Applied Health Economics and Health Policy (2023) 21:119–130 https://doi.org/10.1007/s40258-022-00770-9 ORIGINAL RESEARCH ARTICLE Determining What Represents Value in the Treatment of Refractory or Unexplained Chronic Cough from the Perspective of Key Stakeholders in Spain Using Multi‑Criteria Decision Analysis Christian Domingo1,2 · Mario Fernandez3 · Noe Garin4 · Javier Milara5 · Ignacio Moran6 · Irantzu Muerza6 · Adalberto Pacheco7 · Carlos Teruel8 · Roy Bentley9 · Rafael Subiran10 · Alicia Gil10 Accepted: 9 October 2022 / Published online: 2 November 2022 © The Author(s) 2022 Abstract Background and Objective Chronic cough is defined as cough lasting for more than 8 weeks. It can be described as refractory when persisting despite thorough clinical assessment and treatment of any cough-related underlying condition, or unexplained when no underlying cough-related condition can be identified. Refractory or unexplained chronic cough (RCC|UCC) greatly affects patient health-related quality of life (HRQoL). Although around 10% of the population suffer from chronic cough (with 40–60% of these patients suffering from RCC|UCC), there is limited information available in the literature about the condition and the assessment of treatment success. This study aimed to determine what represents value in the treatment of RCC|UCC from the perspective of key stakeholders in Spain using Multi-Criteria Decision Analysis (MCDA) methodology. Methods A literature review was conducted to adapt the MCDA framework to the specific context of RCC|UCC. A total of 24 participants were involved, representing three key stakeholder groups (7 patients, 9 physicians and 8 hospital pharma- cists). The study was structured in two phases. In Phase 1, participants validated the adapted MCDA framework and assigned relative weights (100-point allocation) to the framework’s value criteria/sub-criteria during three individual stakeholder meetings, one per each stakeholder group. In Phase 2, participants were brought together in a multi-stakeholder meeting to review findings of each stakeholder group, after which stakeholders repeated the weighting exercise as a collective group. All meetings included reflective discussion by participants of each value criteria/sub-criteria included within the adapted MCDA framework, where stakeholders shared their perspectives and opinions on what represents value in RCC|UCC. Results Refractory or unexplained chronic cough is regarded as a chronic medical condition, with variable severity across patients and the potential to heavily impact their HRQoL (including physical, psychological and social/work productivity domains). Current treatments used by healthcare professionals, which have not been specifically developed and are not approved for RCC|UCC, show limited clinical effectiveness and associated safety and tolerability issues, which result in frequent treatment discontinuations. The reduction of the average cough frequency over a 24-h period is regarded as the primary goal of treatment by stakeholders, with the aim of improving HRQoL. Improvement of other cough symptoms, such as intensity, is also considered important. Minor adverse events and a slower onset of treatment effect would be accept- able to stakeholders if accompanied by strong efficacy and improvement in HRQoL. Given the inability to measure cough frequency in clinical practice, Patient-Reported Outcomes (PROs) could be considered a proxy of treatment effectiveness. A multidisciplinary approach to the condition is regarded as key for treatment success. Conclusions Refractory or unexplained chronic cough is a medical condition that seriously impacts patients’ HRQoL. The primary goal of treatment is to improve patients’ HRQoL by reducing the frequency and intensity of cough. * Alicia Gil agil@omakaseconsulting.com Extended author information available on the last page of the article Vol.:(0123456789) 120 C. Domingo et al. include the trial of agents targeting cough hypersensitivity, Key Points for Decision Makers such as low-dose morphine, pregabalin or gabapentin. How- ever, these treatments are used off-label, since they have Refractory or unexplained chronic cough is a frequent, not been specifically developed and are not approved for yet not well known, medical condition that can have seri- chronic cough [1]. Innovative treatment alternatives, which ous impact in patients’ HRQoL. target the nociceptors responsible for the irritant sensation Any reduction in the symptoms of cough needs to be that precedes cough, are currently under development [1, strongly correlated with improvements in HRQoL to be 16]. Among these treatments, the most promising results to considered clinically meaningful and patient-relevant. date have been shown by the P2X3 antagonists [6]. Multi-Criteria decision analysis (MCDA) methodology Minor adverse events and a slower onset of treatment allows the determination of what represents value in a given effect