure patient com-\nprehension and understanding, as well as the ability to\nrespond to items as intended. Through these exercises,\nthe items of the EPDD were revised and refined to ensure\nrelevance to patient pain experience as well as compre-\nhension by patients as intended. Translation and testing\nin Japanese patients allowed for development of a harmo-\nnized instrument.\nThe EPDD resulting from this content validity work\nconsists of five core items relating to dysmenorrhea,\nNMPP , and dyspareunia, and six extended items relating\nTable 5 Impacts Associated With Endometriosis\nSymptom Spontaneous Probed Not Affected Missing\nUS Japan US Japan US Japan US Japan\nProblems doing physical activities 12 (70.6) 11 (64.7) 4 (23.5) 2 (11.8) 1 (5.9) 1 (5.9) – 3 (17.6)\nAffecting other daily activities 6 (35.3) 7 (41.2) 7 (41.2) 7 (41.2) 4 (23.5) 2 (11.8) – 1 (5.9)\nExperience difficulties during or after sexual intercourse\n(changes in relationship with partner)\n8 (47.1) 7 (41.2) 5 (29.4) 5 (29.4) 4 (23.5) 4 (23.5) – 1 (5.9)\nDoing fewer social activities\n(seeing friends and acquaintances less often)\n9 (52.9) 2 (11.8) 7 (41.2) 2 (11.8) 1 (5.9) 12 (70.6) – 1 (5.9)\nHaving problems doing your daily chores at home\n(cleaning, cooking, house maintenance)\n3 (17.6) 4 (23.5) 10 (58.8) 10 (58.8) 4 (23.5) 2 (11.8) – 1 (5.9)\nHaving problems at work\n(with people or with getting your work completed)\n10 (58.8) 6 (35.3) 3 (17.6) 8 (47.1) 4 (23.5) 2 (11.8) – 1 (5.9)\nOther impactsa 12 (70.6) 10 (58.8) NA –– – 5 (29.4) 7 (41.2)\nAll data are presented as n (%)\naOther impacts spontaneously offered by US patients: avoid work out; competitive runner; depression; family life (taking care of her daughter); fatigue; fertility –\nability to have children; having another child; irritable relationship; lifting children; limit time away from home; low libido; medical issue stomach; school; sleep;\nsleep a lot; thinking about having hysterectomy; and tiredness\nOther impacts spontaneously offered by Japanese patients: bowel movement; [have] to stay in bed for 2 days; can ’t [fall] asleep; financial travel plan; avoid those\ntimes (intercourse pain, ovulation period, bowel movement pain); [have] to take a day off in school (past); lying down (sideways); lying down; have to rest; leave\nher alone not to be disturbed; not able to sit; prefer to stay in bed; cannot keep standing especially on Day 1\nTable 6 Key Concepts Identified in Literature, and Expert and\nPatient Interviews\nConcept Literature\nReview\nExpert\nInterviews\nPatient\nInterviews\nPain during menstruation ✓✓ ✓\nPain during/after sexual intercourse ✓✓ ✓\nPain unrelated to sex and/or\nmenstruation (pelvic, back,\ngeneral, headache)\n✓✓ ✓\nPain during defecation ✓✓ ✓\nPain during urination ✓\nOther non-pain symptoms\n(bloating, dizziness, nausea, vomiting)\n✓\nInfertility ✓\nBleeding (during menstruation, sex,\nor irregular)\n✓✓\nGastrointestinal disturbance\n(diarrhea, constipation, flatulence)\n✓\nWork/school limitations ✓✓ ✓\nSexual activity limitations ✓✓ ✓\nDifficulty doing daily activities ✓✓ ✓\nDifficulty doing leisure activities ✓✓\nPhysical activity limitations ✓✓\nSocial/lifestyle limitations ✓✓\nRelationships affected ✓✓ ✓\nEmotional health ✓✓ ✓\nSleep difficulties ✓\nLow energy difficulties ✓\nCoping behaviors ✓\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 8 of 13\n\nto sexual activity, daily activities, and use of pain medi-\ncation, and will serve as a daily, electronic, patient-\nreported measure of endometriosis-related pain. In\nparticular, the instrument was designed and developed\nfor the purpose of detecting a treatment response in the\ncontext of drug development. Content validity of the\nEPDD was demonstrated via a rigorous process consis-\nting of several waves of cognitive interviews. In addition,\nthe translatability assessment confirmed its utility in 