Assessing Side-Effect Bother, Burden, and Tolerability: A Qualitative Study Exploring the Content Validity of the Functional Assessment of Cancer Therapy – Item GP5

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Gilligan, Danielle Altman, Patricia Maeda, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4730587/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Patient-reported measures of overall side effect burden, such as the Functional Assessment of Cancer Therapy- item GP5 (GP5), can be used to inform the tolerability of cancer treatments and be included as an endpoint in clinical trials. The objectives of this qualitative study were to explore how participants with medullary thyroid cancer (MTC) conceptualize side effect bother, burden, and tolerability and to generate evidence to support the GP5 as a fit-for-purpose measure of patient-reported tolerability in the treatment of MTC and to establish which response options constitute “high side effect burden.” Methods A purposive sample of forty participants with MTC enrolled in the LIBRETTO-531 trial (NCT04211337) were recruited via clinical trial sites. Semi-structured interviews were conducted in the participant’s preferred language to examine the concept of tolerability, demonstrate understanding of the GP5 content, and establish which response options constitute “high side effect burden”. Interview transcripts were thematically analyzed with a mix of inductive and deductive coding methods. Results Concept elicitation results found side effect bother to be among the most proximal patient-reported concepts to tolerability and highly relevant to participants. The experience of side effects that are symptomatic and bothersome or burdensome are key contributors to how patients perceive the tolerability of a treatment. Cognitive interviewing showed the GP5 item was clear and understandable to all participants. Participants reported clear and concrete meaningful differences between each response option. Importantly, the qualitative data provide evidence that “high side effect burden” aligns with the response options of “Quite a bit” and “Very much” (score of 3 and 4, respectively) for most (60%, n = 24) interview participants. Conclusion Participants described the concepts of side effect bother, side effect burden, and tolerability as highly relevant and related. The GP5 assesses a concept important to individuals undergoing treatment for MTC in a way that is understandable and relevant. The definition of “high side effect burden” is appropriately reflected by scores of 3 or 4. This qualitative evidence is supportive of the GP5 as a fit-for-purpose measure of comparative tolerability in MTC. Figures Figure 1 Plain English Summary [Optional for SCC] With recent advances in the effectiveness and availability of cancer treatments, more patients are living longer. However, it also means that more patients may live with the potential side-effects of cancer treatments. Research is needed to better understand and evaluate the impact of treatment side effects and their burden. This study was designed to enhance the understanding from the patient perspective on treatment tolerability and the distinction between bother and burden. Moreover, the study examined whether an existing patient-reported measure for assessing the impact of side effects, the GP5 item, was understood by patients and what response options were considered as “high side-effect bother”. Forty participants with medullary thyroid cancer enrolled in the LIBRETTO-531 trial from eight different countries were invited to participate in interviews. The interview transcripts were then analyzed to gain insights into the common features of the patient experience of side effects and differences between tolerability, bother, and burden. The study found that the GP5 question and its response options were clear and easy to understand. Lastly, GP5 response options of “quite a bit” and “very much” reflected a high side-effect bother. In conclusion, GP5 is an appropriate measure to assess patient-reported tolerability in patients with MTC in the context of a clinical trial. Background Side effects that are symptomatic and bothersome may be key contributors to how patients perceive the tolerability of a treatment and their ability or desire to continue it [ 1 ]. Patients who report a greater degree of side-effect burden are at an increased risk for discontinuing treatment before completion [ 2 ]. Understanding how patients experience and perceive side effects has therefore become increasingly crucial for investigating treatment tolerability, predicting treatment discontinuation, and assessing quality of life. There is increasing support for including the patient-reported measurement of tolerability in oncology clinical trials [ 1 , 3 , 4 ]. Crucially, the concept of tolerability is inherently patient-centered; it can be usefully distinguished, for example, from the clinician-centered concept of treatment safety [ 5 ]. Multiple stakeholders, including regulators (both US and EU), researchers, patients, and sponsors, define tolerability as “the degree to which symptomatic and non-symptomatic adverse events associated with the product’s administration affect the ability or desire of the patient to adhere to the dose or intensity of therapy” [ 4 , 5 ]. In addition to the collection of patient-reported data on individual symptomatic adverse events, the FDA and other stakeholder groups identify overall side-effect burden as a “core measurement concept” to inform the tolerability of cancer treatments [ 1 , 6 , 7 ]. An overall side-effect impact summary measure facilitates the comparison of tolerability across clinical trials. Overall side-effect burden has been theorized to be the most proximal patient-reported concept to tolerability [ 4 ]. However, in research to date, the terms overall side-effect impact, burden, and bother are used interchangeably, and often without explicit definitions of the terms [ 7 – 10 ]. While side-effect bother, burden, and impact have not been consistently well defined in the literature [ 11 ], it can be inferred that these terms are used to refer to the physical experience of treatment side effects and their interference with activities of daily living, emotions, social life, and role functioning [ 11 ]. Yet there is limited knowledge of how patients define such terms, including whether patients themselves view these terms as interchangeable. The FDA draft guidance on Core Patient-Reported Outcomes (PROs) in Cancer Clinical Trials identifies the Functional Assessment of Cancer Therapy (FACT) item GP5 (GP5) as a measure for assessing overall side effect impact [ 11 ]. The GP5 is a single-item patient-reported summary measure that assesses the overall impact of treatment toxicity by asking about overall side effect bother [ 12 ]. In the GP5, the statement “I am bothered by side effects of treatment” is measured for the previous 7 days on a 5-level Likert scale: 0 (not at all); 1 (a little bit); 2 (somewhat); 3 (quite a bit); or 4 (very much). Rigorous qualitative methods, including semi-structured interviews and cognitive interviewing with patients, informed the development and validation of the GP5 item as part of the 33-item FACT-General scale between 1987–1992 [ 12 ]. While the GP5 is increasingly used in cancer clinical trials and the content validity of the GP5 as a measure of tolerability has been investigated [ 13 ], there is need for additional qualitative data to support it being fit-for-purpose as a measure of comparative tolerability in clinical trials. In addition, to understand how patients conceptualize side effect bother and tolerability, evidence demonstrating which response options patients interpret as “high side-effect bother” are critical to inform an estimand framework to quantify and compare tolerability in randomized clinical trials [ 14 ]. The objectives of this qualitative study were: (1) to explore how participants with medullary thyroid cancer (MTC) conceptualize side effect bother and burden, and (2) to generate evidence to support the GP5 as a fit-for-purpose measure for patient-reported tolerability and establish which response options constitute “high side effect burden.” Methods Study design and participants This qualitative, non-interventional, descriptive study leveraged cross-sectional qualitative interviews with individuals with MTC participating in the LIBRETTO-531 study. The LIBRETTO-531 study is a global, multi-center, randomized (2:1), open-label, Phase 3 study comparing selpercatinib to physician’s choice of cabozantinib or vandetanib in patients with progressive, advanced, tyrosine kinase inhibitor (TKI)-naïve, rearranged during transfection ( RET) -mutation positive MTC. Within the LIBRETTO-531 trial, comparative tolerability, a key secondary PRO endpoint, was assessed by comparing the proportion of time on treatment, postbaseline, with “high sideeffect bother,” as measured by the GP5 score of 3 or 4, between the selpercatinib arm and the cabozantinib or vandetanib arm. This endpoint allows for evaluation of the overall impact of side effects from the patient’s perspective to further support the clinical benefit of selpercatinib [ 15 ]. Participants were recruited via LIBRETTO-531 trial sites in the US, UK, Australia, Germany, Italy, Poland, the Czechia, and Spain. The clinical sites obtained institutional review board (IRB) approval for the interviews. In addition, clinical site staff underwent training on the study procedures and obtained verbal and written (through completion of a Patient Interviews Contact Information Form) consent from potential participants to be contacted by interview study personnel. Patients were eligible to participate if they met the following criteria at the time of recruitment: were eighteen years of age or older; were active participants in the LIBRETTO-531 trial (defined as still receiving treatment and with no disease progression) participating at one of the clinical trial sites at the time of recruitment; were able to speak one of the following languages: English, Spanish, French, German, Italian, Polish, Portuguese, Czech, or Dutch; and agreed to be contacted for a qualitative interview. Study documents Regulatory and ethical approvals were provided under the aegis of the LIBRETTO-531 clinical trial. Study documents, which were developed and submitted as an addendum to the LIBRETTO-531 trial protocol, included a participant contact form for scheduling purposes, a slide deck to facilitate site training on recruitment and data privacy procedures, the participant interview guide, and the GP5. The validated translations of the GP5 used in Lilly’s LIBRETTO-531 trial were obtained in all study languages. The interview guide and site training slide deck were translated by Global Perspectives, the recruitment agency that was also contracted to moderate, translate, and transcribe the non-English language interviews. Interview methods Qualitative interviews were approximately 30–60 minutes in duration and were conducted utilizing a 1:1 approach with a semi-structured interview guide. Interviews included two components: 1) concept elicitation on the side effect experience and the patient interpretation of the concepts of bother, burden, and tolerability; and 2) cognitive interviewing of the GP5 to assess participants’ interpretation of the item and response choices and which response options participants equated with high side-effect bother. Interviews were conducted online in the language associated with each clinical trial site. English language interviews were conducted by Modus Outcomes and non-English language interviews were conducted by Global Perspectives. During cognitive interviewing, participants read the GP5 item on the screen during the online interview and shared their thought process about how they would answer it. Interviews were audio recorded, transcribed, and anonymized. Non-English language interviews were transcribed directly in English. Lilly extracted the following data elements for each study participant from LIBRETTO-531 clinical data at baseline: age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, year of MTC diagnosis, and number of weeks between the first day of treatment and the interview date. Timing of the interview was targeted at 10–14 weeks from baseline (the first date of treatment), in alignment with the FDA’s recommendation for when peak toxicity can be accurately evaluated [ 16 ]. Data analysis Interview transcripts were thematically analyzed with a mix of inductive and deductive coding methods [ 17 ] using detailed line-by-line coding [ 18 – 20 ] with ATLAS.ti software [ 21 ]. Independent parallel coding was used to initiate coding and ensure consistency using the first two transcripts. The lists of codes and associated quotes obtained by three independent coders were compared for overlaps and inconsistencies and were revised as needed to reach coder alignment. For the concept elicitation analysis, researchers reviewed the raw data assigned to codes to derive a list of side effects and to derive themes related to the conceptualization of side-effect bother and burden ( Supplemental Fig. 1 ). A saturation analysis was conducted to evaluate saturation of the concept elicitation data related to the concepts of bother, burden, and tolerability. The transcripts were ordered chronologically, based on the interview completion dates, and then divided into eight groups of five. Themes in each group were then compared against those in the previous group to determine the degree of thematic saturation achieved. For the cognitive interviewing analysis, structured codes were used to compile data on participant understanding of the item and recall period, interpretation of response options, and opinions on the response options that reflect high side-effect bother. To analyze the participant feedback on what information participants retrieved and thought about when interpreting a response option, researchers inductively categorized the information participants reported based on patterns the research team found in the raw data and reported the information in a table. To investigate the comprehensiveness of the GP5 for measuring bother and burden, themes identified for those concepts were compared to themes identified in relation to how participants interpreted the GP5 response options. Results Sample characteristics Transcripts from forty participants were included in the analysis. A description of the sample is provided in Supplemental Table 1. The mean and median ages of participants were 55.5 (standard deviation [SD] 13.6) years and 60.5 years, respectively, and 67.5% were male. The mean and median number of weeks between the first day of treatment in the trial and the interview date were 62.7 (SD 37.1) and 59, respectively. Concept elicitation interviews Side effects reported by participants Sixty-three unique symptomatic side effects were identified and categorized across the following 12 domains: attention/memory, cardio/circulatory, cutaneous, fatigue, gastrointestinal, neurological, nose and throat, oral, pain, sexual, urinary, and miscellaneous. Side-effect bother Table 1 documents six themes identified in relation to how participants (n=40) conceptualized side-effect bother. The themes are not exclusive (i.e., one participant may have reported a number of themes in relation to each concept of bother). Table 1. Domains, themes, and quotes related to side-effect bother Domains Themes Participant quotes Interference of side effects with daily activities Bothersome side effects interfere with daily activities, such as by limiting which activities participants can do (e.g., going fishing), reducing the amount of time they can do an activity (e.g., length of time shopping), or by making them adapt (e.g., making sure toilets are nearby in public) (n=29) “If I do some hard work and I want to get it done in four hours, but I can’t and I need eight hours for it. That is what “bothered” means to me.” “[Bothered means I] couldn’t do my normal duties in life. Like I got too sick to walk or get up.” Physical experience of side effects Bothersome side effects cause physical discomfort (n=26) “[Bother] is if someone takes a drug and feels any type of discomfort after it… pain, diarrhoea, nausea.” Cognitive and emotional experience of side effects Bothersome side effects increase cognitive effort and cause annoyance/ inconvenience (n=13) “Bothered just means… that [side effects] irritate you throughout the day so that you think about it – that it’s annoying. I’m still able to do most of the things that I would do for my children and my family.” Bothersome side effects cause