would be acceptable if accompanied by strong medical condition, considering criteria that are relevant to efficacy and improvement in HRQoL. inform healthcare decision making in a transparent and sys- tematic manner [17–19]. Multi-Criteria decision analysis enables collaboration through a reflective dialogue among stakeholders to better understand individual perspectives 1 Background and thereby further guide decision making [17, 20, 21]. With innovative treatment options for patients with RCC|UCC cur- Excessive and protracted cough is a common and disabling rently under development, it becomes important to determine, complaint, with recent guidelines defining a cough that per- understand and reflect on the perceptions and expectations of sists longer than 8 weeks as chronic cough [1–3]. Chronic treatment effect by patients, physicians and hospital pharma- cough has the potential to significantly affect patient’s health- cists. The aim of this study was to determine what represents related quality of life (HRQoL), including physical symptoms value in RCC|UCC from the perspective of these three stake- such as incontinence, cough syncope and dysphonia, leading holder groups in Spain using MCDA methodology. to social isolation, depression, difficulties in personal rela- tionships and negative impact on work productivity [1, 4]. Chronic cough can affect up to 10% of the general popula- 2 Methods tion [5]. In approximately 40%–60% of these patients, cough could remain unresolved despite thorough investigation and 2.1 Study Design treatment [6–9]. Refractory Chronic Cough (RCC) persists despite optimal treatment of any underlying cough-related The study was designed following good practice recommen- condition (e.g., Asthma, Gastroesophageal Reflux Disease dations for MCDA methodology [22, 23], namely, literature [GERD], or Upper Airway Cough Syndrome [UACS]) [1, review, MCDA framework adaptation (including definition 2, 10, 11]. Unexplained Chronic Cough (UCC) is a cough of criteria and sub-criteria), criteria/sub-criteria weighting without an identifiable, underlying cough-related condition (100-point allocation) and discussion of results. The Evi- [2, 10]. Together, RCC|UCC is described as a clinical entity dence and Value: Impact on Decision Making (EVIDEM) in itself, whose pathological features and accompanying MCDA framework validated for the Spanish healthcare con- symptomatology deviate beyond the protective physiologi- text was used as the starting point for this study [20, 24, 25]. cal role of cough [6, 8, 10]. The aetiology of RCC|UCC is not yet clear, although 2.2 Literature Review most recent research and expert opinion point to a hyper- sensitivity of airway sensory nerves as the common feature A literature review was performed to obtain relevant informa- behind different chronic cough phenotypes [12–15]. Refrac- tion about RCC|UCC and its current management in Spain. tory or Unexplained Chronic Cough can be heterogeneous Search terms were based on the EVIDEM MCDA framework, clinically, possibly requiring clinical investigation by differ- and no time span limit was applied. The search strategy can ent medical specialties including allergy, otolaryngology, be reviewed in Supplementary Material 1. Original articles gastroenterology and pulmonology [3, 16]. focused on clinical practice and research containing relevant Current RCC|UCC management is described in the lat- information to describe value in RCC|CC were included. est guidelines and recommendations from international bod- Articles were excluded if they were duplicated, written in ies [1, 2]. In Spain, there is a protocol for chronic cough a language other than Spanish or English or related to ani- management available, including a section with recom- mal studies. The search was performed in July 2020 using mendations for RCC|UCC [3]. Currently, there is no treat- the following three biomedical databases: MEDLINE [26], ment approved for RCC|UCC. The latest recommendations Cochrane [27] and MEDES [28]. Grey literature sources, such Value Determination in Refractory or Unexplained Chronic Cough Through MCDA 121 as Google Scholar or the websites of relevant scientific socie- patients (n = 7), physicians (n = 9) and hospital pharmacists ties and patient organisations were used to complement the (n = 8). Each of the homogeneous-profile stakeholder groups search. The search resulted in 26 publications, after screening validated the MCDA framework adapted for RCC|UCC a total of 252 publications by title and abstract. and performed a weighting of the criteria and sub-criteria included in the framework reflecting each group’s interpre- 2.3 MCDA Framework Adapted for RCC|UCC​ tation of the relative importance of the included criteria. Patients, physicians and hospital pharmacists shared their The EVIDEM MCDA framework was specifically adapted perspectives and opinions regarding what represents value to RCC|UCC based on literature review results [29]. Cri- in RCC|UCC during the reflective discussion held during teria definitions were adapted to reflect the specific char- each of the single profile stakeholder meetings. acteristics of RCC|UCC, while sub-criteria relevant for the The weighting was performed using the 100-points allo- condition were included in each criterion. The framework cation weighting method [30], where patients, physicians adaptation was then complemented with data and informa- and hospital pharmacists had to distribute a total of 100 tion obtained through nine initial individual telephone inter- points among the criteria of the framework first, and then views with key stakeholders (2 patients, 4 physicians and perform the same exercise among the sub-criteria in each of 3 hospital pharmacists). Through these interviews, criteria the criteria of comparative efficacy/effectiveness, safety/tol- definitions were completed and additional sub-criteria rel- erability and PROs. The weighting exercise was completed evant for RCC|UCC from the perspective of stakeholders individually by each participant. were identified. The resulting MCDA framework specifi- cally adapted for RCC|UCC included 12 quantitative and 4 2.4.2 Phase 2: Multi‑Stakeholder Meeting contextual criteria as shown in Fig. 1A. Value sub-criteria were defined for each of the criteria in the “comparative In a second phase, a selection of 15 participants from Phase outcomes of the treatment” domain (comparative efficacy/ 1 (5 participants from each of the stakeholder groups) par- effectiveness, safety/tolerability and Patient-Reported Out- ticipated in a multi-stakeholder meeting (held in November comes [PROs]) as shown in Fig. 1B. Criteria/sub-criteria 2020). Participants for the Phase 2 were selected based definitions can be reviewed in Supplementary Material 2. on their degree of involvement and participation during the single profile stakeholder meetings. The total number 2.4 Panel Participants and Development of participants was smaller in Phase 2 to facilitate partici- of the Study pation in group discussions and sharing of perspectives for each profile. The results obtained in the individual stake- Study participants were identified through the literature holder meetings were presented and reflectively discussed review and contacted via email. Participants were selected to as a group. Patients, physicians and hospital pharmacists represent all the relevant stakeholder profiles in RCC|UCC, were able to listen to what the other stakeholder profiles including physicians, hospital pharmacists and patient rep- considered as representative of value in RCC|UCC and resentatives. Physicians represented the different medical then discussed whether any of their initial perspectives specialties involved with the management of the condition had changed from those they had previously considered (Allergy, Otolaryngology, Gastroenterology and Pulmonol- during the single profile stakeholder meetings. After the ogy), including key opinion leaders in Spain with published multi-stakeholder meeting, stakeholders were requested to articles on RCC|UCC. Hospital pharmacists had significant repeat the weighting exercise to assess the consistency of experience in evaluating treatment options for respiratory results. The exercise was sent by email and participants diseases, including members of the working group for respir- completed it remotely. atory diseases of the Spanish Society of Hospital Pharmacy (SEFH). The Spanish Federation for patients with Allergic 2.5 Data Collection and Analysis or Respiratory diseases (FENAER) helped identify and con- tact patients who experienced RCC|UCC for their inclusion Participants completed the weighting exercise in each of in this study. The study was carried out remotely due to the the two phases of the project using an Excel spreadsheet COVID-19 pandemic and structured in two phases. All the specifically designed for this study, available in Supple- meetings were performed online using the Zoom platform. mentary Material 3. The spreadsheet allowed participants to distribute 100 points across each of the criteria and then 2.4.1 Phase 1: Single Profile Stakeholder Meetings subsequently across each of the sub-criteria. All respondents returned their completed weights via email, and these were In the first phase, three separate meetings were held in Octo- then aggregated and analysed by two independent research- ber 2020 with each of the following stakeholder groups: ers (quantitative data results). 122 C. Domingo et al. Fig. 1  Multi-Criteria decision analysis (MCDA) framework adapted included in each of the criteria of the Comparative outcomes of the for refractory or unexplained chronic cough (RCC|UCC). A Crite- treatment domain. QoL quality of life ria in the MCDA framework adapted for RCC|UCC; B Sub-criteria Weighting results were calculated as the mean and stand- paired samples was completed. The statistical analysis was ard deviation (SD) of the scores assigned by stakeholders performed using Microsoft Excel 2016 software. and were then presented in the meetings of the two phases of the project. Stakeholders reflected and discussed the prioriti- sation of criteria and sub-criteria in the MCDA framework. 