17\nlanguages, allowing for the potential use of the EPDD in\nglobal clinical trials in endometriosis. The 17 languages\nincluded in the translatability assessment were chosen\nbased on anticipated countries that would be selected\nfor enrollment in future phase 3 clinical trials. If any of\nthose countries/languages are selected, then a full\ntranslation and linguistic validation process would be\nconducted for each language. The phase 2 TERRA study,\na double-blind, randomized, parallel-group, placebo-\ncontrolled clinical trial, used the EPDD to assess the\nefficacy of a GnRH receptor antagonist, ASP1707, in\nwomen with endometriosis-associated pelvic pain. To\ndetermine a clinically meaningful threshold of improve-\nment, as measured by the EPDD, anchor-based analyses\nof the degrees of improvement in endometriosis-related\npain on the Patient Global Impression of Change, the\nBrief Pain Inventory, the modified Biberoglu and\nBehrman, and the European quality of life 5-dimension\n5-level scale were performed using the EPDDv1. Results\nsuggested that an improvement of 60% (for overall pelvic\npain and NMPP) and 70% (for dysmenorrhea), as mea-\nsured by the EPDD, would be considered clinically\nmeaningful (TERRA; NCT01767090). The successful\ncompletion of this study, which achieved its primary\nendpoint of reducing endometriosis-associated pelvic\npain after 12 weeks of treatment, demonstrates the in-\nternal validity and reliability of the EPDDv1 in a clinical\ntrial context.\nThe PRO reported here has three key advantages\nover existing measures. First, to our knowledge, the\nEPDD is the only PRO for endometriosis-related pain\nthat was developed in accordance with guidance set\nSigns/Symptoms\nBleeding & Spotting\n Related to menstruation\n Menorrhagia\n Oligomenorrhea\n Polymenorrhea\n Not related to menstruation\n During/after intercourse\n During/after defecation\nTarget Patient Population\nPatients with\nendometriosis-related pain  \nDisease Process\nEndometriosis is a condition \nin which endometrial tissue \ngrows outside the uterus. \nThese extra-uterine implants \nrespond to endogenous cyclic \nhormone fluctuations, which \ninduce menstrual bleeding of \nthe implants and lead to \nchronic inflammation.\nImpacts\nEndometriosis-associated pain\n Menstrual pain\n Non -menstrual pain\n– Pain associated with sexual intercourse \n(during/after)\n– Pain associated with defecation\n(during/after)\n– Other non-menstrual pain\nIntermittent/periodic & continuous/constant\nPelvic area pain & non-pelvic area pain\nInfertility\nPhysical functioning limitations\n(including sexual functioning)\nRole functioning limitations\n(including ADL, work)\nEmotional functioning limitations\n(including depression/anxiety, \nstress, self-esteem)\nSocial functioning limitations\n(including leisure activities, sexual \npartner(s), other relationships)\nSleep difficulties\nTired/low \nenergy\nMood \nchanges\nConcen-\ntration\nFig. 2 Conceptual Model of Endometriosis\nNote: Symptoms not related to pain (eg, bleeding, hot flashes, infertility) and impacts not expected to change week by week were not included\nin the EPDDv3 based on regulatory feedback and additional decisions made in a final item refinement and generation meeting held prior to the\ndevelopment of EPDDv3. ADL, activities of daily living\nTable 7 Demographics for US and Japanese Patient Cognitive\nInterviews for the EPDDv2\nCharacteristic US (N = 16) Japan ( N =1 5 )\nAge, years Mean (SD) 33.2 (6.3) 34.9 (6.4)\nMedian 33.0 35.0\nRange 24–43 24 –44\nHighest level of\neducation completed\nHigh school – 7 (46.7%)\nSome college 9 (56.3%) 3 (20.0%)\nBachelor’s degree 5 (31.3%) 5 (33.3%)\nGraduate or\nprofessional school\n2 (12.5%) –\nWorst endometriosis-\nrelated pain during\nmenstruation: (0 = no\npain to 10 = worst pain\nimaginable)\nMean (SD) 8.0 (1.2) 7.5 (1.6)\nMedian 8.0 8.0\nRange 