Examining patient and professional perspectives in the UK for gene therapy in haemophilia.

INTRODUCTION: With the development of gene therapy for people with haemophilia (PWH), it is important to understand how people impacted by haemophilia (PIH) and clinicians prioritise haemophilia treatment attributes to support informed treatment decisions.
OBJECTIVE: To examine the treatment attribute preferences of PIH and clinical experts in the United Kingdom (UK) and to develop a profile of gene therapy characteristics fit for use in future discrete choice experiments (DCEs).
METHODS: Semi-structured interviews were conducted with PIH (n = 14) and clinical experts (n = 6) who ranked pre-defined treatment attributes by importance. Framework analysis was conducted to identify key themes and treatment attributes; points were allocated based on the rankings. Synthesis of results by a multidisciplinary group informed development of a profile of gene therapy characteristics for use in future research.
RESULTS: Key themes identified by PIH and clinical experts included patient relevant features and the importance of 'informed decision making'. The six top-ranked treatment attributes were 'effect on factor level' (79 points), 'uncertainty regarding long-term risks' (57 points), 'impact on daily life' (41 points), 'frequency of monitoring' (33 points), 'impact on ability to participate in physical activity' (29 points), and 'uncertainty regarding long-term benefits' (28 points). The final treatment characteristics were categorised as therapeutic option, treatment effectiveness, safety concerns, impact on self-management and quality of life (role limitations).
CONCLUSION: We identified several gene therapy characteristics important to PIH and clinicians in the UK. These characteristics will be used in a future DCE to further investigate patient preferences for gene therapy.

INTRODUCTION

Background

Gene therapy could be a life‐changing treatment option for people with haemophilia (PWH), offering relief from disease burden as well as the practical burdens associated with currently available haemophilia treatments. Acute and chronic complications of haemophilia also impact health‐related quality of life (HRQoL) particularly when treatment is not effectively managed. , , Prophylactic treatment with replacement therapy for bleed prevention is the standard of care for haemophilia A and B. Replacement factor infusions may also be administered ‘on‐demand’ in response to a breakthrough bleeding event or before an activity posing potential bleeding risk. Where available, subcutaneous injections of bispecific antibodies are also considered a standard of care for haemophilia A. , ,

Considering the lifelong nature of haemophilia and its medical management, understanding the most important treatment attributes to patients can clarify their relative value and can inform comparative assessments of existing and emerging therapeutic options, such as factor replacement, non‐factor therapies and gene therapy. As such, there is growing consensus that the patient perspective should be incorporated into healthcare decision‐making at both individual and national levels. , , , Formal evaluation of stakeholder perspectives is often comprised of preference research, where preferences are defined as ‘qualitative or quantitative statements of the relative desirability or acceptability of attributes that differ among alternative health interventions’. These qualitative methods can identify the most relevant treatment attributes, which can then be examined further in quantitative preference elicitation methods such as discrete choice experiments (DCEs).

In haemophilia, the PAVING study recently explored the preferences of PWH in Belgium for gene therapy attributes. In addition, Sun et al. reported administration (frequency, route, and place) and out‐of‐pocket costs to be the most important gene therapy attributes in their recent DCE among patients with haemophilia A in the United States. Otherwise, preference research in haemophilia has focused on attributes of factor replacement therapy, such as costs, breakthrough bleeds, and impact on physical activities, among subgroups of PWH. , , , , Further understanding of people impacted with haemophilia (PIH) and clinician perspectives on relevant attributes of gene therapy can help support shared treatment decisions, health policy evaluations, and future research.

In the absence of gene therapy‐specific insights, this preference study explored the importance of various treatment attributes for both gene therapy and current haemophilia therapies in the UK. Perspectives were collated from PIH and clinical experts to formulate a comprehensive profile of relevant treatment attributes and related considerations. The most important attributes will be used in a future DCE to further investigate patient preferences for gene therapy attributes.

METHODS

We conducted semi‐structured interviews with PIH and clinical experts to identify and explore preferences for haemophilia treatment attributes related to factor replacement and gene therapy. PIH were members of a patient advocacy group (The Haemophilia Society) and were either PWH or caregivers of PWH. Interviews were conducted between April and June 2020. Interview findings were synthesised with a focus group of clinical experts, industry stakeholders, and experts in patient‐centred and health economics research who refined the interview data into a profile of gene therapy characteristics fit for subsequent patient preference research. The process is further described in Figure 1.