3 Results Researchers compiled the deliberation from each stakehold- ers’ perspectives on what represents value in RCC|UCC 3.1 Single Profile Stakeholder Meetings (qualitative data results) following published MCDA good methodological practices [17, 22, 23, 29]. 3.1.1 Patients To assess potential differences in the weighting results from stakeholders participating in Phases 1 and 2, a t test for Results from the criteria weighting by patients based on points allocated are presented in Fig. 2A. The top three Value Determination in Refractory or Unexplained Chronic Cough Through MCDA 123 most important criteria for patients were disease severity (16.4 ± 3.8). Patients agreed that a reduction in 24-h cough (mean ± SD: 14.7 ± 7.0 points), type of therapeutic benefit frequency (including cough during day- and sleep-time) (12.9 ± 7.5) and unmet needs (10.0 ± 3.9), while crite- represents the most desirable efficacy outcome, given some ria related to costs, including indirect costs (5.3 ± 2.8), patients suffer more from cough-derived sleep disruption other medical costs (5.1 ± 3.1) and cost of the treatment (e.g., GERD patients) while others are more affected in (4.4 ± 3.0) were considered the three least important. their daily activities (e.g., at work). All HRQoL domains Patients stated that the severity of RCC|UCC sustained (physical, psychological and social/work productivity) without resolution through the years greatly impacted can be negatively impacted by RCC|UCC. Some patients on HRQoL. In their view, the benefit provided by a treat- may experience a stronger physical impact, with intense ment is understood mainly as an improvement in HRQoL. cough leading to, for example, urinary incontinence, rib Patients felt that if HRQoL was improved, treatment- fractures and cough syncope. However, other patients related adverse events could be tolerated to a degree. Costs are more impacted at the psychological level: exhausted, were considered secondary to the potential health benefit depressed and frustrated for not achieving cough resolu- of treatment. tion after many years of failed treatment approaches. These Patient sub-criteria weighting results based on points aspects, in turn, can negatively affect the social domain of allocated are presented in Fig. 2B–D. The three most a patient’s HRQoL as well as the patient’s work produc- important sub-criteria were the reduction in 24-h cough tivity, with some patients needing even to stop working frequency (18.7 ± 4.3 points), serious adverse events with negative financial implications for the patient and the (25.0 ± 5.0) and HRQoL: Physical impact (26.4 ± 7.5), family. The safety profile of a new treatment, including while the three least important sub-criteria were the per- any potential tolerability issues, was perceived as second- centage of respondent patients (8.6 ± 3.8), short-term ary to reducing the frequency and intensity of cough and safety (15.7 ± 4.5) and HRQoL: Impact on social/work life improving HRQoL. Fig. 2  Weighting results obtained by patients in the single pro- C Comparative safety/tolerability sub-criteria weighting results; D file stakeholder meeting. A Quantitative criteria weighting results; Comparative Patient-Reported Outcomes (PROs) sub-criteria weight- B Comparative efficacy/effectiveness sub-criteria weighting results; ing results. CPG clinical practice guidelines, QoL quality of life 124 C. Domingo et al. 3.1.2 Physicians Physician sub-criteria weighting results based on points allocated are presented in Fig. 3B–D. The three most impor- Results from the criteria weighting by physicians based tant sub-criteria were the reduction in 24-h cough frequency on points allocated are presented in Fig. 3A. The top 3 (20.1 ± 5.5 points), serious adverse events (31.7 ± 10.6) most important criteria for physicians were disease sever- and HRQoL: Psychological impact (27.2 ± 7.1), while the ity (14.7 ± 5.0 points), comparative efficacy/effectiveness 3 least important sub-criteria were the time of onset of treat- (13.3 ± 3.9) and safety/tolerability (11.0 ± 4.1). The 3 least ment response (5.7 ± 3.8), short-term safety (12.8 ± 5.1) important criteria were cost-related criteria, including cost and impact on dignity (13.6 ± 4.5). Physicians discussed of the treatment (4.6 ± 1.6), other medical costs (3.9 ± 1.2) that an effective treatment should reduce 24-h cough fre- and indirect costs (2.7 ± 2.1). Physicians discussed that quency, improving the disruption caused by cough on both RCC|UCC is a frequent clinical problem in their daily prac- the patient’s sleep quality and their daily activities. Health- tice, which can severely impact patients’ HRQoL. There is related quality of