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Auteurs:
Kellee Howard, Daniel Adelman, Sonal Ghura, Sarah Acaster, Sarah Clifford, Ciaran P. Kelly, Susan A. Martin, Lisa M. Meckley, Daniel A. Leffler
Qualitative and quantitative studies were conducted from 2010 to 2021, including concept elicitation and cognitive debriefing interviews with adult and adolescent participants with CeD (N = 93) diagnosed via biopsy and/or serology and input from eight interviews with CeD clinical experts. During these studies, different iterations of the CDSD were presented to the US Food and Drug Administration and the European Medicines Agency, and modifications were made in line with their feedback.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Introduction
Celiac disease (CeD) is a chronic immune-mediated disorder triggered by the ingestion of gluten in genetically predisposed individuals. CeD has a global prevalence of approximately 1% with reported regional prevalence ranging from 0.5% to 1.4% in the USA and 0.7% to 1.3% in Europe [1‐3].
CeD is characterized by damage to the small intestine and symptoms can include abdominal pain, diarrhea, constipation, vomiting/nausea, bloating/flatulence, fatigue, headaches and joint pain [1, 4]. Complications of CeD are diverse and include malabsorption and malnutrition, anemia, osteoporosis, neurological symptoms, dermatitis herpetiformis, infertility and certain hematological malignancies [1, 4].
The only current management option available for CeD is adherence to a lifelong strict gluten-free diet (GFD); however, many patients continue to experience symptoms and/or intestinal injury owing to inadvertent gluten exposure as well as having a substantial burden imposed by adhering to a strict GFD [2, 4, 5]. CeD symptoms have been shown to have a significant effect on patients’ health-related quality of life (HRQoL) [6, 7]. Studies conducted with adults and adolescents to develop a conceptual model of the impact of CeD revealed the negative impact that CeD symptoms can have on physical functioning, sleep, daily activities, social activities, emotional functioning and relationships [5]. For those patients who respond well to a GFD, despite a reduction in symptoms, many report a persistent impact of CeD on their HRQoL owing to anxiety around inadvertent gluten exposure and lifestyle impacts of adhering to a GFD [5, 8].
To address the unmet need for effective therapies for patients with CeD on a GFD, several treatment options are under development and validated patient-reported outcome (PRO) measures are required to evaluate their efficacy [9]. To comply with the stringent guidelines from regulators on methods for the evaluation of treatment benefits and effectiveness, a fit-for-purpose CeD PRO measure must demonstrate content validity, construct validity and an ability to detect change in relevant symptoms of CeD in the target population [10‐12].
Several PRO measures have previously been used to measure the benefit of potential CeD treatments: Celiac disease-specific modification of the Gastrointestinal Symptoms Rating Scale (GSRS); Psychological General Well-Being (PGWB) Index; Celiac Disease Patient Reported Outcome (CeD PRO); Coeliac Disease Quality of Life (CD QoL) survey; Coeliac Disease Assessment Questionnaire (CDAQ); and Celiac Symptom Index (CSI) [13, 14]. Although some of these PRO measures contain items that evaluate important concepts in CeD, the majority have not been fully developed to meet the stated expectations of the US Food and Drug Administration (FDA) for regulatory purposes [14, 15].
Symptom-related PRO measures are generally accepted as appropriate primary or co-primary endpoints in CeD clinical studies because active CeD is often associated with a high symptom burden [16, 17]. In a draft guidance document from the FDA on the development of drugs for CeD as adjunctive treatment to a GFD (published in April 2022), it is recommended that clinical outcome assessments in CeD clinical trials include a PRO instrument that measures the core signs and symptoms of CeD with daily assessments (24-h recall period) as co-primary endpoints with histology measures, and HRQoL impacts as secondary endpoints [18].
