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What are the unmet needs and most relevant treatment outcomes according to patients with inflammatory bowel disease? A qualitative patient preference study

BACKGROUND AND AIMS: As more therapeutic options with their own characteristics become available for inflammatory bowel disease (IBD), drug development and individual treatment decision-making needs to be tailored towards patients’ preferences and needs. This study aimed to understand patient preferences among IBD patients, and their most important treatment outcomes and unmet needs. METHODS: This qualitative study consisted of 1) a scoping literature review, 2) two focus group discussions (FGDs) with IBD patients (n=11) using the nominal group technique, and 3) two expert panel discussions. RESULTS: IBD patients discussed a multitude of unmet needs regarding their symptoms, side-effects, psychological and social issues for which they would welcome improved outcomes. Particularly, IBD patients elaborated on the uncertainties and fears they experienced regarding the possible need for surgery or an ostomy, the effectiveness and onset of action of their medication, and its long-term effects. Furthermore, participants extensively discussed the mental impact of IBD and their need for more psychological guidance, support, and improved information and communication with healthcare workers regarding their disease and emotional well-being. The following five characteristics were identified during the attribute grading as most important: prevent surgery, long-term clinical remission, improved quality of life (QoL), occurrence of urgency, and improved labor rate. CONCLUSIONS: This study suggests that IBD drug development and treatment decision-making needs to improve IBD symptoms and adverse events that significantly impact IBD patients’ QoL. Furthermore, this study underscores patients need for a shared decision-making process where their desired treatment outcomes and uncertainties are explicitly discussed and considered. the administration of the treatment, namely treatment frequency, place of treatment, and route of administration, which were also not spontaneously raised by patients during the open discussions. The attribute grading exercise also revealed that the characteristics included in the grading exercise did not include the level of detail and full range of aspects patients freely elaborated on in the open discussion (see 3.2.2); patients for example indicated and elaborated on the influence of IBD on their mental wellbeing, a characteristic not included in the attribute grading exercise. This qualitative study revealed in-depth insights into symptoms, side-effects, psychological and social issues that IBD patients find important. During the open discussions, patients highlighted gastrointestinal symptoms, reduced energy, changes in physical appearance, skin manifestations, and vision problems as being major issues reducing their quality of life. In addition, IBD patients elaborated on the uncertainties and fears they experienced regarding the possible need for surgery and in particular an ostomy. The effectiveness and onset of action of medication, and its long-term effects were further identified as major concerns. Lastly, the mental impact of IBD and the need for more psychological guidance, support, and improved communication with healthcare workers regarding key. A possible way to cope with patients’ uncertainties is to improve the communication with healthcare workers; patients who are informed about the side-effects of medication and about the possible need for surgery or an ostomy may experience less uncertainty about their future disease progression. In addition, if patients are given the opportunity to ask for help and advice, symptoms and side-effects are likely better managed. Based on patients’ individual needs, there are three possible efforts to support IBD patients. First, patients may find support in IBD associations where they can receive reliable support from other patients. As confirmed during our FGDs, participants were overall very happy to have participated in the discussion and share their experiences, feelings, and thoughts with other IBD patients as this took away some of their insecurities. Furthermore, Sewitch et al. showed that improving social support can have a favorable impact on psychological distress, ultimately improving health outcomes. Second, staff could be trained in IBD centers to provide more psychological support in the IBD medical care pathway. Third, the results of this study can be used to develop patient decision aids (e.g., flyers, online tools …) that can be integrated in IBD clinical practice to support SDM. During the discussions, patients discussed a multitude of treatment outcomes and unmet needs that should be discussed in clinical practice to enable an informed decision-making. For example, patients mentioned the need for more information regarding the effect of the disease and their treatments on a long and short term, which suggest an opportunity for the development of patient decision aids that can inform patients about these aspects. As a result, the communication between the patient and the health care provider can be facilitated and uncertainties can be addressed. Furthermore, by aligning individual medical treatment decisions with patients’ needs and preferences, higher quality decisions, patients’ compliance, and thereby improved patient’s overall health can be statistically significant impact on patients’ preferences. Furthermore, the results of this qualitative study can aid the development of patient decision aids used to facilitate treatment decision-making in clinical practice by revealing which aspects of treatments (e.g., long-term efficacy and safety of treatments) should be explicitly discussed in clinical practice and communicated to patients. The identified characteristics important to IBD patients may further be useful to assist and optimize the identification of clinical trial endpoints and outcomes that matter most to IBD patients. Including such outcomes in clinical trials could an of how treatments perform regarding patient-relevant outcomes. Obtaining evidence on the to which (new) drugs perform on relevant outcomes within and outside the clinical trial setting are two questions are to resolve at the time of regulatory benefit-risk assessment and Health Technology Assessment (HTA) Such evidence could hence support regulators and HTA assessors in understanding whether (novel) IBD treatments address unmet needs and treatment outcomes that matter to patients, and thereby support initial and post-marketing benefit-risk and reimbursement decisions. Qualitative and quantitative preference results could also be considered to inform (joint) scientific advice discussions by HTA bodies and regulators on the relevance of the clinical trial endpoints proposed by industry applicants e.g., allowing to understand whether relevant measures of quality of life are included in clinical trials 23 . In addition, resource allocation could be optimized to drugs that target the symptoms and side-effects found important to patients. This could result in a drug development process more tailored to patients’ needs 13,23,38,39 . Additionally, the concerns of IBD patients about uncertainties of long-term efficacy and safety can inform future real-world evidence studies. This study shows that IBD drug development and individual treatment decision-making does not only need to focus on controlling IBD patients’ gastrointestinal symptoms, but also on other symptoms and adverse events that significantly impact IBD patients’ quality of life. Furthermore, this study underscores the need for shared decision-making between healthcare providers and IBD patients where treatment outcomes and uncertainties about long-term efficacy and safety of medication are explicitly addressed and considered. Findings from this study may serve pharmaceutical industry, regulators, and HTA bodies/payers in understanding patient-relevant unmet needs and treatment outcomes to enable value-based and patient-centric decision-making that is aligned with the true patients’ needs across the IBD drug life cycle.