life of patients is affected almost equally a need for an effective and safe treatment, since there are no physically and psychologically and any improvement of treatments currently approved for RCC|UCC. Neuromodula- these aspects would be related with an improvement of tors can temporarily improve cough symptoms in some cases patients’ dignity. Physicians do not perform HRQoL ques- but are known to lose effectiveness over a short period of tionnaires on RCC|UCC patients regularly in clinical prac- time and can be associated with safety and tolerability issues tice. An improved safety profile compared to currently used resulting in frequent treatment discontinuations. Physicians neuromodulators would be considered valuable. The time consider the cost of the treatment relevant but secondary to onset of treatment effect is not that relevant given the to other criteria when deciding to prescribe an available chronicity of the condition. Also, the occurrence of some treatment. adverse events and tolerability issues could be acceptable Fig. 3  Weighting results obtained by physicians in the single pro- C Comparative safety/tolerability sub-criteria weighting results; D file stakeholder meeting. A Quantitative criteria weighting results; Comparative Patient-Reported Outcomes (PROs) sub-criteria weight- B Comparative efficacy/effectiveness sub-criteria weighting results; ing results. CPG clinical practice guidelines, QoL quality of life Value Determination in Refractory or Unexplained Chronic Cough Through MCDA 125 if treatment effectiveness, and the consequent perception of Conversely, other medical and indirect costs were considered clinical improvement by the patient, is demonstrated. relatively less important due to the lack of direct impact on the pharmaceutical budget. 3.1.3 Hospital Pharmacists Hospital pharmacist sub-criteria weighting results based on points allocated are presented in Fig. 4B–D. The 3 most Results from the criteria weighting by hospital pharmacists important sub-criteria were the reduction in 24-h cough fre- based on points allocated are presented in Fig. 4A. The top quency (17.2 ± 3.1), serious adverse events (28.1 ± 7.5) and three most important criteria for hospital pharmacists were HRQoL: Physical impact (25.0 ± 6.0). The 3 least important comparative efficacy/effectiveness (13.3 ± 3.5 points), safety/ sub-criteria were the time of onset of treatment response tolerability (11.8 ± 2.3) and quality of evidence (10.4 ± 3.5). (8.8 ± 3.3), short-term safety (15.0 ± 3.8) and the impact on The 3 least important criteria were other medical costs dignity (15.0 ± 5.3). Hospital pharmacists recognised that (5.7 ± 2.3), expert consensus/clinical practice guidelines a reduction in cough frequency could be the only objective (5.6 ± 2.8) and indirect costs (5.1 ± 1.7). Hospital pharma- endpoint to assess treatment effect. Any improvement in the cists initially mentioned a low level of awareness about the safety profile would be considered a benefit when compared severity and impact of RCC|UCC, mainly explained by the with the issues associated with neuromodulators currently lack of available therapeutic options. According to hospital prescribed for treatment. The time until treatment response, pharmacists, the primary focus when performing the assess- as well as short-term safety, were perceived as less impor- ment of a treatment is efficacy and safety. Patient-reported tant sub-criteria, considering the chronicity of the condi- outcomes could also be important, but they are frequently tion. Hospital pharmacists agreed that the negative impact not available. The robustness of the clinical studies is a key of RCC|UCC on patient dignity would be reduced by any aspect when performing an assessment of treatment effect. improvement in patients’ HRQoL. Fig. 4  Weighting results obtained by hospital pharmacists in the sin- results; D Comparative Patient-Reported Outcomes (PROs) sub-cri- gle profile stakeholder meeting. A Quantitative criteria weighting teria weighting results. CPG clinical practice guidelines, QoL quality results; B Comparative efficacy/effectiveness sub-criteria weight- of life ing results; C Comparative safety/tolerability sub-criteria weighting 126 C. Domingo et al. 3.2 Multi‑Stakeholder Meeting score changes between Phase 1 and 2 can be reviewed in the Supplementary Material 4. The results of the weighting scores of criteria/sub-criteria Physicians and hospital pharmacists acknowledged that assigned by stakeholders as one group after the multi-stake- the primary goal of treatment from the patients’ perspective holder group meeting, based on points allocated are pre- was to achieve an improvement in their HRQoL, namely sented in Fig. 5. The 3 most important criteria in RCC|UCC through a reduction of cough symptoms such as frequency from the perspective of key stakeholders in Spain were dis- and intensity. Additionally, stakeholders agreed on the ease severity (13.5 ± 5.6 