6–10 4 –10\nWorst endometriosis-\nrelated pain when not\nmenstruating: (0 = no\npain to 10 = worst\npain imaginable)\nMean (SD) 5.6 (1.7) 4.8 (2.9)\nMedian 5.5 5.0\nRange 2–90 –9\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 9 of 13\n\nforth by the EMA and FDA. Second, the electronic\nformat allows for convenient, real-time completion of\nthe instrument by the patient, without the require-\nment for involvement of investigative research site\nstaff. Third, the requirement for daily entry ensures\naccurate data collection and precludes inaccuracies\nassociated with lengthy recall periods. Conversely,\nlimitations of the EPDD are noteworthy and should\nbe considered. As the instrument was designed specif-\nically for use in clinical trials for the assessment of\npatient response to treatment, important items relat-\ning to patient personal experience with endometriosis\n(ie, work impairment, hot flashes, impact on sleep)\nwere removed from the final version. In addition, the\nEPDD does not address pain during defecation or exer-\ncise, or other non-pain symptoms that are important to\npatients, such as bloating, dizziness, nausea, vomiting,\ndifficulties with physical functioning, work/school li-\nmitations, relationship interference, or emotional func-\ntioning (although many of these were measured in the\ninterim EPDDv2). Together, these characteristics limit the\nuse of the EPDD within clinical practice; however, oppor-\ntunities exist for expansion of the EPDD to broaden its\nclinical application.\nAlthough the EPDDv3 can be considered content\nvalid, the remaining psych ometric properties of the\ninstrument, including reliability, construct validity,\nand ability to detect change have not been\nestablished. Such psychometric data and quantitative\nvalidation can be obtained through the administra-\ntion of the EPDD with other validated PRO\nmeasures (eg, Patient Global Impression of Change)\nin a longitudinal intervention study, and are required\nfor endorsement (eg, FDA) of the EPDD as fit-for-\nTable 8 Full Version of the EPDDv3\n# Item / instruction Response options Logic\nEPDDv3 (core)\n1 The first questions are about vaginal bleeding or spotting that could happen during your period or between periods\n1a During the past 24 h, did you have any vaginal bleeding or spotting? Checklist:\nYes or No\nIf no, go to Section 2\n1b During the past 24 h, have you been on your period? Checklist:\nYes or No\nn/a\n2 The next question is about pain. Please be sure to think only about pain related to your endometriosis when answering this question.\n2a During the past 24 h, at its worst, how severe was your endometriosis-related pain? Numeric rating scale:\n0 (No pain) to 10\n(worst pain imaginable)\nn/a\n3 The next questions are about sexual activity and pain. When answering, think only about pain that occurs during vaginal penetration.\n3a During the past 24 h, did you engage in any sexual activity that involved full vaginal\npenetration?\nChecklist:\nYes or No\nIf no, go to item 3c\n3b During the past 24 h, at its worst, how would you rate your level (degree) of pain felt\nduring or following vaginal penetration?\nNumeric rating scale:\n0 (No pain) to 10\n(worst pain imaginable)\nn/a\nNote: Question only asked if\nanswer to question 3a is yes\nEPDDv3 (extended)\n3c During the past 24 h, did you choose not to have any sexual activity that involved\nfull vaginal penetration for any reason, even though you had the chance?\nChecklist:\nYes or No\nIf no, go to item 3e\n3d During the past 24 h, did you choose not to have any sexual activity that involved\nfull vaginal penetration because of your endometriosis?\nChecklist:\nYes or No\nn/a\nNote: Question only asked if\nanswer to question 3c is yes\n3e During the past 24 h, did your desire toward sexual intimacy decrease due to your\nendometriosis?