Introduction
Inflammatory bowel disease (IBD) is a collective term for a range of clinical phenotypes caused by chronic, idiopathic, and remitting inflammation of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are the two most common forms 1,2 . IBD is a lifelong disease affecting more than 10 million people worldwide, without any cure currently being available 3,4 . Symptoms include abdominal pain, chronic and relapsing episodes of (bloody) diarrhea, urgency, nausea, vomiting, weight loss, anorexia, and fatigue, which negatively impact patients' health and quality of life 5 .
Over the past decades, a transition took place in the therapeutic landscape of IBD; where IBD patients were previously highly dependent on conventional therapies such as aminosalicylates, corticosteroids, and immunosuppressants, more advanced therapies are being developed and entering the market (e.g., biologicals and small molecules) 6 . IBD treatments in development and use today differ in terms of benefits, side-effects, route of administration, cost, mechanism and speed of action, treatment schedule, and uncertainties related to their treatment outcomes on the long and short-term. As more therapeutic options with their own characteristics come on the market and are in the pipeline, it is increasingly recognized that drug development and evaluation need to be tailored towards patients' preferences and needs. In addition, it is increasingly expected that IBD patients are involved in individual treatment decision-making, whereby shared decision-making (SDM) is considered the ideal model 7,8 . This model encourages patients, in consultation with their clinician to 1) consider the available screening, treatment, or management options including their associated benefits, risks, and uncertainties, 2) communicate their preferences, and 3) express their desire for involvement in decision-making 9 . However, in order to facilitate SDM in the clinical encounter, a better understanding of factors that IBD patients find important is needed.
A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjac145 Patient preference studies, usually consisting of a qualitative and a quantitative phase, can help to identify which treatment characteristics are important to patients, how important, which trade-offs patients are willing to make between various characteristics, how preferences may vary according to individual patient characteristics, and how much uncertainty patients accept 10 . The qualitative phase of a patient preference study can generate information about patients' experiences and perspectives to gain in-depth and broad knowledge on the value of medical products and characteristics associated with them 11-13 . In addition, qualitative research is recommended to inform the identification of attributes (treatment features) used in subsequent quantitative research 14,15 . A systematic literature review by Bewtra et al. 16 showed that previous patient preference studies among IBD patients were mostly quantitative in nature, did not use a particular qualitative data collection method (such as individual interviews or group discussions), and/or resulted in limited evidence on the perceived value of treatment attributes according to patients. In addition, these studies were conducted before newer treatments such as biologicals and Janus Kinase (JAK) inhibitors were available, which have been described to affect patients' preferences 16 . Moreover, other published patient preference studies had a specific focus on preferences for surgery and medical management versus colectomy, had the goal to identify preferences for the administration of treatments, or were focused on a specific drug formulation [17][18][19][20][21][22] .
Given the lack of comprehensible and recent qualitative research on IBD patients' preferences that considers different (novel) treatments and their associated characteristics, the present qualitative patient preference study aimed to investigate which patient-relevant treatment characteristics of both treatments in development and use today IBD patients find important and why. More specifically, this study aimed to understand: 1) IBD patients' unmet needs regarding their disease and treatment, and 2) treatment outcomes considered important by IBD patients. Findings from this study were furthermore intended to support the identification and development of attributes and A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjac145 levels for inclusion in a subsequent quantitative patient preference study to obtain more representative quantitative results in a larger sample of IBD patients. Furthermore, findings may inform the development of a patient decision aid to facilitate SDM in clinical practice.