FIGURE 1

Flow Diagram of methodological steps

Participant recruitment

Interview participants consisted of male adults (≥18 years) with haemophilia of any severity, haemophilia caregivers and haemophilia clinical experts in the UK. A minimum sample size of 20 participants was targeted; this was based on prior research upon the number of interviews to reach data saturation and a feasible number of participants we could recruit. Researchers contacted 31 potential participants (16 PIH and 15 clinical experts) who were identified by the patient advocacy group The Haemophilia Society from their members list and were contacted via email, 20 of whom agreed and enrolled (14 PIH and six clinical experts). Participants included 12 PWH, two caregivers of PWH and six haemophilia clinical experts with prior knowledge of gene therapy in haemophilia (two haematologists, two nurses, one psychologist and one physiotherapist). Participants provided written informed consent prior to the interviews being conducted.

Conduct of the interviews

Researchers used an interview guide to standardise interview completion (Appendix A1). Participants were provided with a study summary prior to the interviews and PWH were asked to complete a short pre‐survey about themselves. Interview materials were developed based on those used in the PAVING study which specified three qualitative techniques to explore preferences (open questions, a ranking exercise, and case questions), as no single technique is considered a preferred standalone method in quantitative preference research.

Participants were asked how willing they may be to receive or recommend gene therapy based on their knowledge and the information provided (‘very willing’, ‘willing’, ‘neutral’, or ‘not willing’). Open questions were used to elicit participants’ opinions and thought processes when considering haemophilia treatment attributes (Appendix A1). Researchers avoided using leading questions during the interviews. Prompts and unstructured follow‐up questions were used where applicable.

Participants were then asked to spontaneously identify attributes of gene therapy that they considered to be important (Appendix A2). A list of 18 pre‐defined attributes for gene therapy or factor replacement therapy was also produced based upon the PAVING study and a targeted literature review. The pre‐defined attributes were broadly organised into categories relating to the nature of the treatment (mechanism of action), dosing and administration, follow‐up, benefits, quality of life, and risks (Table 1). Participants then ranked the six most important gene therapy attributes form the pre‐defined list and any spontaneously mentioned attributes they considered most important for themselves or their relatives/patients.

TABLE 1

Pre‐defined attributes used in the attribute ranking exercise based off the PAVING Study

Categories	Attributes
Nature of treatment	Mechanism of action
Administration	Route of administration
	Dose frequency
	Duration of administration
	Dosage strength
	Place of administration
	Ease of administration
	Ease of product storage
Follow‐up	Frequency of monitoring
Benefits	Effect on factor level
	Effect on annual bleeding rate
	Probability that prophylaxis can be stopped after treatment
	Uncertainty regarding long‐term benefits
Quality of life	Impact on daily life
	Impact on participation in physical activity
	Possibility to undergo major surgery
Risks	Probability that liver inflammation will develop
	Uncertainty regarding long‐term risks

Response analysis

A thematic framework analysis was applied to the open question responses to identify the most important overarching themes and gene therapy attributes. Interviews were transcribed by an independent service. Researchers reviewed the transcripts prior to response coding, which was then used to identify nuances within and among participant responses. All lines of text related to the themes were coded and cross‐checked by the study team (using NVivo 12 software). Any disagreements regarding code assignment were resolved via group discussion.

Analysis of participants’ ranking of the six most important attributes, following the PAVING study example, assigned decremental points for each rank, from 6 points for a rank of 1 (most important) to 1 point for a rank of 6. This weighted point system yielded a maximum possible 120 points for a single attribute (if every participant ranked the same attribute as most important). In addition to the weighted point system, the frequency with which each attribute was identified in the top 6 attributes was also recorded (regardless of ranking within the top 6).

Determination of the haemophilia treatment characteristic profile

Following the ranking exercise, a focus group was convened to review the top ranked attributes, consisting of two clinical experts (one haematologist and one psychologist), two industry stakeholders, two health economics researchers and one patient‐centred researcher. The focus group reached consensus on five treatment characteristics; a content review of the consensus was conducted by two PWH.