points), comparative efficacy/effec- importance of assessing the impact on the patients’ HRQoL tiveness (11.0 ± 2.9) and safety/tolerability (10.9 ± 3.5). during clinical visits. While physicians and hospital phar- The 3 least important criteria were those related to costs, macists rely on objective variables (i.e., cough frequency including cost of the treatment (5.1 ± 2.8), other medical in the case of RCC|UCC) for the assessment of treatment costs (4.0 ± 2.5) and indirect costs (3.9 ± 2.2). The 3 most effect, stakeholders agreed on the importance of correlat- important sub-criteria were the reduction in 24-h cough fre- ing improvement in objective measure(s) with those of quency (16.8 ± 3.3), serious adverse events (31.2 ± 9.2), subjective measures including HRQoL in the assessment of and HRQoL: Physical impact (28.5 ± 4.8), and the 3 least RCC|UCC treatment effect. The lack of tools in the clinical important were the time of onset of treatment response setting that can assess cough frequency and the burden of (8.9 ± 3.8), adverse events (15.2 ± 6.0) and convenience of RCC|UCC on the patient’s HRQoL suggests that PROs could treatment (12.9 ± 4.7). The results of the statistical analysis be used as a proxy to assess treatment effect in clinical prac- of the weighting scores between Phase 1 and 2 confirmed the tice. The use of a visual analogue scale (VAS) was proposed consistency of scoring by the stakeholders, as none of the as a simple, easy to use tool that could help evaluate the differences in the criteria/sub-criteria were statistically sig- burden and improvement of cough in RCC|UCC patients in nificant (p > 0.05 in all the criteria/sub-criteria). Weighting clinical practice. All stakeholders agreed on the benefit of a Fig. 5  Weighting results obtained by stakeholders as a group in the C Comparative safety/tolerability sub-criteria weighting results; D multi-stakeholder meeting. A Quantitative criteria weighting results; Comparative Patient-Reported Outcomes (PROs) sub-criteria weight- B Comparative efficacy/effectiveness sub-criteria weighting results; ing results. CPG clinical practice guidelines, QoL quality of life Value Determination in Refractory or Unexplained Chronic Cough Through MCDA 127 multidisciplinary approach to help optimise care of difficult in recent publications [4, 6, 8, 15, 34, 35]. Since impact to treat patients with RCC|UCC. on HRQoL represents the main burden associated with Stakeholders agreed that any reduction in cough fre- RCC|UCC, any reduction in the symptoms of cough needs quency should preferably be maintained throughout the to be strongly correlated with improvements in HRQoL to 24-h period, rather than only during the day or only at night, be considered clinically meaningful and patient-relevant. considering the inter-patient variability of time of day when Reduction in cough frequency throughout a 24-h period is cough impacts on patients. Despite not being one of the top- perceived as valuable since some patients are more affected rated criteria, determining the improvement of cough inten- during waking hours while others suffer from sleep disrup- sity in the assessment of treatment success was discussed as tion. Although the reduction in 24-h cough frequency was a relevant aspect for all stakeholders. There was agreement the top-rated sub-criterion, the improvement of cough inten- that some treatment-related adverse events and tolerability sity was also consistently mentioned by stakeholders as a rel- issues might be acceptable if the reduction in cough fre- evant aspect to be assessed when treating to reduce the bur- quency and subsequent improvement in HRQoL is clinically den of cough. Improvements in the physical, psychological relevant. Finally, participants agreed that key unmet needs and social/work productivity domains of HRQoL are inter- include the awareness about the condition, its impact on related and are considered equally important. Stakeholders HRQoL, and the availability of effective treatment options. agreed that potential adverse events of any new therapeutic option could be acceptable to patients and their treating phy- sicians if the reduction in 24-h cough frequency and subse- 4 Discussion quent improvement on HRQoL was clinically meaningful and patient-relevant. Involving the different relevant medical Cough that persists despite adequate investigation and man- specialties for RCC|UCC in a multidisciplinary approach to agement remains an unsolved clinical problem. Many chal- the condition would be a key aspect to optimising patient lenges are associated with the appropriate diagnosis and management and treatment, as confirmed by recently pub- management of RCC|UCC, starting by a general lack of lished literature [36, 37]. awareness among patients with persistent cough and their Stakeholders first worked within their own homogene- treating health care providers. The heterogeneity of the ous peer group and afterwards came together as a