Materials and methods
A qualitative study consisting out of three phases was designed following the general steps described in the PREFER framework 23 . The three phases ( Figure 1)

Completion of the online form
As preparation for the FGDs, participants were invited to read the information sheet (Appendix 4) and to complete the online form, which consisted of 1) the informed consent form (Appendix 5 Part

Conduct of the focus group discussions using the Nominal Group Technique
FGDs using the NGT were chosen as preference exploration method in close dialogue with clinicians and patient representatives since there was interest in group dynamics and the subject of the discussion was not deemed to be too sensitive to discuss with others. The NGT is a consensus methodology where participants prioritize their thoughts and perspectives, both as group and individually, with the advantage of reaching consensus in a short period of time. As the NGT is During the FGDs, a predefined FGD guide (Appendix 6) was followed, taking into account the four steps of the NGT. Each discussion was executed by the same moderator (ES) and in the native language of the participants (Flemish). Considering the implications of the coronavirus (COVID- 19) pandemic, the discussions were organized online. The discussions lasted around one hour and 45 minutes and were audio-recorded. The content of the online form and the FGD guide was provided with written feedback from a gastroenterologist and a member of a patient organization.

Quantitative descriptive analysis
Participants' self-reported personal and disease-specific characteristics, and their scores on the attribute grading exercise were analyzed descriptively. Health Literacy was determined using the Chews' set of brief screening questions 27 . To obtain a final rank of the treatment characteristics, the A c c e p t e d M a n u s c r i p t

Qualitative thematic analysis
The audio-recordings of all FGDs were transcribed ad verbatim in the original language by a member of the research team (ES) and pseudonymized. Subsequently, the transcripts were subjected to the framework analysis method (using NVivo software), a qualitative content analysis for text data where overarching themes are developed 28 . Analysis started with familiarization through the conduct, transcription, and reading of the FGDs. Themes of the discussion guide informed the creation of deductive codes. Analytical notes were written in the margins of the transcripts and informed the creation of inductive codes. Based on the deductive and inductive codes a 'coding tree' with characteristics was developed. Regular meetings between the researchers that conducted the FGDs (ES, RS, and IH) were held to verify the characteristics were interpreted in the same manner.
After consensus was reached, the coding tree was uploaded in NVivo, and applied to all transcripts, were literal quotations of transcripts relating to a particular theme were classified under the respective code. NVivo was used for charting (summarizing) the data per code in order to have an oversight off al results, making interpretation and analysis of the results both between participants and FGDs possible.