FDA guidelines describe the iterative process that should be followed during PRO instrument development [11]. A preliminary PRO instrument should be developed on the basis of a conceptual framework of the disease (derived from literature and expert reviews and modified as required after patient input) and tested in a relevant patient population to assess content validity and confirm understanding of instructions and appropriate responses to the questions. In response to feedback from qualitative patient interviews and regulatory agencies, the instrument should be modified as required (e.g. changes to items, wording, response options, scoring and recall period). The modified instrument should then be re-assessed in further qualitative patient interviews and this process repeated until the instrument is deemed fit-for-purpose by all stakeholders.
This article describes the historical development and iterative modification of the Celiac Disease Symptom Diary (CDSD), a daily diary that focuses on the key symptoms of CeD including abdominal pain, bloating, diarrhea, nausea and tiredness. During development, different iterations of the CDSD were presented to the FDA and the European Medicines Agency (EMA); modifications to the measure were made in line with their feedback, with the ultimate aim of using the CDSD as a primary endpoint in registrational trials of new CeD therapies.
CDSD development stages. CD cognitive debriefing, CDSD celiac disease symptom diary, CE concept elicitation, EMA, European medicines agency, FDA food and drug administration
Development of the CDSD was initiated in 2010 with concept elicitation interviews conducted with participants with biopsy-confirmed CeD (N = 21) and input from clinical experts (N = 5; four US gastroenterologists and one US registered dietitian specializing in CeD); Fig. 1. Concept saturation for the common and less-frequently reported symptom groups was reached by the sixth and twentieth interviews, respectively; see Online Resource Abstract 1 for full details. Eleven symptoms were spontaneously reported by participants with CeD: abdominal pain, bloating, cognitive difficulties, constipation, diarrhea, fatigue/tiredness, headache, nausea, passing gas, joint pain and skin rash. Clinical experts subsequently endorsed 10 out of 11 of these symptoms but recommended that joint pain be removed because it was not considered to be reliably attributable to CeD and gluten exposure. This resulted in a draft 10-item PRO measure that measured symptom severity using a scale of 0–10 of ‘no pain’ to ‘worst imaginable pain’ for abdominal pain and headache, or a 5-point Likert scale of ‘very mild’ to ‘very severe’ for boating, constipation, diarrhea, nausea, skin rash and tiredness. A 5-point scale of ‘not at all’ through to ‘completely’ was used to measure cognitive difficulties/difficulty thinking clearly and impact of symptoms on activities and sleep. The frequency of diarrhea (with descriptive options for stool consistency) and spontaneous bowel movements was measured using a numerical scale. This preliminary CDSD was designed to be administered via an interactive voice recognition system (IVRS) with a 24-h recall period.
The preliminary CDSD was subsequently reviewed in cognitive debriefing interviews in participants with CeD (N = 15) to confirm concept relevance and to assess any ambiguities in meaning and interpretation. These interviews identified some areas of ambiguity within the diarrhea and constipation items. Although the term ‘diarrhea’ was understood with the descriptor ‘loose stool,’ there was uncertainty around the conceptual linkage with severity. Likewise, ‘constipation’ was understood by all participants, but the term ‘successful bowel movement’ in the follow-up question was not understood. Therefore, 10 supplemental qualitative interviews were conducted in which participants’ understanding of diarrhea severity and interpretation and relevance of the constipation item were specifically explored. An initial psychometric study of the CDSD was also conducted in participants with biopsy-confirmed CeD (N = 202) recruited at three US clinical sites (Beth Israel Deaconess Medical Centre, Boston; Mayo Clinic, Minnesota; or Columbia University, New York). Passing gas, abdominal pain, fatigue and bloating were the most commonly endorsed symptoms across all 7 days of the psychometric study. This study also indicated a poor sensitivity in discriminating between different levels of symptom severity related to constipation/unsuccessful bowel movements, abdominal pain and diarrhea.
At this stage, the FDA did not evaluate content validity of the draft measure and stated that an adequately established and portrayed conceptual framework for CeD would be required to confirm content validity. Studies to support the development of a conceptual model for CeD were undertaken and subsequently reported by Leffler et al. in 2017 [5].