\nChecklist:\nYes or No\nn/a\n4 The following questions are about your daily activities during the past 24 h.\n4a During the past 24 h, how difficult has it been to do your daily activities? Numeric rating scale:\n0 (not difficult) to 10\n(extremely difficult)\nn/a\n5 On the next screens you will be asked to record the medication you took for your endometriosis-related pain.\n5a During the past 24 h, did you use your rescue medication for your endometriosis-\nrelated pain?\nChecklist:\nYes or No\nIf yes, go to item 5b\nIf no, end\n5b During the past 24 h, how many tablets of your rescue medication did you use? Spinner range 0 –20 n/a\nNote: Screen only displayed if\nanswer to question 5a is yes\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 10 of 13\n\nTable 9 Items of the EPDD v1 and v2\nEPDDv1 EPDDv2\nPelvic pain (including dysmenorrhea & NMPP)\nDuring the past 24 h, did you have any vaginal bleeding or spotting? During the past 24 h, did you have any vaginal bleeding or spotting?\nDuring the past 24 h, have you been menstruating (vaginal bleeding or\nspotting during your period)?\nDuring the past 24 h, have you been menstruating (vaginal bleeding or\nspotting during your period)?\nDuring the past 24 h, at its worst, how severe was your endometriosis-\nrelated pain?\nDuring the past 24 h, at its worst, how severe was your endometriosis-\nrelated pain?\n– Was the pain you experienced during the past 24 h:\n1. Stable (constant pain that doesn ’t change much, and never pain free).\n2. Intermittent (I feel pain sometimes, but other times I ’m pain-free)\n3. Variable ( “background” pain all the time, but sometimes pain is worse\nthan at other times)\nDyspareunia and sexual activity\nDuring the past 24 h, did you have sexual intercourse or engage in any\nsexual activity that involved full vaginal penetration?\nDuring the past 24 h, did you have sexual intercourse or engage in any\nother sexual activity that involved full vaginal penetration?\nDuring the past 24 h, at its worst, how would you rate your level\n(degree) of pain at the entrance of the vagina during or following\nvaginal penetration?\nDuring the past 24 h, at its worst, how would you rate your level\n(degree) of pain at the entrance of the vagina during or following\nvaginal penetration?\nDuring the past 24 h, at its worst, how would you rate your level\n(degree) of pain felt DEEP in your vagina during or following DEEP\nvaginal penetration?\nDuring the past 24 h, at its worst, how would you rate your level\n(degree) of pain felt DEEP in your body during or following DEEP\nvaginal penetration?\n– During the past 24 h, did you avoid sexual intercourse?\nDuring the past 24 h, did you avoid sexual intercourse because of\nyour endometriosis?\nYou said you avoided sexual intercourse in the past 24 h. During the past\n24 h, did you avoid sexual intercourse because of your endometriosis?\n– During the past 24 h, did you feel a decreased interest in sexual intimacy?\nPain during defecation\n– During the past 24 h, did you have one or more bowel movements?\n– During the past 24 h, at its worst, how severe was the pain when you\nhad a bowel movement?\nBleeding\nYou said you had been menstruating during the past 24 h. On average,\nhow heavy was this bleeding or spotting compared to your usual\nmenstruation?\nYou said you had been menstruating during the past 24 h. On average,\nhow heavy was this bleeding or spotting compared to your usual\nmenstruation?\nDuring the past 24 h, did you have any vaginal bleeding or spotting\nrelated to sexual activity that involved full vaginal penetration?\nDuring the past 24 h, did you have any vaginal bleeding or spotting\nrelated to sexual activity that involved full vaginal penetration?\nYou said you had vaginal bleeding or spotting related to sexual activity\nduring the past 24 h. On average, how heavy was this bleeding or\nspotting compared to your usual menstruation?