Expert panel discussions
After the conduct of the FGDs, expert panel discussions with patients, patient representatives, clinicians, and preference research experts were held to verify the outcomes of the FGDs and to provide further depth into the identified themes. Furthermore, insights were gathered regarding possible attributes and levels for inclusion in the subsequent quantitative patient preference study, taking into account the criteria and steps as described by Durosini et al. 29 , Petrocchi et al. 30 , and Janssens et al. 31 .
A c c e p t e d M a n u s c r i p t

Scoping literature review to identify characteristics potentially relevant to IBD patients
In total, 22 patient preference studies, 58 phase 3 IBD clinical trials, and 45 IBD treatments fulfilled the inclusion criteria. From the included publications, data was extracted and summarized

Participants' characteristics
First contact was established with 13 IBD patients of which 11 joined the FGDs, resulting in a response rate of 84%. and biologicals (n=1), and aminosalicylates with corticosteroids (n=1). Table 1 gives an overview of the treatment experience of the participants.

Unmet needs and treatment outcomes considered important by IBD patients
IBD patients discussed a multitude of treatment outcomes and unmet needs for which they would welcome improvements both in the context of drug development as well as in the context of decision-making in clinical practice.

Gastrointestinal symptoms
Gastrointestinal symptoms (e.g., abdominal pain and cramps, diarrhea, urgency, incontinence, nocturnal defecation, bowel movements, and constipation) had a significant effect on the participants' life and was seen as detrimental in three ways. First, some participants frequently experienced nocturnal defecation, having an incremental effect on their sleep and therefore causing reduced energy (as further described in 'Reduced energy'). Second, work, sports, or social activities could be hampered, limiting their freedom. Last, knowing that gastrointestinal symptoms could appear at any time had an important psychological impact, making participants worrisome about always having a toilet nearby. Therefore, an improvement in both the frequency and the severity of gastrointestinal problems was seen as the most important treatment outcome for all participants: "Something that really comes at 1 actually." #FG1_E.

Reduced energy
The theme of reduced energy caused by participants' therapy and illness was extensively discussed in both FGDs and was experienced by the majority of the participants. Reduced energy could hinder participants ability to normally participate in daily activities, limiting their quality of life. Therefore, participants wanted to avoid reduced energy caused by their therapy: "For me fatigue is something I A c c e p t e d M a n u s c r i p t could not accept as a side-effect." #FG1_E. Nevertheless, reduced energy could not be avoided for every participant and therefore patients had to adapt their lifestyle around this problem. As a consequence, a couple of participants were not able to exercise, which was seen as another important limiting factor. Reduced energy and fatigue could also result from sleeping problems participants experienced due to their disease or nocturnal defecation, but also other causes of reduced energy were shared (e.g., following psychological problems patients were struggling with or weight fluctuations).

Changes in physical appearance
Patients highlighted that changes in physical appearance, caused both by their altered gut function or as a side-effect of their therapy, made them insecure about their body image. Especially participants treated with corticosteroids had experienced a spectrum of changes (namely moon face, developing facial hair, hair loss, and weight changes) in their physical appearance, which had a detrimental impact on their mental wellbeing. For these participants, the side-effects outranged the benefits of their treatment.
Among the several types of physical changes that emerged during the discussions, (excessive) weight fluctuations were seen as the most important, and the topic seemed to receive particular attention and discussion from female participants. Weight fluctuations caused both by participants' therapy or altered gut function were found detrimental because it made participants uncertain and had a negative effect on their energy levels. Therefore, all participants found it important that their weight was more or less under control. One participant even stated that weight gain was the most important treatment characteristic, and if a choice had to be made between different treatment options, the treatment in which weight gain might occur as a side-effect was to be dropped first.
A c c e p t e d M a n u s c r i p t So, I also think that it depends a little bit in which degree the side-effect occurs." #FG1_B.