RESULTS

Participant characteristics

For PWH (n = 12) the patient characteristics presented in Table 2 were collected. The majority of PWH were Type A (83%) compared to Type B (17%) and had severe haemophilia (83%) compared to mild (8%) and moderate (8%) haemophilia. For current treatment haemophilia treatment of PWH we saw prophylactic (67%) being the most common followed by on‐demand (17%) and Hemlibra (17%). The two caregivers who completed the interviews were both female and cared for a child with haemophilia that was younger than 16.

TABLE 2

People with haemophilia characteristics (self‐reported)

Characteristics	PWH (n = 12)
	N	%
Sex
Females	0	0
Males	12	100
Age, years
18–25	4	33
26–40	4	33
41–60	3	25
>60	1	8
Type of haemophilia
A	10	83
B	2	17
Haemophilia severity
Mild	1	8
Moderate	1	8
Severe	10	83
Current treatment regimen
Prophylactic	8	67
On‐demand	2	17
Hemlibra (emicizumab)	2	17

Knowledge about and willingness to receive gene therapy

All participants indicated awareness of gene therapy for haemophilia, and self‐reported baseline knowledge (before summary information was provided) was good or very good for approximately half of all participants (very good, 25%; good, 30%), and was otherwise deemed to be reasonable (35%), bad (5%) or very bad (5%). Participants indicated a general willingness to receive or recommend gene therapy, with responses ranging from very willing (10%) or willing (45%) to neutral (20%) and not willing (25%).

Identification and coding of themes from interview responses

Two key themes related to considering gene therapy were identified in the participant responses to the open questions. Participants indicated that ‘patient‐relevant features’ and ‘informed decision‐making’ were the most important over‐arching themes from the open questions, which would then help guide interpretation of the treatment attribute selections. The ‘patient‐relevant features’ theme included codes for pros/benefits, cons/disadvantages, and long‐term uncertainty of gene therapy. The ‘informed decision‐making’ theme included codes related to accuracy, accessibility and individual applicability. Illustrative participant quotes from each of the coded themes are provided in Figure 2.

FIGURE 2

Participant quotes supporting each code included within the two key identified themes: patient‐relevant features and informed decision‐making

The potential pros/benefits of gene therapy were mentioned by 95% of all participants as a key factor in their decision‐making. In particular, the possibilities of factor level stability, reduction of long‐term damage, having a less restrictive lifestyle (e.g., travel and physical activity), and better quality of life may be highly influential in decision‐making. All participants expressed concerns about potential cons/disadvantages of gene therapy, including the feasibility of gene therapy within the patient's lifestyle (65%), side effects (55%), uncertainty about long‐term efficacy (45%), and development of inhibitors (30%). All were said to potentially dissuade participants from choosing gene therapy.

Concerns related to long‐term uncertainty were expressed by 95% of participants, specifically citing the duration of gene therapy effectiveness (85%), long‐term side effects (65%), and potential lifestyle limitations (50%). The lack of gene therapy data and uncertainty itself was cited as reasons for unwillingness to receive or recommend gene therapy.

Regarding informed decision‐making, nearly all participants (90%) indicated the importance of accurate, detailed, and up‐to‐date information about gene therapy, as well as information about alternative options (65%). Participants believed that PWH should be fully informed about how gene therapy works and any potential side effects (75%), lifestyle changes (70%), and follow‐up and monitoring requirements (35%). All participants noted that information about gene therapy should be easy for lay people to understand, emphasising the importance of having information that PWH could apply to their own circumstances.

Treatment attributes ranking exercise

The weighted points analysis yielded a total of 417 points across the totality of the attributes in the ranking exercise; the top 10 ranked attributes are presented in Figure 3. Across all 20 interviews, 19 participants selected their top 6 treatment attributes (one participant only ranked their top 4 attributes). All of the top 6 ranked attributes were from the pre‐defined list: ‘effect on factor level’ (79 points), ‘uncertainty regarding long‐term risks’ (57 points), ‘impact on daily life’ (41 points), ‘frequency of monitoring’ (33 points), ‘impact on ability to participate in physical activity’ (29 points), and ‘uncertainty regarding long‐term benefits’ (28 points). Of the spontaneously mentioned attributes, only four received any ranking within the top 6 (‘life span of efficacy of gene therapy’, ‘level of knowledge and research on gene therapies’, ‘family opinions on gene therapy’ and ‘impact on working life’).