additional thought burden, mental health problems, or negative emotions, such as worry, concern, or reduced joy (n=10) “Fatigue takes the joy of going on a walk or on a bike ride away from you; same thing goes for taste loss and appetite loss.” Bothersome side effects affect appearance in a stigmatizing way (n=4) “[Bother includes] if it restricted me in some physical movement, in some physical activity, or I don't know, let's say, I don't know, maybe I would get some kind of rash that would actually change my appearance.” Comparison of clinical efficacy to the side effect experience The benefits of the treatment (e.g., effectiveness, survival) are weighed against the harms of side effects when considering the degree to which side effects are bothersome (n=5) “[Bothered] means that I am happy anyway. I have some bother but I’m still alive. If it wasn’t for this drug, I would be dead.” Side-effect burden Nine themes were identified in relation to how participants (n=40) conceptualized side-effect burden (Table 2). Themes were organized into the following four domains: burden compared to bother, interference of side effects with daily activities, physical experience of side effects, and the cognitive and emotional experience of side effects. Table 2: Domains, themes, and quotes related to side-effect burden Domains Themes Participant quote Burden compared to bother Side-effect burden is similar to side-effect bother, but burden implies a greater degree of side effect severity or interference in daily activities in general (high side-effect bother) (n=31) “Bother is just an inconvenience ... a burden is I’ve had to change the way I live my life.” “The word "burden" is much more heavy [than “bother”] . Interference of side effects with daily activities Burdensome side-effects interfere with daily activities, such as by limiting which activities participants can do (e.g., going fishing), reducing the amount of time they can do an activity (e.g., length of time shopping), or by making them adapt (e.g., making sure toilets are nearby in public) (n=17) “[If I] get diarrhoea ten times a day… when I'm working and I'm in a meeting at work, I have to just leave the room to go to the toilet, or I have to get up at night and go to the toilet, which means I feel like I'm falling asleep again afterwards… it's a burden on me.” Burdensome side-effects interfere with daily activities more than bothersome side effects (n=18) “Bother is what you feel. A burden would be if I was no longer able to work… not being able to be active and turn around and do the sort of things that I’ve done for 50-odd years… there’d be a lot of frustration there.” Physical experience of side effects Burdensome side-effects cause physical discomfort (n=9) “My burden issue is... here is this tightening at the neck and shoulders… Like if you put your two hands around my neck and you press down.” Burdensome side-effects are more severe than bothersome side effects (n=14) “[Burden] means greater pain [than bother], when I could not get out of bed.” Burdensome side-effects have a longer duration than bothersome side effects (n=7) “Bother is only temporary… [a burden] is not temporary anymore.” Burdensome side-effects are more frequent than bothersome side effects (n=4) “If the diarrhoea was more than twice a day, that's already some minor burden.” Cognitive and emotional experience of side effects Burdensome side-effects cause mental health problems or negative emotions (n=10) “[Burden] is you’re weighed down with problems and feeling anxious.” Burdensome side-effects cause a greater cognitive effort and/or have a greater and more negative impact on mental health or emotional well-being than bothersome side effects (n=8) “Something bothersome is tolerable, not worrying; on the contrary, a heavy side-effect can create concern. Swelling on the eye does not worry me, whereas an alteration in blood values does because it could upset the physiological balance.” Tolerability Seven themes were identified in relation to how participants (n=40) conceptualized tolerability (Table 3). Themes were organized into the following six domains: tolerability compared to bother and burden, clinical efficacy, interference of side effects with daily activities, the cognitive and emotional experience of side effects, comparison of clinical efficacy to the side effect experience, and the physical experience of side effects. Table 3: Domains, themes, and quotes related to tolerability Domains Themes Participant quote Tolerability compared to bother and burden Tolerability is related to bother and/or burden (n=31) “[Bother and tolerability] are related because for me, if it's just a nuisance and not a burden, that just means it's more tolerable.” “[Burden and tolerability are related] because as I said, burden’s more psychological, and when my body couldn’t tolerate it and wasn’t adjusting to it, it would have a big psychological impact on me.” Clinical efficacy The efficacy of the treatment is considered when determining how tolerable its side effects are (n=20) “Tolerable means I'm taking something that is targeted, that blocks or limits the growth of my tumour so to say, and when by taking the treatment I reach the goal—that the tumour doesn't grow further.” Interference of side effects with daily activities Side effects are tolerable if they don’t significantly interfere with daily activities (n=18) “[Tolerable] means you can grit your teeth and still [walk], but if something hurts a lot then you just sit down and wait for it to subside.” “If I can’t lead my life… if I can’t manage my household anymore, I would say that it’s not tolerable anymore.” Cognitive and emotional experience of side effects Side effects are tolerable if they are bearable (n=18) “I know I just have to take it, I have to persevere, I just have to accept what is… when [the side effects] started it wasn’t nice, so I know what something better means.” “[Tolerable] means bearable; that you can bear it and live with it.” Comparison of clinical efficacy to the side effect experience The benefits of the treatment (e.g., effectiveness, survival) are weighed against the harms when determining how tolerable the side effects are (n=16) “[The treatment] is tolerable because I want to recover from cancer… life is worth it. It’s worth it to suffer to live.” The side effects and clinical efficacy of other treatments are compared to side effects and clinical efficacy of one’s own treatment when determining how tolerable its side effects are (n=6) “What makes it tolerable is [that it] gives you a better quality of life in comparison to other treatments… The opposite would be a devastating treatment, that prevents you from leading a normal life, and maybe causes a rebound effect, meaning that it gives positive results during the first months, but then you “bounce back” to square one.” Physical experience of side effects Side effects are tolerable if their or severity is none to mild (n=8) “[Tolerable] means that I take my tablets. They don’t affect me when I take them.” “Tolerable would be a mild pain I can actually handle and tolerate on a day-to-day basis.” Thematic saturation Conceptual saturation of themes related to bother, burden, and tolerability was achieved in transcript group 2 (i.e., the second group of n=5 interviews analyzed). Cognitive Interviewing Overall, the majority (92.5%, 37 out of 40) of participants found the response options for the GP5 to be clear and easy to understand. Only one participant expressed that the item was difficult to answer, stating challenges in distinguishing their cancer symptoms from treatment side-effects. All participants (100.0%, 40 out of 40) reported that the GP5 item measures bother, that the content of the GP5 item was clear, and nothing was needed to make it easier to understand. Relevance Only 7.5% of participants (3 out of 40) reported the item was not relevant to them. The reasons for irrelevance included: two participants were not experiencing or bothered by side effects and one participant questioned whether the item was relevant in the context of a clinical trial, since participating in a trial reflects a willingness to experience side effects. Item clarity and interpretation All 40 participants (100.0%) reported that the GP5 content was clear. One participant suggested adding to the question whether a new side-effect occurred in the past 7 days to capture the fluctuating nature of the treatment side effects. When asked what the item meant to them, participants offered various descriptions to interpret the item’s meaning (Table 4). Retrieval of information Two participants (5.0%) reported challenges with the 7-day recall period. Some participants reported having used different recall methods to answer the question, which was contrary to the instructions to focus on the past 7 days. Participants also reported reflecting on various types of content to answer the question as well as factors that influence their responses. See Table 4 for a description of results. General response options feedback Three participants (7.5%) reported issues with the response options (n=1 participant had two comments). One participant noted that the response options “A little,” “Somewhat,” and “Quite a bit” needed to be elaborated as the wording did not accurately capture their experience. One participant suggested turning the options into a scale of 1 to 100 for more granularity and adding another response option after “Very Much.” One participant shared that the item was difficult to answer as they could not distinguish their cancer symptoms from treatment side-effects (Table 4). Table 4. Cognitive interviewing of GP5: Item understanding, retrieval of information, and response option feedback Item clarity and interpretation Retrieval of information General response options feedback How do participants understand the item? 40 out of 40 participants reported that the GP5 content was clear and that nothing would be needed to make it easier to understand. Suggestion Suggested adding to the question whether a new side effect occurred in the past 7 days (n=1) Interpretation of the item How much the side effects are impacting their life (e.g., quality of life, hobbies, work) (n=12) Being bothered/worried by side effects (n=11) What condition they are in at the moment (e.g., well-being, how treatment is progressing (n=3) Side effect severity (n=1) Side effect type (e.g., pain) (n=1) Side effect variation (n=1) Being able to stand side effects/not be disturbed by them (n=1) Whether the benefit of the drug is outweighing the side effects (balance) (n=1) What do participants consider when arriving at a response? (symptoms, impacts, timeframe, etc.) 38 out of 40 participants reported that it was easy to recall and retrieve information to answer the GP5. N=2 reported problems with the 7-day recall period Hard to answer due to the varying nature of side effects (n=1) Difficult to recall the past 7 days (n=1) Thought process: Recall period Thought about the past 7 days, as instructed (n=6) Thought about the most severe day of the week (n=1) Thought about the average over the week (n=5) Thought about the past 2-3 days, which is inconsistent with the instructions (n=1) Thought about how one feels at the moment (n=2), which is inconsistent with the instructions Thought process: Content recalled Reflected on their side effects (n=22) Reflected on how one feels (e.g., physical and cognitive/emotional experience) (n=9) Reflected on impact on daily life (n=6) Response influence Response was influenced by comparing to other cancer patients (n=2) Response was influenced by comparing with other conditions (n=1) Response was influenced by comparing to other treatment experience (e.g., more invasive procedures) (n=1) Response was influenced by comparing to their trial experience at the beginning (n=1) Response was influenced by reflecting on the overall benefit of the drug (n=2) Are response options appropriate for respondents? 37 out of 40 participants reported the response options were appropriate. N=3 participants reported problems with the response options (n=1 participant had two comments): Response options not sufficient to cover everything (n=1) Suggested making the response options into a scale (e.g., 100-point) (n=1) Suggested adding another response option after “Very much” (n=1) Reported difficulty answering the item (hard to distinguish cancer symptoms from side effects) (n=1) Participant interpretation of response options When selecting a response option and reporting on what each response option meant to them, participants (n=40) reflected on the cognitive and emotional experience of side effects, such as their level of worry or concern about them, the physical experience of side effects, and/or the level of interference of side effects in their daily activities. Some participants reflected on whether the side effects were severe or impactful enough to consider contacting their doctor. A few participants reflected on clinical efficacy, the effectiveness of treatments for the side effects, and/or whether side effects were severe or impactful enough to consider dose delay, treatment discontinuation, or dose modification. Table 5 details the full participant interpretation of each response option, accompanied by illustrative quotes. Table 5. Participant interpretation of GP5 response options Response option Participant interpretation Participant quote 0 – Not at All Cognitive/emotional experience of side effects : No worries, problems, concerns, or bother (n=22) ; Minor annoyance (n=1); Have coped with/gotten used to it (n=3) Physical experience of side effects : Side effect existence : Side effects not present (n=12) Severity : Side effects present but were not severe at all (n=4) Duration : Short (1 – 2 week) duration: (n=1) Daily activity interference : No impacts on day-to-day activities or functioning (n=8) Clinical efficacy : Treatment is effective (n=1); compare benefits to harms (n=1) Treatment of side effects : Side effects are successfully treatable (n=1) Not sure: (n=1) “Well, not at all, for me, means I haven’t got – I don’t know what to say. How can you say not at all? I have no concerns at all. It’s not on my mind. Nothing’s happening to me, basically, other than normal things.” “Not at all means that I don’t feel absolutely anything, that there’s no repercussion, no side effect following the treatment.” “It would mean that I feel as I did before I started treatment, I may have developed acne, for example, or this change in hair color, but it does not hinder my functioning in any way.” 1 – A Little Bit Cognitive/emotional experience of side effects : No bother (e.g., feeling like nothing is wrong, not minding the side effects or only thinking about the side effects occasionally in the back of mind) (n=8); Causes light bother (n=20); Can endure it (n=2) Daily activity interference : No impacts on daily activities or functioning (n=7); Light impacts on daily activities or functioning (n=9) Physical experience of side effects : Severity : Mild severity (n=14); 20-25% of discomfort (n=1) Duration : Short duration (e.g., a few minutes, a day, a few weeks) (n=5) Frequency : Low frequency (1 – 7 times a week) (n=10) Clinical efficacy : Compare benefits to harms (n=1) Contact provider/ask for meds: Ask the doctor about how to treat side effects (n=1) “I’m not worried about it, because I’m feeling healthy. I feel good. So yeah, I’m a little bit worried, because I have the cancer, but I’m not really – yeah, I feel healthy.” “Mild side-effects that are worth mentioning but not severe.” “Well, again, like in my case, the person has a bloated belly, it’s nothing serious, it just bothers, but only for an hour, half an hour, two hours once or twice a month, I guess.” 