multi- patient population that requires the collaboration of several stakeholder group. The weighting results obtained in the medical specialties, the lack of an effective treatment, and two phases were consistent, showing that the perception the lack of agreement on the optimal approach to assessing of what represents value for a given attribute is inherent to treatment success are some of the barriers that physicians each stakeholder profile. Patients placed emphasis on the and hospital pharmacists will continue to face in the near severity of the disease and the goal of treatment to improve term. Further understanding of RCC|UCC and its impact HRQoL, while trusting physicians and hospital pharmacists on HRQoL could help optimise patient access to upcoming to assess the efficacy and safety of the new treatments that therapeutic options expected to become available in the next are expected to become available in the upcoming years. few years [31–33]. Physicians emphasised the relevance of following a patient- Throughout the study, participants helped determine the focused treatment approach and agreed on the importance of general level of awareness about RCC|UCC in Spain and adopting a standardised HRQoL assessment tool in clinical define what represents value in RCC|UCC from their own practice to help assess impact of the condition and improve- perspective, facilitated through the adaptation of an MCDA ment attributable to treatment. Physicians discussed that a framework specific to RCC|UCC. All criteria and sub-cri- VAS could assess HRQoL of RCC|UCC patients quickly and teria considered relevant for healthcare decision making in easily in clinical practice. Hospital pharmacists primarily RCC|UCC were identified and integrated into the adapted considered objective variables, such as efficacy and safety, MCDA framework, which was subsequently validated when evaluating a new treatment but recognised that impact through the input of study participants. on HRQoL could be used as a proxy of clinical relevance in Patients, physicians and hospital pharmacists agreed that RCC|UCC patients. Bringing different stakeholder perspec- RCC|UCC is a condition with a high degree of unmet need. tives together was key to help study participants gain a bet- Refractory or unexplained chronic cough affects patients to ter understanding of the condition. Study participants were varying degrees of severity, yet frequently, its impact is not able to discuss, reflect and agree on key aspects, such as appropriately assessed by the medical community. In certain the potential severity of RCC|UCC, its associated burden on patients, RCC|UCC can be severe and produce significant HRQoL and health care resources as well as that improve- burden on all aspects of the patient’s HRQoL, including ment in objective variables (such as cough frequency) should physical, psychological and social impact as well as impair- correlate with improvements in HRQoL in order to be con- ment of the ability to work. This is in line with that reported sidered clinically meaningful and patient relevant. Given 128 C. Domingo et al. the lack of clinical practice tools that can record objective inconsistency of how treatment success is assessed and rec- cough measures (frequency), stakeholders recognised that ognised in clinical practice. This study brings to light the PRO measures could be used as a proxy for assessing treat- serious impact RCC|UCC can have on patients and health ment effectiveness in clinical practice. care resources and the importance of assessing the improve- Recent studies in Spain have used the EVIDEM MCDA ment in HRQoL when treating to reduce the frequency and framework to help assess value across different medical intensity of cough. conditions and therapeutic areas [21, 24, 25, 38–41]. One Supplementary Information The online version contains supplemen- of the limitations typically highlighted in these studies is tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 40258-0​ 22-0​ 0770-9. the relatively small number of participants. In an attempt to overcome this limitation, this study included a larger number Acknowledgements The authors would like to thank the participants of participants across a diverse set of stakeholders’ profiles. that constituted the RCC|UCC MCDA study group for their contribu- tion during the study. However, the present study is not exempt from some other limitations. First, a risk of bias in the selection of partici- Declarations pants cannot be totally excluded, since experts were identi- fied through a literature review specific for RCC|UCC, and Funding This study was funded by Shionogi Inc. hence their experience and knowledge of the condition is above that of the general population. This study could ben- Conflict of interest CD, MF, NG, JMP, AP and CT received fees for efit from further investigation with physicians and payers their participation in the study. IMF is a member of the patient