The FDA also recommended replacing the word ‘fatigue’ with ‘tiredness’ and suggested that the wording related to spontaneous bowel movements, diarrhea and bloating be refined and/or definitions be included to clarify their meaning (pending further qualitative studies). In response, further clarifications were made to the wording of the CDSD. The questionnaire was also modified such that the constipation item was skipped if a patient answered ‘yes’ to experiencing diarrhea or spontaneous complete bowel movements.
The FDA also recommended that reference to CeD be removed when asking patients about a specific symptom, because patients should be asked to report on a symptom without having to make an assessment concerning its cause or origin. This change was also accepted and implemented.
For some of the response options it was unclear to the FDA whether or not patients could reliably distinguish between ‘very mild’ and ‘mild’ or between ‘very severe’ and ‘severe.’ The FDA also deemed that the scoring algorithm was inadequate because response options were transformed to a 0–10 scale that resulted in assigning a score of zero for very mild or infrequent symptoms (e.g. having diarrhea once or twice). The FDA suggested that a score of zero should be used to indicate the absence of a symptom and further assessment of the response options was recommended by the FDA to implement the necessary refinements. The FDA also indicated that the original number of questions included would be too burdensome for a daily diary and reiterated that removal of non-GI symptom items would help to reduce respondent burden.
After modifications of the CDSD in response to the above FDA feedback, the resulting PRO measure had 6 items with response options that included a numerical scale (0–10) for abdominal pain, a 5-point Likert scale (very mild to very severe) for bloating, nausea and tiredness, and frequency options (once to ≥ 10 times) for diarrhea and spontaneous bowel movement.
The FDA also suggested that the severity scales and frequency options should not be combined into a single score (in particular, that diarrhea frequency and non-stool GI severity items should be analyzed separately). The FDA again requested that evidence from participants’ interviews be provided to confirm that patients with CeD can distinguish between the response options of ‘very mild’ and ‘mild’ and between ‘very severe’ and ‘severe,’ and a reduction in response options should be considered accordingly. It was also suggested that nausea and bloating severity scores should include zero (for patients who report none of these symptoms) and abdominal pain scoring should align with nausea and bloating scores (0 to 5).
In response to a direct question, the FDA agreed that the Bristol Stool Form Scale (BSFS) [21] could be used to ensure participants’ responses to the diarrhea question align with the relevant stool descriptors.
In addition, the FDA reviewed a Weekly CDSD Severity Score algorithm in which the daily symptom scores for all items were averaged across a 7-day period (proposed for use in clinical trials) and recommended that ‘tiredness’ should not be included in this weekly severity score (to focus potential clinical trial endpoints on GI symptoms only).
After the above changes, concept elicitation and cognitive debriefing interviews were conducted with adult (N = 16) and adolescent (N = 16) participants with CeD. Targeted recruitment of younger adolescent participants (to ensure comprehension of items in this age group) was successful, with half of adolescent participants aged 12–14 years (n = 8). The inclusion criteria used were aimed at reflecting patient populations in planned CeD clinical trials (see Online Resource Abstract 3).
A Weekly CDSD Severity Score has been proposed for use in clinical trials in which the daily symptoms scores for all GI items are averaged across a 7-day period. As per FDA recommendations, the Weekly CDSD Severity Score does not include the ‘tiredness’ item.
The authors would like to thank Jacob Devine, Jack Syage (on behalf of ImmunogenX), Sam Wang, Peter H. R. Green and Vandana Nehra for their contributions to the development of the Celiac Disease Symptom Diary. Guarantor of the article: Daniel A Leffler.
The studies described in this manuscript were approved by the relevant Institutional Review Board (IRB) for each institution (see Online Resource).
Consent to participate
Written IRB-approved informed consent documents (or assent documents for participants 17 years of age or younger) were obtained from all participants prior to taking part in each study. Each study was fully explained to all potential participants, including the purpose of the study, the type of questions asked and the time required. Participants were able to ask questions before agreeing to participate.
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