2 – Somewhat Cognitive/emotional experience of side effects : Causes moderate bother or annoyance (e.g., more worried that drug is not working, bother is more on the mind, more noticeable, having negative feelings) (n=26); Bother turns into burden (n=4); Can still cope with it or bear it (e.g., still within limits) (n=6) Daily activity interference : Need to change or reduce daily activities (e.g., needing to rest during the day, impact activities for a few hours, feeling inconvenienced) (n=15); Do not have to change or reduce daily activities (n=2) Physical experience of side effects : Number of side effects : Experiencing multiple side effects (n=2) Severity : Moderate severity (e.g., SE more severe, experiencing changes in health) (n=4); 40% of discomfort level (n=1); Mild severity (n=1) Duration : Duration is constant (e.g., throughout day) (n=5); Few hours (n=2) Frequency : High frequency (3 – 7 times a week, more frequent) (n=8) Treatment of side effects: None needed (n=1); Have to do something about the side effects (n=1) Clinical efficacy : Comparison of own’s treatment and side effects to those of other cancer patients (n=1) “Well, somewhat would mean I’m not handling the drug. Like I’ve got a few problems. Yeah, I’m starting to worry. Maybe it’s not working. Maybe these side effects are a bit too much.” “If I had to answer somewhat, it would mean that at least once during that day, it had affected what I do during the day. It would have been something that lasted for a few hours or a day or meant that I had to rest or put my feet up or whatever. So that would be somewhat to me.” “Well, then it’s already a bit more uncomfortable. But still in a way that I can bear it.” 3 – Quite a Bit Cognitive/emotional experience of side effects : Causes a lot of bother (e.g., feeling sudden changes in health, negative feelings like annoyance, worry, concern) (n=11); Feeling burden (n=3); Unbearable (n=4); Can be endured (n=1) Daily activity interference : Big impact on day-to-day activities (e.g., difficulty doing things such as physical functioning, eating, watching TV, working, speaking to people) (n=20); Reduced quality of life (n=2) Physical experience of side effects : Number of side effects : Experiencing multiple side effects (n=1) Severity : Strong severity (e.g., more painful/unacceptable (n=11); 70% of discomfort level (n=1) Duration : Constant duration (n=3) Frequency : High frequency of side effects (range of 2 to more than 10 times per week) (n=7); Persistent regularity or recurrence of side effects (n=3) Contact provider/ask for SE treatment: Need treatments (e.g., consulting the doctor, getting more treatments or higher dose of treatments to reduce side effects) (n=6); Side effects do not respond to treatment (n=1) Clinical efficacy : Compare benefits to harms (n=2) Consider discontinuing treatment (n=1) “ So if all of a sudden, things started changing a lot more, I would definitely be more worried.” “I cannot eat like I used to before, I have difficulty swallowing, I eat yogurts, I can still eat some food, but it causes me pain, I don’t have much saliva, I have to support myself with water, in the same way calluses are quite painful, I try not to walk too much, I am limited.” “Well, that it’s not as good as it was, that it’s worse, that it’s gotten worse, well… That my skin would crack more and it wouldn’t be the same.” “That would be where I’m starting to lose patience and thinking that – is it worth taking the drug? I need to contact somebody to find out more information about what’s happening or a solution to whatever was happening.” 4 – Very Much Cognitive/emotional experience of side effects : High bother (e.g., very worried about what’s going on, things don’t feel right, not understanding what’s going on) (n=9); Feeling burden (n=1; Unbearable/Unable to cope (n=8) Daily activity interference : Big changes in lifestyle (e.g., extreme difficulties with activities such as physical functioning, going outside, working, eating; needing help) (n=18) Physical experience of side effects : Number of side effects : Experiencing multiple side effects (n=1) Severity : Extreme severity (n=11); 80% or more of discomfort level (n=1) Duration : Constant duration (n=2); Lasts a week (n=1) Frequency : Daily occurrence (n=3) Contact provider/ask for meds: Ask for medical help (e.g., call provider, seek medication, immediate need to go to emergency room (n=8) Consider dose delay/dose modification/ discontinuing treatment : Change dose/drug (n=3); Consider discontinuing treatment (n=2); Decide to discontinue treatment (n=3) Clinical efficacy : Compare benefits to harms (n=2) “The fact that you actually start to wonder if it’s better not to live than to live. Yeah, that you’re in tremendous pain. Like forget going anywhere with a diaper at all, it’s just, it’s nice, you’ve got a diaper on, but you’re actually having such cramps, or I don’t know, things like that, that you don’t actually think about going to the store anymore.” “If it was affecting me very much, that’d be a big change in my lifestyle then. I’d be thinking I can’t do this. I can’t go out of the house. I can’t go to work. Or even if I do, I can’t carry on as normal.” “‘Very much means that you can hardly stand it anymore. That you really consider to discontinue the medication because you felt almost worse with the medication .” “And then I had difficulties to see, because there was this puffiness under the eyes, and the legs were so swollen that I could not put on the shoes.” Response options reflecting high side-effect bother and discontinuing treatment Participants were asked to select a response option at which high side-effect bother starts. Six participants chose not to answer; of those, two participants found it difficult to select a response that best reflected high side-effect bother, and four provided unclear responses (Figure 1). Of the 34 participants who selected a response option that best reflected the concept of high side-effect bother, 24 (70.6%) selected “Quite a bit” or “Very much.” A question of when participants would consider discontinuing treatment was also asked. Of the 30 participants that were asked this question, the majority (18, 60.0%) selected “Quite a bit” or “Very much.” Twelve participants could not decide (n=7) or provided an unclear answer (n=5). Discussion This study utilized concept elicitation and cognitive interviewing methods to generate the necessary qualitative evidence to support the GP5 as a fit-for-purpose PRO measure of comparative tolerability. Concept elicitation results demonstrated that side-effect bother is among the most proximal patient-reported concepts to tolerability and that the concepts of side-effect bother, side-effect burden, and tolerability are related and highly relevant to participants. The study found that side effects that are symptomatic and bothersome or burdensome are key contributors to how patients perceive the tolerability of a treatment. This aligns with a recent study that debriefed the GP5, which found that for most patients the severity of side effects determines bother; and moreover that functional impact, emotional impact, physical impact, specific symptoms, and overall quality of life were also considered by patients when interpreting the concept of bother [ 13 ]. Side-effect bother, burden, and impact have been used interchangeably in regulatory and scientific guidance on the measurement of patient-reported treatment tolerability [ 4 , 22 ]. Notably, most participants in this study reported that they defined side-effect burden in the same way they defined side-effect bother, except that “burden” implied greater physical discomfort, greater interference with daily activities, or greater mental or emotional distress than “bother.” In this study, nearly all participants considered side effects bothersome and/or burdensome if they caused physical discomfort, interference in daily activities, and/or mental or emotional distress. Furthermore, the majority of participants also described tolerability as conceptually related to bother and/or burden. Tolerability was also discussed by half of the participants in the study in terms of weighing the efficacy of the treatment against the side effects. Cognitive interviewing showed the GP5 item was clear and understandable to all participants and easy to answer for nearly all participants. Participants reported clear and concrete meaningful differences between each response option. Importantly, qualitative data provides evidence that the definition of “high side-effect bother” in the LIBRETTO-531 trial aligns with GP5 response options of “Quite a bit” and “Very much,” the response options most interview participants reported reflected high side-effect bother and/or consideration to discontinue treatment. These findings are similar to those of another study, which found that the majority of participants reported bother would proportionally increase with side-effect worsening and proportionally decrease with side-effect improvement [ 13 ]. As increasing emphasis is placed on understanding the link between tolerability and treatment discontinuation, researchers have begun to investigate the association between treatment discontinuation and specific response options on overall side effect summary burden measures such as the GP5. Wagner 2018 et al. found that a moderate to severe degree of patient-reported side-effect bother at baseline (defined as including the response options ‘‘quite a bit’’ and ‘‘very much” on the GP5) was quantitatively associated with higher risk of early treatment discontinuation in a breast cancer clinical trial [ 23 ], suggesting the GP5 may be well-positioned to predict treatment discontinuation [ 24 , 25 ]. When we asked open-ended (unprobing) questions about the meaning of response options, only n = 1 and n = 8 participants respectively associated the response options “quite a bit” and “very much” with considering dose modification or treatment discontinuation. However, when asked probing questions about which response option they associated with considering discontinuing treatment, most participants reported they would associate “quite a bit” and “very much” with discontinuation. Notably, nearly one-quarter of participants reported that associating a response option with discontinuing treatment was either not relevant to them as a cancer patient or was impossible for them to do. Participants further elaborated that clinical efficacy mattered to them and/or they did not feel the item and its response options allowed them to account for the consideration of clinical efficacy. Across our concept elicitation and cognitive interviewing data sets, including elicitation on the concept of tolerability, participants emphasized that survival is of such importance that overall side-effect bother would need to approach unbearable levels for treatment discontinuation to be considered (in the context of a treatment regimen that has clinical efficacy). Overall, our data supports the association of the GP5 response options “quite a bit” and “very much” with considerations of treatment discontinuation, but additional research may be warranted to understand the degree to which GP5 data can be used to predict treatment discontinuation. The study boasts several points of strength and differentiation. Firstly, the participants included in this study represented a heterogenous sample in terms of age, national residence, language, and year of MTC diagnosis. Such a diverse sample assures greater representation and helps to overcome numerous potential forms of sampling bias. Another signal strength of the study was the methodology, which included the triangulation of concept elicitation data and cognitive interviewing data to explore the content validity of the GP5 as a measure of side-effect bother, burden, and of the threshold for high side-effect bother. There are also limitations that require mentioning. The time from baseline (the date of first treatment) to interview was targeted at 10–14 weeks, however, the majority of interviews (n = 36) fell outside that timeframe. Despite that, nearly all participants were able to describe their side-effect experience in depth. Potential selection bias should be considered when interpreting results of this qualitative study among clinical trial participants. Differences between clinical trial participants and non-clinical trial participants have been observed in regards to demographic, socio-economic factors, and health factors [ 26 , 27 ]. These factors could be associated with different interpretations of bother, burden and tolerability, as well as different views on which response options they would associate with high side-effect bother and with potential treatment discontinuation. Finally, participants were asked how GP5 response options related to the hypothetical scenario of discontinuing treatment; hypothetical questions pose potential risk for bias because they ask participants to guess how they would act in an imagined situation and may be incongruent with how they would act in actuality [ 28 ]. Conclusion In this study, participants described the concepts of side-effect bother, side-effect burden, and tolerability as highly relevant and related. The qualitative evidence generated in this study is supportive of the GP5 as a fit-for-purpose measure of comparative tolerability in MTC clinical trials. The GP5 assesses a concept important to individuals undergoing treatment for MTC in a way that is understandable and relevant. The definition of “high side-effect bother” is appropriately reflected by scores of 3 or 4. Declarations Funding This research was funded by Eli Lilly and Company. Author information Affiliations Eli Lilly and Company, Indianapolis, IN, USA Nalin Payakachat, Adrienne M. Gilligan, Patricia Maeda, Shannon Bourke, Rebecca M. Speck Modus Outcomes, Cary, NC, USA Danielle Altman, Julia Choi, Erica Spies Department of Oncology, 2nd Faculty of Medicine of Charles University and Motol University Hospital, Prague, Czech Republic Katerina Kopeckova Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Rossella Elisei Weston Park Cancer Centre, Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom Jonathan Wadsley Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland Jolanta Krajewska Contributions All authors read and approved the final manuscript. DA, JC, and ES contributed to research design, interview conduct, qualitative analysis, interpretation, and manuscript development. NP, AMG, PM, SB, and RMS contributed to research design, interpretation, and manuscript development. KK, RE, JW, and JK contributed to manuscript development. Corresponding author Correspondence [email protected] Editorial assistance Medical writing support for this manuscript was provided by Trais Pearson, PhD, of Modus Outcomes and was funded by Eli Lilly and Company, Indianapolis, IN, USA. Disclosures NP, AMG, PM, SB and RMS are employed by Eli Lilly and Company. DA, JC, and ES are employed of Modus Outcomes and was funded by Eli Lilly and Company, Indianapolis, IN, USA. KK reports consultancy role for Eli Lilly and Company. RE reports consultancy role for Eisai, Eli Lilly, Bayer, Roche, and Ipsen. JW reports fees to institution for speaker/advisor fees from Eli Lilly, Novartis, Eisai, AstraZeneca, Ipsen, Bayer, Roche and Incyte. JK reports consultant role for Bayer, Ewopharma, Exelixis, Ipsen, Eli Lilly, Sanofi-Genzyme. Honoraria (clinical trials) and travel grants: AstraZeneca, Bayer, Eisai, Exelixis, Ipsen, Eli Lilly, Novartis, Sanofi-Genzyme. Compliance with ethics guidelines Ethics approval and consent to participate The research was conducted in accordance with consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. Study documents, including the protocol, demographic and health information form, interview guide, screener, and informed consent and assent forms were subject to IRB review and received ethical approval in each of the study countries (see Supplementary Materials for full details). All participants provided informed consent to participate in the study. Consent for publication Consent and assent via written consent forms were obtained from participants before proceeding with the interviews. Data Availability All data generated or analyzed during this study are included in this published article. References Kluetz, P.G., et al., Informing the Tolerability of Cancer Treatments Using Patient-Reported Outcome Measures: Summary of an FDA and Critical Path Institute Workshop . Value in Health, 2018. 21(6): p. 742–747. Wagner, L.I., et al., Patient-reported predictors of early treatment discontinuation: treatment-related symptoms and health-related quality of life among postmenopausal women with primary breast cancer randomized to anastrozole or exemestane on NCIC Clinical Trials Group (CCTG) MA.27 (E1Z03) . Breast Cancer Research and Treatment, 2018. 169(3): p. 537–548. Peipert, J.D., M.L. Smith, and E.S. Team, Reconsidering tolerability of cancer treatments: opportunities to focus on the patient . Supportive Care in Cancer, 2022: p. 1–3. Basch, E., et al., Broadening the definition of tolerability in cancer clinical trials to better measure the patient experience . Friends Cancer Res, 2018. 10. Peipert, J.D. and M.L. Smith, Reconsidering tolerability of cancer treatments: opportunities to focus on the patient . Supportive Care in Cancer, 2022. 30(5): p. 3661–3663. Kluetz, P., H. Klepin, and S.W. Gray. FDA-ASCO Public Workshop 2019 Clinical Outcome Assessments in Cancer Clinical Trials Fourth Annual Workshop . 