FIGURE 3

Top 10 ranked treatment attributes resulting from the ranking exercise

Focus group consensus: Gene therapy treatment characteristics profile

The final profile of five treatment characteristics, based on the focus group's distillation of the qualitative analysis findings, was:

Therapeutic option

Treatment effectiveness

Safety concerns

Hospital attendances and self‐management

Quality of life (Role limitations)

The discussions highlighted that the top ranked attribute ‘effect on factor level’ could be separated into two characteristics: ‘Therapeutic Option’ (the method of how treatment is provided, i.e., gene therapy or different frequencies and administration routes of factor infusions) and ‘Treatment Effectiveness’ (whether additional treatment is needed for situations involving an increased risk of bleeding, such as major or minor surgery, or traumatic or spontaneous bleeds). The characteristic ‘Safety Concerns’ comprised the 2nd ranked attribute (‘uncertainty regarding long‐term risks’) and the 7th ranked attribute (‘probability that liver inflammation will develop’), focusing on how safety risks differ between gene therapy and current standard of care. The 3rd (‘impact on daily life’) and 4th (‘frequency of monitoring’) ranked attributes were accounted for in the ‘Hospital attendances and self‐management’ characteristic. The final characteristic ‘Quality of life (‘role limitations)’ was also based on the 3rd (‘impact on daily life’) and the 5th (‘impact on participation in physical activity’) ranked attributes.

DISCUSSION

This study examined the perspectives of PWH, their caregivers and clinicians in the UK regarding important attributes of gene therapy and existing treatment options for haemophilia. The key themes identified in the semi‐structured survey were benefits, disadvantages and long‐term uncertainty of gene therapy. Accuracy, accessibility and individual applicability of patient information about gene therapy was also deemed essential for truly informed decisions. The treatment attribute ranking exercise placed high importance on treatment effect on factor level, uncertainty around long‐term benefits, and quality of life, particularly related to performing regular activities of life without concerns about bleeds/factor levels. Uncertainty regarding long‐term risks and frequency of monitoring stood out among topics related to risks and follow‐up. The focus group of experts ultimately reached consensus on five key treatment characteristics to be included in future DCE studies of patient preferences for gene therapy in haemophilia, which were derived from the participant‐identified priorities, encompassing treatment choice and effectiveness, safety concerns, follow‐up and self‐management considerations, and quality of life.

Our findings were largely consistent with those of the PAVING study (conducted with 20 PWH in Belgium), where seven of the top 10 ranked attributes were the same between studies. Specifically, ‘the effect of a treatment on factor level’, ‘uncertainty regarding long‐term risks’, and ‘impact on daily life’ were ranked in the top 5 attributes in both studies. Unlike in this study, participants in the PAVING study ranked ‘effect on annual bleeding rate’ the highest (47 points), followed closely by ‘effect on factor level’ (43 points), perhaps due to different participant mix and greater importance given to the impact on daily life and participation in physical activities. Findings from both studies are consistent with those reported by van Balen et al. from members of the Netherlands Haemophilia Society, where participants ‘expressed their concerns about the short‐ and long‐term safety of new treatments and believed the effects of gene therapy were not yet fully understood’. Interestingly, ‘frequency of monitoring’, ‘impact on participation in physical activity’ and ‘uncertainty regarding long‐term benefits’ were in the top 10 in our study but not in the PAVING study. Different perspectives on monitoring may have been related to logistical differences between countries, where travel to follow‐up appointments may be less of a burden for PWH in Belgium, or that the relative knowledge of gene therapy haemophilia may be more widespread in the UK versus Belgium and thus the practical impact of follow up may have been recognised more. Travel burden has been cited as a reason for reduced treatment adherence among PWH. Differences regarding uncertainty around long‐term benefits in terms of bleeding rates and factor levels may be attributable to the different participant mix in each study: the PAVING study included PWH from the general haemophilia population whereas our participants were recruited via a patient advocacy group and were a mix of PWH, caregivers and clinical experts. Carlsson et al. also reported ‘participating in physical activity’ as an important treatment attribute in a Swedish patient preference study for haemophilia A treatments, as this impacts factor levels, treatment management, and quality of life.