\nYou said you had vaginal bleeding or spotting related to sexual activity\nduring the past 24 h. On average, how heavy was this bleeding or\nspotting compared to your usual menstruation?\n– During the past 24 h, did you have any vaginal bleeding or spotting\nrelated to one or more bowel movements?\n– You said you had vaginal bleeding or spotting related to one or more\nbowel movements during the past 24 h. On average, how heavy was this\nbleeding or spotting compared to your usual menstruation?\nDuring the past 24 h, did you have any vaginal bleeding or spotting,\nnot related to menstruation? (Please do not include vaginal bleeding or\nspotting related to sexual activity that involved full vaginal penetration)\nDuring the past 24 h, did you have any other vaginal bleeding or\nspotting, not related to menstruation? (Please do not include vaginal\nbleeding or spotting related to bowel movements or sexual activity that\ninvolved full vaginal penetration)\nYou said you had other vaginal bleeding or spotting during the past\n24 h that was not due to your period or sexual activity or bowel\nmovements. On average, how heavy was this bleeding or spotting\ncompared to your usual menstruation?\nYou said you had other vaginal bleeding or spotting during the past\n24 h that was not due to your period or sexual activity or bowel\nmovements. On average, how heavy was this bleeding or spotting\ncompared to your usual menstruation?\nHot flashes\nDuring the past 24 h, did you have any hot flashes? During the past 24 h, did you have any hot flashes?\nDuring the past 24 h, how many hot flashes did you have? During the past 24 h, how many hot flashes did you have?\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 11 of 13\n\npurpose for use in clinical trials of endometriosis\ninterventions.\nConclusions\nThe EPDD is a PRO for the evaluation of endometriosis-\nrelated pain. The EPDD represents an important step in\nproviding an effective PRO to evaluate pain associated\nwith endometriosis and its related impacts on patients.\nAbbreviations\nADL: activities of daily living; CHMP: Committee for Medicinal Products for\nHuman Use; CPSSS: Composite Pelvic Signs and Symptoms Score;\nEHP: Endometriosis Health Profile; EMA: European Medicines Agency;\nEPBD: Endometriosis Pain and Bleeding Diary; EPDD: Endometriosis Pain\nDaily Diary; FDA: Food and Drug Administration; NMPP: non-menstrual pelvic\npain; PRO: patient-reported outcome; US: United States\nAcknowledgments\nWe thank SuccinctChoice Medical Communications (Chicago, IL) for medical\nwriting and editorial assistance funded by Astellas Pharma Inc.\nFunding\nThis study was performed and funded by Astellas Pharma Inc.\nAvailability of data and materials\nAll data supporting the results and conclusions presented herein are\nincluded in this published article.\nAuthors’ contributions\nAll authors made substantial contributions to the study design. JC, FEVN, CAE,\nand JP: acquisition of data. JC, FEVN, MR, and CAE: analysis and interpretation of\nthe data. All authors were involved in drafting of the manuscript or revising it\ncritically for important intellectual content, approved the final version to be\npublished, and agreed to be accountable for all aspects of the work in ensuring\nthat questions related to the accuracy or integrity of any part of the work are\nappropriately investigated and resolved.\nEthics approval and consent to participate\nInstitutional review board approval for the study protocol, the informed\nconsent form, and data collection forms for interviews with patients in the\nUS was provided by Quorum Review (Seattle, WA).\nConsent for publication\nNot applicable.\nTable 9 Items of the EPDD v1 and v2 (Continued)\nEPDDv1 EPDDv2\nDaily activities\nDuring the past 24 h, how much did your endometriosis-related pain\ninterfere with your daily activities?