2019 [cited 2020 January 14]; Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-asco-public-workshop-2019-clinical-outcome-assessments-cancer-clinical-trials-fourth-annual . Kluetz, P.G., et al., Patient-reported outcomes in cancer clinical trials: measuring symptomatic adverse events with the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) . American Society of Clinical Oncology Educational Book, 2016. 36: p. 67–73. Kluetz, P. and H. Klepin. FDA-ASCO Public Workshop: 2019 Clinical Outcome Assessments in Cancer Clinical Trials Fourth Annual Workshop . 2019 14 January 2020]; Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-asco-public-workshop-2019-clinical-outcome-assessments-cancer-clinical-trials-fourth-annual . Kluetz, P.G., et al., Informing the tolerability of cancer treatments using patient-reported outcome measures: summary of an FDA and Critical Path Institute Workshop . Value in Health, 2018. 21(6): p. 742–747. Roy, U.B., et al., Learning from patients: reflections on use of patient-reported outcomes in lung cancer trials . Journal of Thoracic Oncology, 2018. 13(12): p. 1815–1817. Pearman, T.P., et al., Validity and usefulness of a single-item measure of patient-reported bother from side effects of cancer therapy . Cancer, 2018. 124(5): p. 991–997. Cella, D.F., et al., The Functional Assessment of Cancer Therapy scale: development and validation of the general measure . 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Regnault, A., et al., Evidence To Support the Use of the Functional Assessment of Cancer Therapy – General Item GP5 (FACT-GP5) To Assess Comparative Tolerability Endpoint: Results From the LIBRETTO-531 Trial , in Annual Meeting of the Professional Society for Health Economics and Outcomes Research (ISPOR) 2024: Atlanta, GA. Altman, D., et al., Content Validity of FACT-GP5 to Assess Treatment Tolerability in Participants with Progressive, Advanced, Kinase Inhibitor-Naïve, RET-Mutant Medullary Thyroid Cancer: Qualitative Interview Sub-Study of the LIBRETTO-531 Trial , in Annual Meeting of the Professional Society for Health Economics and Outcomes Research (ISPOR) . 2024: Atlanta, GA. Bodicoat, D.H., et al., Promoting inclusion in clinical trials—a rapid review of the literature and recommendations for action . Trials, 2021. 22(1): p. 1–11. Byrne, M.M., et al., Participation in cancer clinical trials: why are patients not participating? Medical Decision Making, 2014. 34(1): p. 116–126. Kaderabek, A. and J. Sinibaldi, Assessing Measurement Error in Hypothetical Questions . Survey Practice, 2022. Additional Declarations Competing interest reported. Disclosures NP, AMG, PM, SB and RMS are employed by Eli Lilly and Company. DA, JC, and ES are employed of Modus Outcomes and was funded by Eli Lilly and Company, Indianapolis, IN, USA. KK reports consultancy role for Eli Lilly and Company. RE reports consultancy role for Eisai, Eli Lilly, Bayer, Roche, and Ipsen. JW reports fees to institution for speaker/advisor fees from Eli Lilly, Novartis, Eisai, AstraZeneca, Ipsen, Bayer, Roche and Incyte. JK reports consultant role for Bayer, Ewopharma, Exelixis, Ipsen, Eli Lilly, Sanofi-Genzyme. Honoraria (clinical trials) and travel grants: AstraZeneca, Bayer, Eisai, Exelixis, Ipsen, Eli Lilly, Novartis, Sanofi-Genzyme. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4730587","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":330965295,"identity":"01a4f0a9-eb8e-42b6-b860-8e570550f9d1","order_by":0,"name":"Nalin Payakachat","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYNCCAwwMBgwMjA8eGFjIkKKFmdkgwUCChyQtbBIJDERoMZdufibx44ydvDn7+WMVCQUSPAYHmB8+uoFHi+WcY2aSPTeSDXf2JLPdADnM4ACbsXEOHi0GNxLMJHg+MCcYHIBr4WGTxq8l/Zvknw/1CQbnH7MVEKklx0ya58bhBIMbyWwMxGm5c6bYWubMccMNNx4bS4C0SB4m5Jfb7RtvvjlWLW9wPvHhhw9/bOT4jjc/fIxPC4MEA4sEioDCYXzKIVqYP6AIyDcQ0jIKRsEoGAUjDQAA3/RN0WQ8OZIAAAAASUVORK5CYII=","orcid":"","institution":"Eli Lilly and Company","correspondingAuthor":true,"prefix":"","firstName":"Nalin","middleName":"","lastName":"Payakachat","suffix":""},{"id":330965299,"identity":"60abdf3b-3f2d-4fb9-b5df-d278f4c5638a","order_by":1,"name":"Adrienne M. 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Disclosures\nNP, AMG, PM, SB and RMS are employed by Eli Lilly and Company. DA, JC, and ES are employed of Modus Outcomes and was funded by Eli Lilly and Company, Indianapolis, IN, USA. KK reports consultancy role for Eli Lilly and Company. RE reports consultancy role for Eisai, Eli Lilly, Bayer, Roche, and Ipsen. JW reports fees to institution for speaker/advisor fees from Eli Lilly, Novartis, Eisai, AstraZeneca, Ipsen, Bayer, Roche and Incyte. JK reports consultant role for Bayer, Ewopharma, Exelixis, Ipsen, Eli Lilly, Sanofi-Genzyme. Honoraria (clinical trials) and travel grants: AstraZeneca, Bayer, Eisai, Exelixis, Ipsen, Eli Lilly, Novartis, Sanofi-Genzyme.","formattedTitle":"Assessing Side-Effect Bother, Burden, and Tolerability: A Qualitative Study Exploring the Content Validity of the Functional Assessment of Cancer Therapy – Item GP5","fulltext":[{"header":"Plain English Summary [Optional for SCC]","content":"\u003cp\u003eWith recent advances in the effectiveness and availability of cancer treatments, more patients are living longer. However, it also means that more patients may live with the potential side-effects of cancer treatments. Research is needed to better understand and evaluate the impact of treatment side effects and their burden. This study was designed to enhance the understanding from the patient perspective on treatment tolerability and the distinction between bother and burden. Moreover, the study examined whether an existing patient-reported measure for assessing the impact of side effects, the GP5 item, was understood by patients and what response options were considered as \u0026ldquo;high side-effect bother\u0026rdquo;. Forty participants with medullary thyroid cancer enrolled in the LIBRETTO-531 trial from eight different countries were invited to participate in interviews. The interview transcripts were then analyzed to gain insights into the common features of the patient experience of side effects and differences between tolerability, bother, and burden. The study found that the GP5 question and its response options were clear and easy to understand. Lastly, GP5 response options of \u0026ldquo;quite a bit\u0026rdquo; and \u0026ldquo;very much\u0026rdquo; reflected a high side-effect bother. In conclusion, GP5 is an appropriate measure to assess patient-reported tolerability in patients with MTC in the context of a clinical trial.\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003eSide effects that are symptomatic and bothersome may be key contributors to how patients perceive the tolerability of a treatment and their ability or desire to continue it [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Patients who report a greater degree of side-effect burden are at an increased risk for discontinuing treatment before completion [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Understanding how patients experience and perceive side effects has therefore become increasingly crucial for investigating treatment tolerability, predicting treatment discontinuation, and assessing quality of life.\u003c/p\u003e \u003cp\u003eThere is increasing support for including the patient-reported measurement of tolerability in oncology clinical trials [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Crucially, the concept of tolerability is inherently patient-centered; it can be usefully distinguished, for example, from the clinician-centered concept of treatment safety [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Multiple stakeholders, including regulators (both US and EU), researchers, patients, and sponsors, define tolerability as “the degree to which symptomatic and non-symptomatic adverse events associated with the product’s administration affect the ability or desire of the patient to adhere to the dose or intensity of therapy” [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition to the collection of patient-reported data on individual symptomatic adverse events, the FDA and other stakeholder groups identify overall side-effect burden as a “core measurement concept” to inform the tolerability of cancer treatments [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. An overall side-effect impact summary measure facilitates the comparison of tolerability across clinical trials. Overall side-effect burden has been theorized to be the most proximal patient-reported concept to tolerability [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, in research to date, the terms overall side-effect impact, burden, and bother are used interchangeably, and often without explicit definitions of the terms [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile side-effect bother, burden, and impact have not been consistently well defined in the literature [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], it can be inferred that these terms are used to refer to the physical experience of treatment side effects and their interference with activities of daily living, emotions, social life, and role functioning [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Yet there is limited knowledge of how patients define such terms, including whether patients themselves view these terms as interchangeable.\u003c/p\u003e \u003cp\u003eThe FDA draft guidance on Core Patient-Reported Outcomes (PROs) in Cancer Clinical Trials identifies the Functional Assessment of Cancer Therapy (FACT) item GP5 (GP5) as a measure for assessing overall side effect impact [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The GP5 is a single-item patient-reported summary measure that assesses the overall impact of treatment toxicity by asking about overall side effect bother [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In the GP5, the statement “I am bothered by side effects of treatment” is measured for the previous 7 days on a 5-level Likert scale: 0 (not at all); 1 (a little bit); 2 (somewhat); 3 (quite a bit); or 4 (very much). Rigorous qualitative methods, including semi-structured interviews and cognitive interviewing with patients, informed the development and validation of the GP5 item as part of the 33-item FACT-General scale between 1987–1992 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile the GP5 is increasingly used in cancer clinical trials and the content validity of the GP5 as a measure of tolerability has been investigated [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], there is need for additional qualitative data to support it being fit-for-purpose as a measure of comparative tolerability in clinical trials. In addition, to understand how patients conceptualize side effect bother and tolerability, evidence demonstrating which response options patients interpret as “high side-effect bother” are critical to inform an estimand framework to quantify and compare tolerability in randomized clinical trials [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The objectives of this qualitative study were: (1) to explore how participants with medullary thyroid cancer (MTC) conceptualize side effect bother and burden, and (2) to generate evidence to support the GP5 as a fit-for-purpose measure for patient-reported tolerability and establish which response options constitute “high side effect burden.”\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eStudy design and participants\u003c/p\u003e\u003cp\u003eThis qualitative, non-interventional, descriptive study leveraged cross-sectional qualitative interviews with individuals with MTC participating in the LIBRETTO-531 study. The LIBRETTO-531 study is a global, multi-center, randomized (2:1), open-label, Phase 3 study comparing selpercatinib to physician’s choice of cabozantinib or vandetanib in patients with progressive, advanced, tyrosine kinase inhibitor (TKI)-naïve, rearranged during transfection (\u003cem\u003eRET)\u003c/em\u003e-mutation positive MTC. Within the LIBRETTO-531 trial, comparative tolerability, a key secondary PRO endpoint, was assessed by comparing the proportion of time on treatment, postbaseline, with “high sideeffect bother,” as measured by the GP5 score of 3 or 4, between the selpercatinib arm and the cabozantinib or vandetanib arm. This endpoint allows for evaluation of the overall impact of side effects from the patient’s perspective to further support the clinical benefit of selpercatinib [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eParticipants were recruited via LIBRETTO-531 trial sites in the US, UK, Australia, Germany, Italy, Poland, the Czechia, and Spain. The clinical sites obtained institutional review board (IRB) approval for the interviews. In addition, clinical site staff underwent training on the study procedures and obtained verbal and written (through completion of a Patient Interviews Contact Information Form) consent from potential participants to be contacted by interview study personnel.\u003c/p\u003e\u003cp\u003ePatients were eligible to participate if they met the following criteria at the time of recruitment: were eighteen years of age or older; were active participants in the LIBRETTO-531 trial (defined as still receiving treatment and with no disease progression) participating at one of the clinical trial sites at the time of recruitment; were able to speak one of the following languages: English, Spanish, French, German, Italian, Polish, Portuguese, Czech, or Dutch; and agreed to be contacted for a qualitative interview.\u003c/p\u003e\u003cp\u003eStudy documents\u003c/p\u003e\u003cp\u003eRegulatory and ethical approvals were provided under the aegis of the LIBRETTO-531 clinical trial. Study documents, which were developed and submitted as an addendum to the LIBRETTO-531 trial protocol, included a participant contact form for scheduling purposes, a slide deck to facilitate site training on recruitment and data privacy procedures, the participant interview guide, and the GP5. The validated translations of the GP5 used in Lilly’s LIBRETTO-531 trial were obtained in all study languages. The interview guide and site training slide deck were translated by Global Perspectives, the recruitment agency that was also contracted to moderate, translate, and transcribe the non-English language interviews.\u003c/p\u003e\u003cp\u003eInterview methods\u003c/p\u003e\u003cp\u003eQualitative interviews were approximately 30–60 minutes in duration and were conducted utilizing a 1:1 approach with a semi-structured interview guide. Interviews included two components: 1) concept elicitation on the side effect experience and the patient interpretation of the concepts of bother, burden, and tolerability; and 2) cognitive interviewing of the GP5 to assess participants’ interpretation of the item and response choices and which response options participants equated with high side-effect bother.\u003c/p\u003e\u003cp\u003eInterviews were conducted online in the language associated with each clinical trial site. English language interviews were conducted by Modus Outcomes and non-English language interviews were conducted by Global Perspectives. During cognitive interviewing, participants read the GP5 item on the screen during the online interview and shared their thought process about how they would answer it.\u003c/p\u003e\u003cp\u003eInterviews were audio recorded, transcribed, and anonymized. Non-English language interviews were transcribed directly in English. Lilly extracted the following data elements for each study participant from LIBRETTO-531 clinical data at baseline: age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, year of MTC diagnosis, and number of weeks between the first day of treatment and the interview date.\u003c/p\u003e\u003cp\u003eTiming of the interview was targeted at 10–14 weeks from baseline (the first date of treatment), in alignment with the FDA’s recommendation for when peak toxicity can be accurately evaluated [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003ch2\u003eData analysis\u003c/h2\u003e\u003cp\u003eInterview transcripts were thematically analyzed with a mix of inductive and deductive coding methods [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] using detailed line-by-line coding [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e–\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] with ATLAS.ti software [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Independent parallel coding was used to initiate coding and ensure consistency using the first two transcripts. The lists of codes and associated quotes obtained by three independent coders were compared for overlaps and inconsistencies and were revised as needed to reach coder alignment.