Vision problems
One participant stated to have a deteriorated eyesight: "I am suffering from tear duct inflammation.
However, it remained largely unclear whether vision problems could also be an extra-intestinal manifestation associated with having a chronic autoimmune disease like IBD. As participants knew that a lot of medication could cause eye infections or other visual disturbances, suffering from (permanent) vision problems was seen as an important treatment characteristic.

Risk of surgery
Most of the participants saw surgery as their last resort and were resistant to it: "I think surgery that is often the last step." #FG2_D. Despite this, more than half of the participants underwent surgery in the past because they had to. Participants, especially the persons diagnosed with CD, knew that repeatedly removing sections of their gut was not sustainable in the long run and were afraid that their bowels would become too short to take in enough nutrients. In addition, they looked at it as 'a path without an end'. Nevertheless, some participants stated that their symptoms were more or less under control after they underwent surgery.

Risk of an ostomy
The need for an ostomy was extensively discussed during both focus groups, with some participants expressing their fear about ever going to need it. An ostomy was something they wanted to avoid at all costs because it would be an additional limitation and would hurt their self-image. Additionally, A c c e p t e d M a n u s c r i p t

An effective and fast working medication
On several occasions, participants discussed the psychological burden of uncertainties regarding the effectiveness and onset of action of their medication. Participants found it frustrating to start with a new treatment, not knowing if the medication was ever going to work for them and for how long it was going to work before losing its efficacy. As a result, most participants had tried various medications until they found (or were still searching for) the one that worked for them. In addition, participants complained about the uncertainty regarding the onset of action of the new treatment.
This had a negative impact in two ways: 1) because they did not know if the medication would eventually work for them, and whether they would need to switch to another medication, or whether they would need to give it more time to be effective, and 2) because during this bridging period, participants' symptoms stayed present. Therefore, one participant explicitly stated that a fast clinical response was the most important treatment characteristic.

Normal social interactions and activities
All participants experienced limitations on their social interactions and activities due to their disease and the unpredictable nature thereof. Making plans, such as going on a vacation, was seen as difficult by some participants. In addition, some participants raised that they frequently needed to cancel activities with their friends because they were not feeling well or were experiencing pain, and A c c e p t e d M a n u s c r i p t

Mental and psychological support
In general, participants tried to maintain a positive mindset: "No matter how sick I"ve been, I did always persevere and believe in it." #FG1_B. However, as many participants suffered greatly from their disease; the disease, to some extent, dictated what they could or could not do in their daily lives. As a result, this had a giant impact on the participants mental wellbeing and some patients were even struggling with mental disorders (e.g., loneliness, anxiety, depression). Therefore, multiple participants indicated that they needed professional mental and psychological help to cope with their disease:"I have been at the point where I thought: "I just can"t get out of here, not mentally, not physically". That I also sat with very dark thoughts." #FG2_D. Participants found that too little attention in the clinical encounter was given to the whole mental aspect of the disease and liked to have had more guidance.
They experienced sometimes that clinicians did not have a full understanding of the impact of the disease on their daily lives. As a result, participants extensively discussed the lack of mental support some of them needed. Some participants stated that their clinician did advise them to contact a psychologist if they needed to. However, participants felt that once they left the hospital, they were completely on their own.

Information regarding the effect of the disease and treatments on a long and short term
Some participants expressed the lack of information they received on how their disease would progress and felt uncertain about the long-term effects of their medication, as these effects are relatively unknown. Participants found it very important that they would not struggle with other diseases later in their lives and some participants expressed their fear about the possible emergence of cancer. Despite this, participants still used these medication as they wanted to stay in remission.
In addition, certain participants had tried so many different medications, they had no other options:

Attribute grading
In addition to the open discussion revealing patients' unmet needs and treatment outcomes and goals, the attribute grading allowed to explore and trigger further discussion on which treatment and disease related characteristics matter most to patients. In general, most participants gave a very high score to all the 55 treatment characteristics on the attribute grading exercise (bottom-up) and several participants stated during the discussion of the list that they found all characteristics important. The top ten characteristics, based upon the attribute grading exercise, are shown in Table   2 (full results can be found in Appendix 8). To a large extent, these characteristics align with the qualitative results; gastrointestinal problems, characteristics related to quality of life, and surgery received a very high score (see 3 While some participants stated that their reason for scoring an attribute was based on long-term reasoning, other participants only looked at the present. However, scoring could also be influenced by patients' previous treatment or disease experience. Particularly, whether they had experienced a certain symptom or side-effect could have determined their grading. In addition, some patients stated that when side-effects were temporary or could be resolved with other medication, they became manageable and therefore less 'important'.