\nDuring the past 24 h, how difficult has it been to do your daily activities ?\n– During the past 24 h, have you walked?\n– During the past 24 h, how difficult has it been to walk?\n– During the past 24 h, have you exercised?\n– During the past 24 h, how difficult has it been to exercise?\n– During the past 24 h, have you done any social activities?\n– During the past 24 h, how difficult has it been to do social activities?\n– During the past 24 h, have you done any leisure activities?\n– During the past 24 h, how difficult has it been to do leisure activities?\n– During the past 24 h, have you done any household activities?\n– During the past 24 h, how difficult has it been to do household activities?\n– During the past 24 h, have you done any work or school activities?\n– During the past 24 h, how difficult has it been to do work or school activities?\n– Do you have a spouse/partner?\n– During the past 24 h, how difficult has your relationships been with your\npartner?\n– During the past 24 h, how difficult have your relationships been with\nother important people in your life, e.g., family, friends, people at work?\n– During the past 24 h, how difficult has it been to wash or dress yourself?\n– During the past 24 h, how difficult has it been to fall asleep?\n– During the past 24 h, how difficult has it been to stay asleep?\nRescue medication/protection\nDuring the past 24 h, how many sanitary products (panty liners, pads\nor tampons) did you use for any type of vaginal bleeding?\nDuring the past 24 h, how many sanitary products (panty liners, pads or\ntampons) did you use for any type of vaginal bleeding?\nDuring the past 24 h, did you use your rescue medication for your\nendometriosis-related pain?\nDuring the past 24 h, did you use your rescue medication for your\nendometriosis-related pain?\nDuring the past 24 h, how many tablets of your rescue medication did\nyou use?\nDuring the past 24 h, how many tablets of your rescue medication did\nyou use?\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 12 of 13\n\nCompeting interests\nFloortje E. van Nooten was employed by Astellas at the time of work. Jen\nCline, Celeste A. Elash, Jean Paty, and Matthew Reaney were employed by\nERT at the time of this work; Jean Paty was also employed by Quintiles.\nPublisher’sN o t e\nSpringer Nature remains neutral with regard to jurisdictional claims in\npublished maps and institutional affiliations.\nAuthor details\n1Astellas Pharma, Leiden, the Netherlands. 2PinneyAssociates, 201 N. Craig\nstreet, suite 320, Pittsburgh, PA 15213, USA. 3ERT, 225 W Station Square Dr,\nSte 220, Pittsburgh, PA 15219, USA. 4Quintiles IMS Incorporated, One IMS\nWay, Plymouth Meeting, PA 19462, USA. 5ERT, Peterborough PE2 6FZ, UK.\nReceived: 13 July 2017 Accepted: 30 November 2017\nReferences\n1. Kennedy S, Bergqvist A, Chapron C, D ’Hooghe T, Dunselman G, Greb R, et\nal. ESHRE guideline for the diagnosis and treatment of endometriosis. 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Principles of good practice for the translation and cultural\nadaptation process for patient-reported outcomes (PRO) measures:\nreport of the ISPOR task force for translation and cultural adaptation.\nValue Health. 2005;8:94 –104.\n18. Muhr T. User's manual for ATLAS.Ti 5.0. Berlin: ATLASti Scientific Software\nDevelopment GmbH; 2004.\n•  We accept pre-submission inquiries \n  Our selector tool helps you to find the most relevant journal\n  We provide round the clock customer support \n  Convenient online submission\n  Thorough peer review\n  Inclusion in PubMed and all major indexing services \n  Maximum visibility for your research\nSubmit your manuscript at\nwww.biomedcentral.com/submit\nSubmit your next manuscript to BioMed Central \nand we will help you at every step:\nvan Nooten et al. Health and Quality of Life Outcomes  (2018) 16:3 Page 13 of 13","source_license":"CC0","license_restricted":false}