\u003c/p\u003e\u003cp\u003eFor the concept elicitation analysis, researchers reviewed the raw data assigned to codes to derive a list of side effects and to derive themes related to the conceptualization of side-effect bother and burden (\u003cb\u003eSupplemental Fig.\u0026nbsp;1\u003c/b\u003e). A saturation analysis was conducted to evaluate saturation of the concept elicitation data related to the concepts of bother, burden, and tolerability. The transcripts were ordered chronologically, based on the interview completion dates, and then divided into eight groups of five. Themes in each group were then compared against those in the previous group to determine the degree of thematic saturation achieved.\u003c/p\u003e\u003cp\u003eFor the cognitive interviewing analysis, structured codes were used to compile data on participant understanding of the item and recall period, interpretation of response options, and opinions on the response options that reflect high side-effect bother. To analyze the participant feedback on what information participants retrieved and thought about when interpreting a response option, researchers inductively categorized the information participants reported based on patterns the research team found in the raw data and reported the information in a table. To investigate the comprehensiveness of the GP5 for measuring bother and burden, themes identified for those concepts were compared to themes identified in relation to how participants interpreted the GP5 response options.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003eSample characteristics\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eTranscripts from forty participants were included in the analysis. A description of the sample is provided in Supplemental Table 1. The mean and median ages of participants were 55.5 (standard deviation [SD] 13.6) years and 60.5 years, respectively, and 67.5% were male. The mean and median number of weeks between the first day of treatment in the trial and the interview date were 62.7 (SD 37.1) and 59, respectively.\u003c/p\u003e\n\u003ch2\u003eConcept elicitation interviews\u003c/h2\u003e\n\u003ch3\u003eSide effects reported by participants\u003c/h3\u003e\n\u003cp\u003eSixty-three unique symptomatic side effects were identified and categorized across the following 12 domains: attention/memory, cardio/circulatory, cutaneous, fatigue, gastrointestinal, neurological, nose and throat, oral, pain, sexual, urinary, and miscellaneous.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eSide-effect bother\u003c/h3\u003e\n\u003cp\u003eTable 1\u0026nbsp;documents six themes identified in relation to how participants (n=40) conceptualized side-effect bother. The themes are not exclusive (i.e., one participant may have reported a number of themes in relation to each concept of bother).\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;1. Domains, themes, and quotes related to side-effect bother\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.846153846153847%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDomains\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\"\u003e\n \u003cp\u003e\u003cstrong\u003eThemes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.53846153846154%\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipant quotes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.846153846153847%\"\u003e\n \u003cp\u003e\u003cstrong\u003eInterference of side effects with daily activities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\" valign=\"top\"\u003e\n \u003cp\u003eBothersome side effects interfere with daily activities, such as by limiting which activities participants can do (e.g., going fishing), reducing the amount of time they can do an activity (e.g., length of time shopping), or by making them adapt (e.g., making sure toilets are nearby in public) (n=29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.53846153846154%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;If I do some hard work and I want to get it done in four hours, but I can\u0026rsquo;t and I need eight hours for it. That is what \u0026ldquo;bothered\u0026rdquo; means to me.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Bothered means I] couldn\u0026rsquo;t do my normal duties in life. Like I got too sick to walk or get up.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.846153846153847%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhysical experience of side effects\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\" valign=\"top\"\u003e\n \u003cp\u003eBothersome side effects cause physical discomfort (n=26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.53846153846154%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Bother] is if someone takes a drug and feels any type of discomfort after it\u0026hellip; pain, diarrhoea, nausea.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.846153846153847%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eCognitive and emotional experience of side effects\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\" valign=\"top\"\u003e\n \u003cp\u003eBothersome side effects increase cognitive effort and cause annoyance/ inconvenience (n=13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.53846153846154%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;Bothered just means\u0026hellip; that [side effects] irritate you throughout the day so that you think about it \u0026ndash; that it\u0026rsquo;s annoying. I\u0026rsquo;m still able to do most of the things that I would do for my children and my family.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.648648648648646%\" valign=\"top\"\u003e\n \u003cp\u003eBothersome side effects cause additional thought burden, mental health problems, or negative emotions, such as worry, concern, or reduced joy (n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.351351351351354%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;Fatigue takes the joy of going on a walk or on a bike ride away from you; same thing goes for taste loss and appetite loss.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.648648648648646%\" valign=\"top\"\u003e\n \u003cp\u003eBothersome side effects affect appearance in a stigmatizing way (n=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.351351351351354%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Bother includes] if it restricted me in some physical movement, in some physical activity, or I don\u0026apos;t know, let\u0026apos;s say, I don\u0026apos;t know, maybe I would get some kind of rash that would actually change my appearance.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.846153846153847%\"\u003e\n \u003cp\u003e\u003cstrong\u003eComparison of clinical efficacy to the side effect experience\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\" valign=\"top\"\u003e\n \u003cp\u003eThe benefits of the treatment (e.g., effectiveness, survival) are weighed against the harms of side effects when considering the degree to which side effects are bothersome (n=5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.53846153846154%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Bothered] means that I am happy anyway. I have some bother but I\u0026rsquo;m still alive. If it wasn\u0026rsquo;t for this drug, I would be dead.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch3\u003eSide-effect burden\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eNine themes were identified in relation to how participants (n=40) conceptualized side-effect burden (Table 2). Themes were organized into the following four domains: burden compared to bother, interference of side effects with daily activities, physical experience of side effects, and the cognitive and emotional experience of side effects.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2: Domains, themes, and quotes related to side-effect burden\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.617304492512478%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDomains\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.108153078202996%\"\u003e\n \u003cp\u003e\u003cstrong\u003eThemes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.27454242928452%\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipant quote\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.617304492512478%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBurden compared to bother\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.108153078202996%\" valign=\"top\"\u003e\n \u003cp\u003eSide-effect burden is similar to side-effect bother, but burden implies a greater degree of side effect severity or interference in daily activities in general (high side-effect bother) (n=31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.27454242928452%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;Bother is just an inconvenience ... a burden is I\u0026rsquo;ve had to change the way I live my life.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;The word \u0026quot;burden\u0026quot; is much more heavy [than \u0026ldquo;bother\u0026rdquo;]\u003c/em\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.617304492512478%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eInterference of side effects with daily activities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.108153078202996%\" valign=\"top\"\u003e\n \u003cp\u003eBurdensome side-effects interfere with daily activities, such as by limiting which activities participants can do (e.g., going fishing), reducing the amount of time they can do an activity (e.g., length of time shopping), or by making them adapt (e.g., making sure toilets are nearby in public) (n=17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.27454242928452%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[If I] get diarrhoea ten times a day\u0026hellip; when I\u0026apos;m working and I\u0026apos;m in a meeting at work, I have to just leave the room to go to the toilet, or I have to get up at night and go to the toilet, which means I feel like I\u0026apos;m falling asleep again afterwards\u0026hellip; it\u0026apos;s a burden on me.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.881796690307326%\" valign=\"top\"\u003e\n \u003cp\u003eBurdensome side-effects interfere with daily activities more than bothersome side effects (n=18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.118203309692674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;Bother is what you feel. A burden would be if I was no longer able to work\u0026hellip; not being able to be active and turn around and do the sort of things that I\u0026rsquo;ve done for 50-odd years\u0026hellip; \u0026nbsp;there\u0026rsquo;d be a lot of frustration there.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.617304492512478%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhysical experience of side effects\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.108153078202996%\" valign=\"top\"\u003e\n \u003cp\u003eBurdensome side-effects cause physical discomfort (n=9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.27454242928452%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;My burden issue is... here is this tightening at the neck and shoulders\u0026hellip; Like if you put your two hands around my neck and you press down.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.881796690307326%\" valign=\"top\"\u003e\n \u003cp\u003eBurdensome side-effects are more severe than bothersome side effects (n=14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.118203309692674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Burden] means greater pain [than bother], when I could not get out of bed.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.881796690307326%\" valign=\"top\"\u003e\n \u003cp\u003eBurdensome side-effects have a longer duration than bothersome side effects (n=7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.118203309692674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;Bother is only temporary\u0026hellip; [a burden] is not temporary anymore.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.881796690307326%\" valign=\"top\"\u003e\n \u003cp\u003eBurdensome side-effects are more frequent than bothersome side effects (n=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.118203309692674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;If the diarrhoea was more than twice a day, that\u0026apos;s already some minor burden.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.617304492512478%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCognitive and emotional experience of side effects\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.108153078202996%\" valign=\"top\"\u003e\n \u003cp\u003eBurdensome side-effects cause mental health problems or negative emotions (n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.27454242928452%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Burden] is you\u0026rsquo;re weighed down with problems and feeling anxious.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.881796690307326%\" valign=\"top\"\u003e\n \u003cp\u003eBurdensome side-effects cause a greater cognitive effort and/or have a greater and more negative impact on mental health or emotional well-being than bothersome side effects (n=8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.118203309692674%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;Something bothersome is tolerable, not worrying; on the contrary, a heavy side-effect can create concern. Swelling on the eye does not worry me, whereas an alteration in blood values does because it could upset the physiological balance.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch3\u003eTolerability\u003c/h3\u003e\n\u003cp\u003eSeven themes were identified in relation to how participants (n=40) conceptualized tolerability (Table 3). Themes were organized into the following six domains: tolerability compared to bother and burden, clinical efficacy, interference of side effects with daily activities, the cognitive and emotional experience of side effects, comparison of clinical efficacy to the side effect experience, and the physical experience of side effects.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3: Domains, themes, and quotes related to tolerability\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.846153846153847%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDomains\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.846153846153847%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eThemes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.30769230769231%\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipant quote\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.076923076923077%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTolerability compared to bother and burden\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\" colspan=\"2\"\u003e\n \u003cp\u003eTolerability is related to bother and/or burden (n=31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.30769230769231%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Bother and tolerability] are related because for me, if it\u0026apos;s just a nuisance and not a burden, that just means it\u0026apos;s more tolerable.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Burden and tolerability are related] because as I said, burden\u0026rsquo;s more psychological, and when my body couldn\u0026rsquo;t tolerate it and wasn\u0026rsquo;t adjusting to it, it would have a big psychological impact on me.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.076923076923077%\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical efficacy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\" colspan=\"2\"\u003e\n \u003cp\u003eThe efficacy of the treatment is considered when determining how tolerable its side effects are (n=20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.30769230769231%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;Tolerable means I\u0026apos;m taking something that is targeted, that blocks or limits the growth of my tumour so to say, and when by taking the treatment I reach the goal\u0026mdash;that the tumour doesn\u0026apos;t grow further.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.076923076923077%\"\u003e\n \u003cp\u003e\u003cstrong\u003eInterference of side effects with daily activities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\" colspan=\"2\"\u003e\n \u003cp\u003eSide effects are tolerable if they don\u0026rsquo;t significantly interfere with daily activities (n=18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.30769230769231%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Tolerable] means you can grit your teeth and still [walk], but if something hurts a lot then you just sit down and wait for it to subside.