or- ganisation FENAER. IM is a member of the patient organisation AS- with lesser experience with RCC|UCC, where displacements MABI. FENAER and ASMABI received a donation from Shionogi from their initial perspectives could be higher and which for the participation of its member in the study. RB is an employee could be more representative of their respective stakeholder of Shionogi Inc. RS and AG are employees of Omakase Consulting group. The information used to adapt the MCDA frame- S.L. Omakase Consulting S.L. received funding from Shionogi Inc. to develop and conduct this study. work to RCC|UCC was limited by the information and data publicly available at the time of the study. The current value Ethics approval The study was developed following all the legal framework could, therefore, benefit from further work once and ethical requirements for Market Research studies established by more information about the condition and the upcoming National and International Authorities and is compliant with the 2021 Codes of Conduct by Farmaindustria (Spain) and EPHMRA (Europe). treatments becomes available. The number of stakehold- ers that participated in Phase 1 was reduced in Phase 2 to Consent to participate All participants agreed to participate in the allow for a higher level of participation and more in-depth study, formalised through the signature of a contract which included analysis of the value criteria. This selection could have also a detailed description of the activities to be performed. Patients were contracted through the Spanish Federation for patients with Allergic or introduced some potential bias. To overcome this limita- Respiratory diseases (FENAER), in accordance with the requirements tion and increase result robustness, a statistical analysis of set in the 2021 Farmaindustria Code of Conduct. the stakeholders’ weighting results from Phase 1 and 2 was performed and confirmed that weighting results did not sig- Consent for publication All participants yielded the right to use and publish the data obtained in the study to the sponsor of the study. nificantly change between the two phases. Adapting the EVIDEM MCDA framework to RCC|UCC Availability of data and material No additional data available. has proven to be useful for value determination in this specific medical condition. This study represents the first Code availability Not applicable. attempt to assess value in RCC|UCC from the perspective of Author contributions CD, MF, NG, JMP, AP, CT, IMF, IM, RB, RS key stakeholders in Spain. The MCDA framework adapted and AG contributed to the design of the study, data acquisition, analy- for RCC|UCC developed during this study may be used as sis, and interpretation, drafting of the work, revising the work criti- the starting point for discussions of value contribution dur- cally for important intellectual content, approved the final version to be published and agreed to be accountable for all aspects of the work in ing the assessment of upcoming treatments and for future ensuring that questions related to the accuracy or integrity of any part studies in the field of RCC|UCC. of the work are appropriately investigated and resolved. Open Access This article is licensed under a Creative Commons Attri- bution-NonCommercial 4.0 International License, which permits any 5 Conclusions non-commercial use, sharing, adaptation, distribution and reproduc- tion in any medium or format, as long as you give appropriate credit Refractory or unexplained chronic cough is not a well under- to the original author(s) and the source, provide a link to the Creative stood medical condition. Key unmet needs include the level Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the arti- of awareness across medical specialties and hospital phar- cle's Creative Commons licence, unless indicated otherwise in a credit macists, lack of multidisciplinary patient management, line to the material. 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Implementing reflective multicriteria decision analysis Authors and Affiliations Christian Domingo1,2 · Mario Fernandez3 · Noe Garin4 · Javier Milara5 · Ignacio Moran6 · Irantzu Muerza6 · Adalberto Pacheco7 · Carlos Teruel8 · Roy Bentley9 · Rafael Subiran10 · Alicia Gil10 1 6 Pulmonology Department, Hospital Parc Tauli, Sabadell, Spanish Federation of Patient Organisations with Allergic Spain and Respiratory Diseases (FENAER), Madrid, Spain 2 7 Medicine Department, Universitat Autònoma de Barcelona, Chronic Cough Unit, Medical Consultation Habana 17, Barcelona, Spain Madrid, Spain 3 8 Otolaryngology Department, Hospital General Universitario Gastroenterology Department, Hospital Ramon y Cajal, Gregorio Marañon, Madrid, Spain Madrid, Spain 4 9 Pharmacy Department, Hospital de la Santa Creu i Sant Pau, Global Market Access, Shionogi Inc., New Jersey, USA Barcelona, Spain 10 Omakase Consulting S.L., Barcelona, Spain 5 Pharmacy Department, Hospital General de Valencia, Valencia, Spain