.2.2). Characteristics found relatively less important were related to
[Insert Table 2 here]

Expert panel discussions to ensure the relevance and correct interpretation of the identified characteristics
Two expert panel discussions were held with i) patients (n=2) and patient representatives (n=4) to verify the importance, relevance, comprehensiveness, and understandability of the identified characteristics, ii) clinicians (n=3) to ensure plausibility from a clinical perspective, and iii) preference research experts (n=2) to give insights regarding possible attributes and levels compliant with the corresponding rules 14,15 . During the expert panel discussions, the unmet needs and treatment outcomes important to IBD patients as identified during the FGDs were presented and the relevance and correct interpretation thereof was confirmed. In particular, in-depth discussions were held regarding the following characteristics: reduced energy, mental disorders that patients could struggle with, and the impact of IBD on patients' A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjac145 social interactions and activities. As an outcome, the expert panel discussions led to more detail and insights into the identified themes.

Discussion
This qualitative study revealed in-depth insights into symptoms, side-effects, psychological and social issues that IBD patients find important. During the open discussions, patients highlighted gastrointestinal symptoms, reduced energy, changes in physical appearance, skin manifestations, and vision problems as being major issues reducing their quality of life. In addition, IBD patients elaborated on the uncertainties and fears they experienced regarding the possible need for surgery and in particular an ostomy. The effectiveness and onset of action of medication, and its long-term effects were further identified as major concerns. Lastly, the mental impact of IBD and the need for more psychological guidance, support, and improved communication with healthcare workers regarding patients' emotional well-being was found key.
Our findings show that IBD patients are confronted with both physical and psychological issues that require further support, which has been confirmed in several studies investigating the impact of IBD on patients' health related quality of life. For example, Spagnuolo et al. 32 assessed the satisfaction with social roles and physical function in IBD patients by evaluating patient reported outcomes (PROs) and revealed that IBD patients had an impaired ability to perform normal daily activities compared to a control group. Likewise, Iaquinta et al. 33 collected PRO data and concluded that IBD patients have increased fatigue and anxiety compared with healthy persons. The study from Dudley-Brown et al. 34 identified the following main themes corresponding to our study findings: uncertainty surrounding exacerbations, the desperate need to find successful treatment, and the feeling of being controlled by the disease. Sewitch et al. 35 showed that improving social support can have a favorable impact on psychological distress, ultimately improving health outcomes. Second, staff could be trained in IBD centers to provide more psychological support in the IBD medical care pathway. Third, the results of this study can be used to develop patient decision aids (e.g., flyers, online tools …) that can be integrated in IBD clinical practice to support SDM. During the discussions, patients discussed a multitude of treatment outcomes and unmet needs that should be discussed in clinical practice to enable an informed decision-making. For example, patients mentioned the need for more information regarding the effect of the disease and their treatments on a long and short term, which suggest an opportunity for the development of patient decision aids that can inform patients about these aspects. As a result, the communication between the patient and the health care provider can be facilitated and uncertainties can be addressed. Furthermore, by aligning individual medical treatment decisions with patients' needs and preferences, higher quality decisions, improved patients' compliance, and thereby improved patient's overall health can be achieved 36,37 .
Comparing the disease and treatment characteristics found in this study to those identified in previous IBD patient preference studies (Appendix 1) reveals that some attributes overlap, while others were new. Important to note is that almost all previous studies had a specific scope and A c c e p t e d M a n u s c r i p t should also be viewed in the specific drug therapy context and the influence of the individual drug therapy experience of participants on the identified symptoms and side-effects; the IBD treatment landscape is rapidly evolving, with new therapies that have entered the market or are emerging.
These new treatments have different (long-term) side-effects and efficacy profiles from those currently available. This may explain why patients expressed uncertainties regarding the effectiveness and onset of action of their medication, and the long-term side-effects such as the increased risk of cancer, particularly regarding these treatments that have only being marketed and described for a relative short time.