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;If I can\u0026rsquo;t lead my life\u0026hellip; if I can\u0026rsquo;t manage my household anymore, I would say that it\u0026rsquo;s not tolerable anymore.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.076923076923077%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCognitive and emotional experience of side effects\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\" colspan=\"2\"\u003e\n \u003cp\u003eSide effects are tolerable if they are bearable (n=18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.30769230769231%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;I know I just have to take it, I have to persevere, I just have to accept what is\u0026hellip; when [the side effects] started it wasn\u0026rsquo;t nice, so I know what something better means.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Tolerable] means bearable; that you can bear it and live with it.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.076923076923077%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eComparison of clinical efficacy to the side effect experience\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\" colspan=\"2\"\u003e\n \u003cp\u003eThe benefits of the treatment (e.g., effectiveness, survival) are weighed against the harms when determining how tolerable the side effects are (n=16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.30769230769231%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[The treatment] is tolerable because I want to recover from cancer\u0026hellip; life is worth it. It\u0026rsquo;s worth it to suffer to live.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45%\" colspan=\"2\"\u003e\n \u003cp\u003eThe side effects and clinical efficacy of other treatments are compared to side effects and clinical efficacy of one\u0026rsquo;s own treatment when determining how tolerable its side effects are (n=6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"55%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;What makes it tolerable is [that it] gives you a better quality of life in comparison to other treatments\u0026hellip; The opposite would be a devastating treatment, that prevents you from leading a normal life, and maybe causes a rebound effect, meaning that it gives positive results during the first months, but then you \u0026ldquo;bounce back\u0026rdquo; to square one.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.076923076923077%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhysical experience of side effects\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.61538461538461%\" colspan=\"2\"\u003e\n \u003cp\u003eSide effects are tolerable if their or severity is none to mild (n=8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.30769230769231%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;[Tolerable] means that I take my tablets. They don\u0026rsquo;t affect me when I take them.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;Tolerable would be a mild pain I can actually handle and tolerate on a day-to-day basis.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch3\u003eThematic saturation\u003c/h3\u003e\n\u003cp\u003eConceptual saturation of themes related to bother, burden, and tolerability was achieved in transcript group 2 (i.e., the second group of n=5 interviews analyzed).\u003c/p\u003e\n\u003ch2\u003eCognitive Interviewing\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eOverall, the majority (92.5%, 37 out of 40) of participants found the response options for the GP5 to be clear and easy to understand. Only one participant expressed that the item was\u0026nbsp;difficult to answer, stating challenges in distinguishing their cancer symptoms from treatment side-effects.\u0026nbsp;All participants (100.0%, 40 out of 40) reported that the GP5 item measures bother, that the content of the GP5 item was clear, and nothing was needed to make it easier to understand.\u003c/p\u003e\n\u003ch3\u003eRelevance\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eOnly 7.5% of participants (3 out of 40) reported the item was not relevant to them. The reasons for irrelevance included: two participants were not experiencing or bothered by side effects and one participant questioned whether the item was relevant in the context of a clinical trial, since participating in a trial reflects a willingness to experience side effects.\u003c/p\u003e\n\u003ch3\u003eItem clarity and interpretation\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eAll 40 participants (100.0%) reported that the GP5 content was clear. One participant suggested adding to the question whether a new side-effect occurred in the past 7 days to capture the fluctuating nature of the treatment side effects. When asked what the item meant to them, participants offered various descriptions to interpret the item\u0026rsquo;s meaning (Table 4).\u003c/p\u003e\n\u003ch3\u003eRetrieval of information\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eTwo participants (5.0%) reported challenges with the 7-day recall period. Some participants reported having used different recall methods to answer the question, which was contrary to the instructions to focus on the past 7 days. Participants also reported reflecting on various types of content to answer the question as well as factors that influence their responses.\u0026nbsp;See\u0026nbsp;Table 4\u0026nbsp;for a description of results.\u003c/p\u003e\n\u003ch3\u003eGeneral response options feedback\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eThree participants (7.5%) reported issues with the response options (n=1 participant had two comments). One participant noted that the response options \u0026ldquo;A little,\u0026rdquo; \u0026ldquo;Somewhat,\u0026rdquo; and \u0026ldquo;Quite a bit\u0026rdquo; needed to be elaborated as the wording did not accurately capture their experience. One participant suggested turning the options into a scale of 1 to 100 for more granularity and adding another response option after \u0026ldquo;Very Much.\u0026rdquo; One participant shared that the item was difficult to answer as they could not distinguish their cancer symptoms from treatment side-effects\u0026nbsp;(Table 4).\u003c/p\u003e\n\u003cp\u003eTable 4. Cognitive interviewing of GP5: Item understanding, retrieval of information, and response option feedback\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eItem clarity and interpretation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.37373737373738%\" valign=\"top\"\u003e\n \u003cp\u003eRetrieval of information\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eGeneral response options feedback\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eHow do participants understand the item?\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e40 out of 40 participants reported\u0026nbsp;that the GP5 content was clear and that nothing would be needed to make it easier to understand.\u003c/p\u003e\n \u003cp\u003e\u003cu\u003eSuggestion\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003eSuggested adding to the question whether a new side effect occurred in the past 7 days (n=1)\u003c/p\u003e\n \u003cp\u003e\u003cu\u003eInterpretation of the item\u003c/u\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eHow much the side effects are impacting their life (e.g., quality of life, hobbies, work) (n=12)\u003c/li\u003e\n \u003cli\u003eBeing bothered/worried by side effects (n=11)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eWhat condition they are in at the moment (e.g., well-being, how treatment is progressing (n=3)\u003c/li\u003e\n \u003cli\u003eSide effect severity (n=1)\u003c/li\u003e\n \u003cli\u003eSide effect type (e.g., pain) (n=1)\u003c/li\u003e\n \u003cli\u003eSide effect variation (n=1)\u003c/li\u003e\n \u003cli\u003eBeing able to stand side effects/not be disturbed by them (n=1)\u003c/li\u003e\n \u003cli\u003eWhether the benefit of the drug is outweighing the side effects (balance) (n=1)\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.37373737373738%\" valign=\"top\"\u003e\n \u003cp\u003eWhat do participants consider when arriving at a response? (symptoms, impacts, timeframe, etc.)\u003c/p\u003e\n \u003cp\u003e38 out of 40 participants reported that it was easy to recall and retrieve information to answer the GP5.\u003c/p\u003e\n \u003cp\u003eN=2 reported problems with the 7-day recall period\u0026nbsp;\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eHard to answer due to the varying nature of side effects (n=1)\u003c/li\u003e\n \u003cli\u003eDifficult to recall the past 7 days (n=1)\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003cu\u003eThought process: Recall period\u003c/u\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eThought about the past 7 days, as instructed (n=6)\u003c/li\u003e\n \u003cli\u003eThought about the most severe day of the week (n=1)\u003c/li\u003e\n \u003cli\u003eThought about the average over the week (n=5)\u003c/li\u003e\n \u003cli\u003eThought about the past 2-3 days, which is inconsistent with the instructions (n=1)\u003c/li\u003e\n \u003cli\u003eThought about how one feels at the moment (n=2), which is inconsistent with the instructions\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003cu\u003eThought process: Content recalled\u003c/u\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eReflected on their side effects (n=22)\u003c/li\u003e\n \u003cli\u003eReflected on how one feels (e.g., physical and cognitive/emotional experience) (n=9)\u003c/li\u003e\n \u003cli\u003eReflected on impact on daily life (n=6)\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003cu\u003eResponse influence\u003c/u\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eResponse was influenced by comparing to other cancer patients (n=2)\u003c/li\u003e\n \u003cli\u003eResponse was influenced by comparing with other conditions (n=1)\u003c/li\u003e\n \u003cli\u003eResponse was influenced by comparing to other treatment experience (e.g., more invasive procedures) (n=1)\u003c/li\u003e\n \u003cli\u003eResponse was influenced by comparing to their trial experience at the beginning (n=1)\u003c/li\u003e\n \u003cli\u003eResponse was influenced by reflecting on the overall benefit of the drug (n=2)\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eAre response options appropriate for respondents?\u003c/p\u003e\n \u003cp\u003e37 out of 40 participants reported the response options were appropriate.\u003c/p\u003e\n \u003cp\u003eN=3 participants reported problems with the response options (n=1 participant had two comments):\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eResponse options not sufficient to cover everything (n=1)\u003c/li\u003e\n \u003cli\u003eSuggested making the response options into a scale (e.g., 100-point) (n=1)\u003c/li\u003e\n \u003cli\u003eSuggested adding another response option after \u0026ldquo;Very much\u0026rdquo; (n=1)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eReported difficulty answering the item (hard to distinguish cancer symptoms from side effects) (n=1)\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch3\u003eParticipant interpretation of response options\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eWhen selecting a response option and reporting on what each response option meant to them, participants (n=40) reflected on the cognitive and emotional experience of side effects, such as their level of worry or concern about them, the physical experience of side effects, and/or the level of interference of side effects in their daily activities. Some participants reflected on whether the side effects were severe or impactful enough to consider contacting their doctor. A few participants reflected on clinical efficacy, the effectiveness of treatments for the side effects, and/or whether side effects were severe or impactful enough to consider dose delay, treatment discontinuation, or dose modification.\u0026nbsp;Table 5\u0026nbsp;details the full participant interpretation of each response option, accompanied by illustrative quotes.\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;5. Participant interpretation of GP5 response options\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"648\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.88888888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse option\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.370370370370374%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipant interpretation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.74074074074074%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipant quote\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.88888888888889%\" valign=\"top\"\u003e\n \u003cp\u003e0 \u0026ndash; Not at All\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.370370370370374%\" valign=\"top\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eCognitive/emotional experience of side effects\u003c/strong\u003e: No worries, problems, concerns, or bother (n=22)\u003cstrong\u003e;\u003c/strong\u003e Minor annoyance (n=1); Have coped with/gotten used to it (n=3)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePhysical experience of side effects\u003c/strong\u003e:\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSide effect existence\u003c/strong\u003e: Side effects not present (n=12)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSeverity\u003c/strong\u003e: Side effects present but were not severe at all (n=4)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDuration\u003c/strong\u003e: Short (1 \u0026ndash; 2 week) duration: (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDaily activity interference\u003c/strong\u003e: No impacts on day-to-day activities or functioning (n=8)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eClinical efficacy\u003c/strong\u003e: Treatment is effective (n=1); compare benefits to harms (n=1)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTreatment of side effects\u003c/strong\u003e: Side effects are successfully treatable (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eNot sure:\u0026nbsp;\u003c/strong\u003e(n=1)\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.74074074074074%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;Well, not at all, for me, means I haven\u0026rsquo;t got \u0026ndash; I don\u0026rsquo;t know what to say. How can you say not at all? I have no concerns at all. It\u0026rsquo;s not on my mind. Nothing\u0026rsquo;s happening to me, basically, other than normal things.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;Not at all means that I don\u0026rsquo;t feel absolutely anything, that there\u0026rsquo;s no repercussion, no side effect following the treatment.\u0026rdquo; \u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;It would mean that I feel as I did before I started treatment, I may have developed acne, for example, or this change in hair color, but it does not hinder my functioning in any way.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.88888888888889%\" valign=\"top\"\u003e\n \u003cp\u003e1 \u0026ndash; A Little Bit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.370370370370374%\" valign=\"top\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eCognitive/emotional experience of side effects\u003c/strong\u003e: No bother (e.g., feeling like nothing is wrong, not minding the side effects or only thinking about the side effects occasionally in the back of mind) (n=8); Causes light bother (n=20); Can endure it (n=2)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDaily activity interference\u003c/strong\u003e: No impacts on daily activities or functioning (n=7); Light impacts on daily activities or functioning (n=9)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePhysical experience of side effects\u003c/strong\u003e:\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSeverity\u003c/strong\u003e: Mild severity (n=14); 20-25% of discomfort (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDuration\u003c/strong\u003e: Short duration (e.g., a few minutes, a day, a few weeks) (n=5)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFrequency\u003c/strong\u003e: \u0026nbsp;Low frequency (1 \u0026ndash; 7 times a week) (n=10)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eClinical efficacy\u003c/strong\u003e: Compare benefits to harms (n=1)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eContact provider/ask for meds:\u0026nbsp;\u003c/strong\u003eAsk the doctor about how to treat side effects (n=1)\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.74074074074074%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cem\u003e\u0026ldquo;I\u0026rsquo;m not worried about it, because I\u0026rsquo;m feeling healthy. I feel good. So yeah, I\u0026rsquo;m a little bit worried, because I have the cancer, but I\u0026rsquo;m not really \u0026ndash; yeah, I feel healthy.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;Mild side-effects that are worth mentioning but not severe.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;Well, again, like in my case, the person has a bloated belly, it\u0026rsquo;s nothing serious, it just bothers, but only for an hour, half an hour, two hours once or twice a month, I guess.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.88888888888889%\" valign=\"top\"\u003e\n \u003cp\u003e2 \u0026ndash; Somewhat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.370370370370374%\" valign=\"top\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eCognitive/emotional experience of side effects\u003c/strong\u003e: Causes moderate bother or annoyance (e.g., more worried that drug is not working, bother is more on the mind, more noticeable, having negative feelings) (n=26); Bother turns into burden (n=4); Can still cope with it or bear it (e.g., still within limits) (n=6)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDaily activity interference\u003c/strong\u003e: Need to change or reduce daily activities (e.g., needing to rest during the day, impact activities for a few hours, feeling inconvenienced) (n=15); Do not have to change or reduce daily activities (n=2)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePhysical experience of side effects\u003c/strong\u003e:\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eNumber of side effects\u003c/strong\u003e: Experiencing multiple side effects (n=2)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSeverity\u003c/strong\u003e: Moderate severity (e.g., SE more severe, experiencing changes in health) (n=4); 40% of discomfort level (n=1); Mild severity (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDuration\u003c/strong\u003e: Duration is constant (e.g., throughout day) (n=5); Few hours (n=2)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFrequency\u003c/strong\u003e: \u0026nbsp;High frequency (3 \u0026ndash; 7 times a week, more frequent) (n=8)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTreatment of side effects:\u0026nbsp;\u003c/strong\u003eNone needed (n=1); Have to do something about the side effects (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eClinical efficacy\u003c/strong\u003e: Comparison of own\u0026rsquo;s treatment and side effects to those of other cancer patients (n=1)\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.74074074074074%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;Well, somewhat would mean I\u0026rsquo;m not handling the drug. Like I\u0026rsquo;ve got a few problems. Yeah, I\u0026rsquo;m starting to worry. Maybe it\u0026rsquo;s not working. Maybe these side effects are a bit too much.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;If I had to answer somewhat, it would mean that at least once during that day, it had affected what I do during the day. It would have been something that lasted for a few hours or a day or meant that I had to rest or put my feet up or whatever. So that would be somewhat to me.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;Well, then it\u0026rsquo;s already a bit more uncomfortable. But still in a way that I can bear it.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.88888888888889%\" valign=\"top\"\u003e\n \u003cp\u003e3 \u0026ndash; Quite a Bit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.370370370370374%\" valign=\"top\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eCognitive/emotional experience of side effects\u003c/strong\u003e: Causes a lot of bother (e.g., feeling sudden changes in health, negative feelings like annoyance, worry, concern) (n=11); Feeling burden (n=3); Unbearable (n=4); Can be endured (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDaily activity interference\u003c/strong\u003e: Big impact on day-to-day activities (e.g., difficulty doing things such as physical functioning, eating, watching TV, working, speaking to people) (n=20); Reduced quality of life (n=2)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePhysical experience of side effects\u003c/strong\u003e:\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eNumber of side effects\u003c/strong\u003e: Experiencing multiple side effects (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSeverity\u003c/strong\u003e: Strong severity (e.g., more painful/unacceptable (n=11); 70% of discomfort level (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDuration\u003c/strong\u003e: Constant duration (n=3)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFrequency\u003c/strong\u003e: High frequency of side effects (range of 2 to more than 10 times per week) (n=7); Persistent regularity or recurrence of side effects (n=3)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eContact provider/ask for SE treatment:\u0026nbsp;\u003c/strong\u003eNeed treatments (e.g., consulting the doctor, getting more treatments or higher dose of treatments to reduce side effects) (n=6); Side effects do not respond to treatment (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eClinical efficacy\u003c/strong\u003e: Compare benefits to harms (n=2)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eConsider discontinuing treatment\u003c/strong\u003e (n=1)\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.74074074074074%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026ldquo;\u003cem\u003eSo if all of a sudden, things started changing a lot more, I would definitely be more worried.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cem\u003e\u0026ldquo;I cannot eat like I used to before, I have difficulty swallowing, I eat yogurts, I can still eat some food, but it causes me pain, I don\u0026rsquo;t have much saliva, I have to support myself with water, in the same way calluses are quite painful, I try not to walk too much, I am limited.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026ldquo;Well, that it\u0026rsquo;s not as good as it was, that it\u0026rsquo;s worse, that it\u0026rsquo;s gotten worse, well\u0026hellip; That my skin would crack more and it wouldn\u0026rsquo;t be the same.\u0026rdquo;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cem\u003e\u0026ldquo;That would be where I\u0026rsquo;m starting to lose patience and thinking that \u0026ndash; is it worth taking the drug? I need to contact somebody to find out more information about what\u0026rsquo;s happening or a solution to whatever was happening.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.88888888888889%\" valign=\"top\"\u003e\n \u003cp\u003e4 \u0026ndash; Very Much\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.370370370370374%\" valign=\"top\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eCognitive/emotional experience of side effects\u003c/strong\u003e: High bother (e.g., very worried about what\u0026rsquo;s going on, things don\u0026rsquo;t feel right, not understanding what\u0026rsquo;s going on) (n=9); Feeling burden (n=1; Unbearable/Unable to cope (n=8)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDaily activity interference\u003c/strong\u003e: Big changes in lifestyle (e.g., extreme difficulties with activities such as physical functioning, going outside, working, eating; needing help) (n=18)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePhysical experience of side effects\u003c/strong\u003e:\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eNumber of side effects\u003c/strong\u003e: Experiencing multiple side effects (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSeverity\u003c/strong\u003e: Extreme severity (n=11); 80% or more of discomfort level (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDuration\u003c/strong\u003e: Constant duration (n=2); Lasts a week (n=1)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFrequency\u003c/strong\u003e: Daily occurrence (n=3)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eContact provider/ask for meds:\u0026nbsp;\u003c/strong\u003eAsk for medical help (e.g., call provider, seek medication, immediate need to go to emergency room (n=8)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eConsider dose delay/dose modification/ discontinuing treatment\u003c/strong\u003e: Change dose/drug (n=3); Consider discontinuing treatment (n=2); Decide to discontinue treatment (n=3)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eClinical efficacy\u003c/strong\u003e: Compare benefits to harms (n=2)\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.74074074074074%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026ldquo;The fact that you actually start to wonder if it\u0026rsquo;s better not to live than to live. Yeah, that you\u0026rsquo;re in tremendous pain. Like forget going anywhere with a diaper at all, it\u0026rsquo;s just, it\u0026rsquo;s nice, you\u0026rsquo;ve got a diaper on, but you\u0026rsquo;re actually having such cramps, or I don\u0026rsquo;t know, things like that, that you don\u0026rsquo;t actually think about going to the store anymore.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026ldquo;If it was affecting me very much, that\u0026rsquo;d be a big change in my lifestyle then. I\u0026rsquo;d be thinking I can\u0026rsquo;t do this. I can\u0026rsquo;t go out of the house. \u0026nbsp;I can\u0026rsquo;t go to work. Or even if I do, I can\u0026rsquo;t carry on as normal.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026ldquo;\u0026lsquo;Very much means that you can hardly stand it anymore. That you really consider to discontinue the medication because you felt almost worse with the medication\u003c/em\u003e.\u0026rdquo;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026ldquo;And then I had difficulties to see, because there was this puffiness under the eyes, and the legs were so swollen that I could not put on the shoes.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch3\u003eResponse options reflecting high side-effect bother and discontinuing treatment\u003c/h3\u003e\n\u003cp\u003eParticipants were asked to select a response option at which high side-effect bother starts. Six participants chose not to answer; of those, two participants found it difficult to select a response that best reflected high side-effect bother, and four provided unclear responses (Figure 1). Of the 34 participants who selected a response option that best reflected the concept of high side-effect bother, 24 (70.6%) selected \u0026ldquo;Quite a bit\u0026rdquo; or \u0026ldquo;Very much.\u0026rdquo; A question of when participants would consider discontinuing treatment was also asked. Of the 30 participants that were asked this question, the majority (18, 60.0%) selected \u0026ldquo;Quite a bit\u0026rdquo; or \u0026ldquo;Very much.\u0026rdquo; Twelve participants could not decide (n=7) or provided an unclear answer (n=5).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study utilized concept elicitation and cognitive interviewing methods to generate the necessary qualitative evidence to support the GP5 as a fit-for-purpose PRO measure of comparative tolerability. Concept elicitation results demonstrated that side-effect bother is among the most proximal patient-reported concepts to tolerability and that the concepts of side-effect bother, side-effect burden, and tolerability are related and highly relevant to participants. The study found that side effects that are symptomatic and bothersome or burdensome are key contributors to how patients perceive the tolerability of a treatment.\u003c/p\u003e \u003cp\u003eThis aligns with a recent study that debriefed the GP5, which found that for most patients the severity of side effects determines bother; and moreover that functional impact, emotional impact, physical impact, specific symptoms, and overall quality of life were also considered by patients when interpreting the concept of bother [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Side-effect bother, burden, and impact have been used interchangeably in regulatory and scientific guidance on the measurement of patient-reported treatment tolerability [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Notably, most participants in this study reported that they defined side-effect burden in the same way they defined side-effect bother, except that \u0026ldquo;burden\u0026rdquo; implied greater physical discomfort, greater interference with daily activities, or greater mental or emotional distress than \u0026ldquo;bother.\u0026rdquo;\u003c/p\u003e \u003cp\u003eIn this study, nearly all participants considered side effects bothersome and/or burdensome if they caused physical discomfort, interference in daily activities, and/or mental or emotional distress. Furthermore, the majority of participants also described tolerability as conceptually related to bother and/or burden. Tolerability was also discussed by half of the participants in the study in terms of weighing the efficacy of the treatment against the side effects.\u003c/p\u003e \u003cp\u003e Cognitive interviewing showed the GP5 item was clear and understandable to all participants and easy to answer for nearly all participants. Participants reported clear and concrete meaningful differences between each response option. Importantly, qualitative data provides evidence that the definition of \u0026ldquo;high side-effect bother\u0026rdquo; in the LIBRETTO-531 trial aligns with GP5 response options of \u0026ldquo;Quite a bit\u0026rdquo; and \u0026ldquo;Very much,\u0026rdquo; the response options most interview participants reported reflected high side-effect bother and/or consideration to discontinue treatment. These findings are similar to those of another study, which found that the majority of participants reported bother would proportionally increase with side-effect worsening and proportionally decrease with side-effect improvement [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs increasing emphasis is placed on understanding the link between tolerability and treatment discontinuation, researchers have begun to investigate the association between treatment discontinuation and specific response options on overall side effect summary burden measures such as the GP5. Wagner 2018 et al. found that a moderate to severe degree of patient-reported side-effect bother at baseline (defined as including the response options \u0026lsquo;\u0026lsquo;quite a bit\u0026rsquo;\u0026rsquo; and \u0026lsquo;\u0026lsquo;very much\u0026rdquo; on the GP5) was quantitatively associated with higher risk of early treatment discontinuation in a breast cancer clinical trial [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], suggesting the GP5 may be well-positioned to predict treatment discontinuation [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e When we asked open-ended (unprobing) questions about the meaning of response options, only n\u0026thinsp;=\u0026thinsp;1 and n\u0026thinsp;=\u0026thinsp;8 participants respectively associated the response options \u0026ldquo;quite a bit\u0026rdquo; and \u0026ldquo;very much\u0026rdquo; with considering dose modification or treatment discontinuation. However, when asked probing questions about which response option they associated with considering discontinuing treatment, most participants reported they would associate \u0026ldquo;quite a bit\u0026rdquo; and \u0026ldquo;very much\u0026rdquo; with discontinuation. Notably, nearly one-quarter of participants reported that associating a response option with discontinuing treatment was either not relevant to them as a cancer patient or was impossible for them to do. Participants further elaborated that clinical efficacy mattered to them and/or they did not feel the item and its response options allowed them to account for the consideration of clinical efficacy.\u003c/p\u003e \u003cp\u003eAcross our concept elicitation and cognitive interviewing data sets, including elicitation on the concept of tolerability, participants emphasized that survival is of such importance that overall side-effect bother would need to approach unbearable levels for treatment discontinuation to be considered (in the context of a treatment regimen that has clinical efficacy). Overall, our data supports the association of the GP5 response options \u0026ldquo;quite a bit\u0026rdquo; and \u0026ldquo;very much\u0026rdquo; with considerations of treatment discontinuation, but additional research may be warranted to understand the degree to which GP5 data can be used to predict treatment discontinuation.