Implications and further use
The characteristics identified in this study will be useful in informing the design of a subsequent quantitative online patient preference survey to obtain insights from a geographically dispersed and heterogeneous sample of IBD patients. Such a survey will enable to obtain quantitative insights regarding the relative importance of attributes, and whether patient characteristics (e.g., type of treatments received, subtype of IBD, disease state, and experience with symptoms) have a A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjac145

Strengths and limitations
By performing discussions with patients as drug end-users to understand their experiences with both their illness as their treatment, this study demonstrates the value of performing a qualitative patient preference study. Furthermore, the use of focus group discussions with open questions allowed to obtain both broad and in-depth information on the treatment and disease related characteristics that IBD patients find most important. In addition, the plausibility, quality, and comprehensiveness of both the patient material and the study, as the interpretation of the results, was ensured by collaborating with gastroenterologist and members of patient organizations before and after the conduct of the focus group discussions.
Patients with different treatment experiences who may or may not have been in remission at the time of the discussions were included in the study. As a result, participant heterogeneity was introduced to avoid biases in the data; it was envisioned that these individual patient characteristics and experiences could have an influence on participants' opinions. As a consequence, interaction between patients with a different disease and treatment background emerged, ensuring the identified characteristics are found important for patients along the IBD spectrum. Likewise, an extensive literature review was performed to ensure patients also discussed potential 'future' treatment outcomes and side-effects of novel therapies, as well as favorable and unfavorable aspects associated with therapies already being prescribed to IBD patients, and thus not only treatment outcomes and side-effects participants already experienced themselves.
We did not differentiate the results according to drug therapy and IBD subtype as the goal was to provide an overarching view of important themes to IBD patients across therapies. Furthermore, it is worth noting that during the focus group discussions, it was not always possible to differentiate the This study was performed during the COVID-19 pandemic, wherein the social distancing and hospital guidelines in Belgium did not allow face-to-face focus group discussions. Therefore, the discussions were organized online. This may have resulted in participants withholding to interact with others.
Furthermore, it is likely that participants who were not comfortable with online discussions were less likely to participate (e.g., older participants). However, the median age of diagnosis of UC patients in this study was 28.3 and of CD patients 25.3, which is respectively 6.6 years and 3.7 years younger than the average age of diagnosis 40 . Furthermore, as only two focus group discussions were performed and the discussions only contained participants living in Belgium, it cannot be determined if data saturation was reached and if the results can be extrapolated to patients outside Belgium.
Therefore, we could speculate that the inclusion of additional patients from other countries could affect the derived themes.
Finally, it should be noted that the qualitative analysis of the focus group discussions was conducted by one researcher as opposed to multiple researchers, meaning that no cross-check was performed.
Nevertheless, regular meetings between the researchers that conducted the focus group discussions minimized subjective interpretation of the data.

Conclusion
This study shows that IBD drug development and individual treatment decision-making does not only need to focus on controlling IBD patients' gastrointestinal symptoms, but also on other symptoms and adverse events that significantly impact IBD patients' quality of life. Furthermore, this study underscores the need for shared decision-making between healthcare providers and IBD patients where treatment outcomes and uncertainties about long-term efficacy and safety of medication are explicitly addressed and considered. Findings from this study may serve pharmaceutical industry, regulators, and HTA bodies/payers in understanding patient-relevant unmet needs and treatment outcomes to enable value-based and patient-centric decision-making that is aligned with the true patients' needs across the IBD drug life cycle.
M a n u s c r i p t   10 Prevent flare-ups 9,00 1,79 10 4