\u003c/p\u003e \u003cp\u003eThe study boasts several points of strength and differentiation. Firstly, the participants included in this study represented a heterogenous sample in terms of age, national residence, language, and year of MTC diagnosis. Such a diverse sample assures greater representation and helps to overcome numerous potential forms of sampling bias. Another signal strength of the study was the methodology, which included the triangulation of concept elicitation data and cognitive interviewing data to explore the content validity of the GP5 as a measure of side-effect bother, burden, and of the threshold for high side-effect bother.\u003c/p\u003e \u003cp\u003eThere are also limitations that require mentioning. The time from baseline (the date of first treatment) to interview was targeted at 10\u0026ndash;14 weeks, however, the majority of interviews (n\u0026thinsp;=\u0026thinsp;36) fell outside that timeframe. Despite that, nearly all participants were able to describe their side-effect experience in depth. Potential selection bias should be considered when interpreting results of this qualitative study among clinical trial participants. Differences between clinical trial participants and non-clinical trial participants have been observed in regards to demographic, socio-economic factors, and health factors [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. These factors could be associated with different interpretations of bother, burden and tolerability, as well as different views on which response options they would associate with high side-effect bother and with potential treatment discontinuation. Finally, participants were asked how GP5 response options related to the hypothetical scenario of discontinuing treatment; hypothetical questions pose potential risk for bias because they ask participants to guess how they would act in an imagined situation and may be incongruent with how they would act in actuality [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this study, participants described the concepts of side-effect bother, side-effect burden, and tolerability as highly relevant and related. The qualitative evidence generated in this study is supportive of the GP5 as a fit-for-purpose measure of comparative tolerability in MTC clinical trials. The GP5 assesses a concept important to individuals undergoing treatment for MTC in a way that is understandable and relevant. The definition of \u0026ldquo;high side-effect bother\u0026rdquo; is appropriately reflected by scores of 3 or 4.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by Eli Lilly and Company.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAffiliations\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEli Lilly and Company, Indianapolis, IN, USA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNalin Payakachat, Adrienne M. Gilligan, Patricia Maeda, Shannon Bourke, Rebecca M. Speck\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eModus Outcomes, Cary, NC, USA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDanielle Altman, Julia Choi, Erica Spies\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of Oncology, 2nd Faculty of Medicine of Charles University and Motol University Hospital, Prague, Czech Republic\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaterina Kopeckova\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEndocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRossella Elisei\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWeston Park Cancer Centre, Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJonathan Wadsley\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJolanta Krajewska\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eContributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript. DA, JC, and ES contributed to research design, interview conduct, qualitative analysis, interpretation, and manuscript development. NP, AMG, PM, SB, and RMS contributed to research design, interpretation, and manuscript development. KK, RE, JW, and JK contributed to manuscript development.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCorresponding author\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence [email protected]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEditorial assistance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedical writing support for this manuscript was provided by Trais Pearson, PhD, of Modus Outcomes and was funded by Eli Lilly and Company, Indianapolis, IN, USA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNP, AMG, PM, SB and RMS are employed by Eli Lilly and Company. DA, JC, and ES are employed of Modus Outcomes and was funded by Eli Lilly and Company, Indianapolis, IN, USA.\u0026nbsp;KK reports consultancy role for Eli Lilly and Company.\u0026nbsp;RE\u0026nbsp;reports consultancy role for Eisai, Eli Lilly, Bayer, Roche, and Ipsen. JW reports fees to institution for speaker/advisor fees from Eli Lilly, Novartis, Eisai, AstraZeneca, Ipsen, Bayer, Roche and Incyte. JK\u0026nbsp;reports consultant role for Bayer, Ewopharma, Exelixis, Ipsen, Eli Lilly, Sanofi-Genzyme. Honoraria (clinical trials) and travel grants: AstraZeneca, Bayer, Eisai, Exelixis, Ipsen, Eli Lilly, Novartis, Sanofi-Genzyme.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with ethics guidelines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe research was conducted in accordance with\u0026nbsp;consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines.\u0026nbsp;Study documents, including the protocol, demographic and health information form, interview guide, screener, and informed consent and assent forms were subject to IRB review and received ethical approval in each of the study countries (see Supplementary Materials for full details). All participants provided informed consent to participate in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConsent and assent via written consent forms were obtained from participants before proceeding with the interviews.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKluetz, P.G., et al., \u003cem\u003eInforming the Tolerability of Cancer Treatments Using Patient-Reported Outcome Measures: Summary of an FDA and Critical Path Institute Workshop\u003c/em\u003e. Value in Health, 2018. 21(6): p. 742\u0026ndash;747.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWagner, L.I., et al., \u003cem\u003ePatient-reported predictors of early treatment discontinuation: treatment-related symptoms and health-related quality of life among postmenopausal women with primary breast cancer randomized to anastrozole or exemestane on NCIC Clinical Trials Group (CCTG) MA.27 (E1Z03)\u003c/em\u003e. Breast Cancer Research and Treatment, 2018. 169(3): p. 537\u0026ndash;548.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeipert, J.D., M.L. Smith, and E.S. Team, \u003cem\u003eReconsidering tolerability of cancer treatments: opportunities to focus on the patient\u003c/em\u003e. Supportive Care in Cancer, 2022: p. 1\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasch, E., et al., \u003cem\u003eBroadening the definition of tolerability in cancer clinical trials to better measure the patient experience\u003c/em\u003e. Friends Cancer Res, 2018. 10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeipert, J.D. and M.L. Smith, \u003cem\u003eReconsidering tolerability of cancer treatments: opportunities to focus on the patient\u003c/em\u003e. Supportive Care in Cancer, 2022. 30(5): p. 3661\u0026ndash;3663.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKluetz, P., H. Klepin, and S.W. 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Value in Health, 2018. 21(6): p. 742\u0026ndash;747.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoy, U.B., et al., \u003cem\u003eLearning from patients: reflections on use of patient-reported outcomes in lung cancer trials\u003c/em\u003e. Journal of Thoracic Oncology, 2018. 13(12): p. 1815\u0026ndash;1817.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePearman, T.P., et al., \u003cem\u003eValidity and usefulness of a single-item measure of patient-reported bother from side effects of cancer therapy\u003c/em\u003e. Cancer, 2018. 124(5): p. 991\u0026ndash;997.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCella, D.F., et al., \u003cem\u003eThe Functional Assessment of Cancer Therapy scale: development and validation of the general measure\u003c/em\u003e. J Clin Oncol, 1993. 11(3): p. 570\u0026ndash;579.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeipert, J.D., et al., \u003cem\u003eHow do patients interpret and respond to a single-item global indicator of cancer treatment tolerability?\u003c/em\u003e Supportive Care in Cancer, 2022. 31(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeipert, J.D., et al., \u003cem\u003e[Special issue PRO] Considering endpoints for comparative tolerability of cancer treatments using patient report given the estimand framework\u003c/em\u003e. Journal of Biopharmaceutical Statistics, 2024: p. 1\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrose, M.S., et al., \u003cem\u003eComparative patient-reported tolerability (PRT): a multiplicity-controlled analysis of LIBRETTO-531, a randomized controlled trial (RCT) in medullary thyroid cancer (MTC)\u003c/em\u003e, in \u003cem\u003e2024 ASCO Annual Meeting\u003c/em\u003e. 2024: Chicago, IL.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKluetz P, M.K., Klepin H. \u003cem\u003eConsiderations for assessment frequency and how it relates to the measurement of tolerability\u003c/em\u003e in \u003cem\u003eFDA-ASCO PUBLIC WORKSHOP: 2020 Clinical Outcome Assessments in Cancer Clinical Trials Fifth Annual Workshop: Session 2 of Workshop U.S. Food \u0026amp; Drug Administration\u003c/em\u003e. 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClarke, V., V. Braun, and N. Hayfield, \u003cem\u003eThematic analysis.\u003c/em\u003e Qualitative psychology: A practical guide to research methods, 2015. 3: p. 222\u0026ndash;248.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBowling, A., \u003cem\u003eResearch Methods in Health: Investigating Health and Health Services\u003c/em\u003e. 3rd ed. 2009, Maidenhead: Open University Press.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichie, J., et al., \u003cem\u003eAnalyzing qualitative data\u003c/em\u003e. London, GBR: Routledge, 1994.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomas, D.R., \u003cem\u003eA general inductive approach for analyzing qualitative evaluation data\u003c/em\u003e. American journal of evaluation, 2006. 27(2): p. 237\u0026ndash;246.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFriese, S. \u003cem\u003eATLAS.ti 7 User Guide and Reference\u003c/em\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUS Federal Drug Administration, \u003cem\u003eCore Patient-Reported Outcomes in Cancer Clinical Trials: Draft Guidance for Industry\u003c/em\u003e. 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWagner, L.I., et al., \u003cem\u003ePatient-reported predictors of early treatment discontinuation: treatment-related symptoms and health-related quality of life among postmenopausal women with primary breast cancer randomized to anastrozole or exemestane on NCIC Clinical Trials Group (CCTG) MA. 27 (E1Z03).\u003c/em\u003e Breast cancer research and treatment, 2018. 169: p. 537\u0026ndash;548.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRegnault, A., et al., \u003cem\u003eEvidence To Support the Use of the Functional Assessment of Cancer Therapy \u0026ndash; General Item GP5 (FACT-GP5) To Assess Comparative Tolerability Endpoint: Results From the LIBRETTO-531 Trial\u003c/em\u003e, in \u003cem\u003eAnnual Meeting of the Professional Society for Health Economics and Outcomes Research (ISPOR)\u003c/em\u003e 2024: Atlanta, GA.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAltman, D., et al., \u003cem\u003eContent Validity of FACT-GP5 to Assess Treatment Tolerability in Participants with Progressive, Advanced, Kinase Inhibitor-Na\u0026iuml;ve, RET-Mutant Medullary Thyroid Cancer: Qualitative Interview Sub-Study of the LIBRETTO-531 Trial\u003c/em\u003e, in \u003cem\u003eAnnual Meeting of the Professional Society for Health Economics and Outcomes Research (ISPOR)\u003c/em\u003e. 2024: Atlanta, GA.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBodicoat, D.H., et al., \u003cem\u003ePromoting inclusion in clinical trials\u0026mdash;a rapid review of the literature and recommendations for action\u003c/em\u003e. Trials, 2021. 22(1): p. 1\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eByrne, M.M., et al., \u003cem\u003eParticipation in cancer clinical trials: why are patients not participating?\u003c/em\u003e Medical Decision Making, 2014. 34(1): p. 116\u0026ndash;126.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaderabek, A. and J. Sinibaldi, \u003cem\u003eAssessing Measurement Error in Hypothetical Questions\u003c/em\u003e. Survey Practice, 2022.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4730587/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4730587/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003ePatient-reported measures of overall side effect burden, such as the Functional Assessment of Cancer Therapy- item GP5 (GP5), can be used to inform the tolerability of cancer treatments and be included as an endpoint in clinical trials. The objectives of this qualitative study were to explore how participants with medullary thyroid cancer (MTC) conceptualize side effect bother, burden, and tolerability and to generate evidence to support the GP5 as a fit-for-purpose measure of patient-reported tolerability in the treatment of MTC and to establish which response options constitute \u0026ldquo;high side effect burden.\u0026rdquo;\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA purposive sample of forty participants with MTC enrolled in the LIBRETTO-531 trial (NCT04211337) were recruited via clinical trial sites. Semi-structured interviews were conducted in the participant\u0026rsquo;s preferred language to examine the concept of tolerability, demonstrate understanding of the GP5 content, and establish which response options constitute \u0026ldquo;high side effect burden\u0026rdquo;. Interview transcripts were thematically analyzed with a mix of inductive and deductive coding methods.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eConcept elicitation results found side effect bother to be among the most proximal patient-reported concepts to tolerability and highly relevant to participants. The experience of side effects that are symptomatic and bothersome or burdensome are key contributors to how patients perceive the tolerability of a treatment. Cognitive interviewing showed the GP5 item was clear and understandable to all participants. Participants reported clear and concrete meaningful differences between each response option. Importantly, the qualitative data provide evidence that \u0026ldquo;high side effect burden\u0026rdquo; aligns with the response options of \u0026ldquo;Quite a bit\u0026rdquo; and \u0026ldquo;Very much\u0026rdquo; (score of 3 and 4, respectively) for most (60%, n\u0026thinsp;=\u0026thinsp;24) interview participants.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eParticipants described the concepts of side effect bother, side effect burden, and tolerability as highly relevant and related. The GP5 assesses a concept important to individuals undergoing treatment for MTC in a way that is understandable and relevant. The definition of \u0026ldquo;high side effect burden\u0026rdquo; is appropriately reflected by scores of 3 or 4. This qualitative evidence is supportive of the GP5 as a fit-for-purpose measure of comparative tolerability in MTC.\u003c/p\u003e","manuscriptTitle":"Assessing Side-Effect Bother, Burden, and Tolerability: A Qualitative Study Exploring the Content Validity of the Functional Assessment of Cancer Therapy – Item GP5","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-26 14:03:25","doi":"10.21203/rs.3.rs-4730587/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"262f9c1a-9240-49eb-a8c4-55af95671dfe","owner":[],"postedDate":"August 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-21T13:54:09+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-26 14:03:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4730587","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4730587","identity":"rs-4730587","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}