Our multidisciplinary focus group distilled the participants’ perspectives into 5 core treatment characteristics, including treatment choice, effectiveness, safety, quality of life, and impact on daily life. These will be included in a future DCE to further examine preferences for haemophilia treatment on a larger scale, which may provide essential insights into how PWH will consider the potentially transformative nature of gene therapy for haemophilia.

Strengths and limitations

Our sample consisted of a mixture of PIH and clinical experts following best practices for patient preference research in healthcare , by including a unique multidimensional perspective. While this multi‐stakeholder approach is a key strength it did not include PWH who were not affiliated with The Haemophilia Society. Inclusion of this additional group of people may have elicited additional preferences that could have supported or added to our thematic analysis. Future work should look to conduct a study specific for patients and clinical experts to assess how patient‐driven attributes and clinical expert‐driven attributes differ. However, our findings are consistent with recently published work in this area, reinforcing its relevance concerning gene therapy attributes. , ,

We took several measures to standardise participants’ awareness of gene therapy, but their baseline (pre‐aided) knowledge was highly variable and may have influenced subsequent responses. The interview guide was based on that used in the PAVING study where the omission of attributes such as alcohol reduction or viral shedding may have been relevant. Little demographic data were collected during the interviews, which limited subgroup assessments and evaluation of sample heterogeneity. In future, characteristics of all participants should be collected, not just PWH. The ranking exercise is limited in the fact it uses a linear weighting which may not be truly representative of the actual weighting of one attribute to the next. Interviews were conducted by two researchers to minimise variability using the same interview materials. Both researchers had attended a seminar on gene therapy and had participated in haemophilia research.

The focus group was composed of multidisciplinary experts. However, lack of inclusion of PIH could be seen as limitation as they could have provided additional value to the discussions. The decision to not include PIH in the focus group was due to wanting a concentrated group to enable efficient discussion. Two PWH subsequently reviewed the final content and language to ensure the suitability of the conclusions of the focus group. An informal process was used to reach consensus but the final treatment characteristics selected had encompassed all of the key attributes identified by the participants. Quantitative techniques such as DCEs can provide weighting to preferences and relative importance of specific attributes and degrees of attributes. This may yield meaningful, detailed insights into the determinants of patient preferences for different haemophilia treatments, including gene therapy.

CONCLUSION

Treatment choice, effectiveness, safety, patient self‐management and quality of life are important decision factors for PWH in the UK when deciding about treatment options. Further research is needed to better understand the relative importance that PWH ascribe to different haemophilia treatment attributes, particularly when considering existing or new treatment options such as gene therapy.

CONFLICTS OF INTEREST

HCD Economics who were paid consultants to Pfizer, Inc. and Pfizer, Ltd in connection with this research and the development of this manuscript. APM and MC were employees of HCD Economics during the conduct of the study. Editorial/medical writing support was provided by Jeff Frimpter, MPH, of Integrative Life Sciences and was funded by HCD Economics. Jack Brownrigg, Jim Thomson, Ian Winburn and Ione Woollacott, employees of Pfizer Ltd. Eline van Overbeeke is an employee of Pfizer NV/SA Belgium but was an employee of the University of Leuven during the conduct of the study. Pratima Chowdary has received grant/research support from Bayer, CSL Behring, Freeline Therapeutics, Novo Nordisk, Pfizer, Sobi and Takeda (Shire); and consultancy fees from Bayer, CSL Behring, Chugai, Freeline Therapeutics, Novo Nordisk, Pfizer, Roche, Spark Therapeutics, Sanofi, Sobi and Takeda (Shire).

AUTHOR CONTRIBUTIONS

Jamie O'Hara, George Morgan, Eline van Overbeeke, and Sissel Michelsen contributed to the concept and design. Bethany Franks, George Morgan, Jim Thomson, and Ione Woollacott performed the research. George Morgan, Matthew Cawson, Bethany Franks, Jim Thomson, Ian Winburn, and Ione Woollacott analysed the data. All authors contributed to interpreting the data and writing of the paper.

Interview number

Date

Location

Name interviewer

Supervisor

Starting time

Ending time

Categories	Elements	Definition	Ranking
Nature of treatment	Mechanism of action	The specific process through which a treatment produces its effect (e.g., through delivering a gene to liver cells in the case of gene therapy; or through delivering factor to the body in the case of factor replacement therapy)
Administration	Route of administration	The path by which a treatment is administered to the body (e.g., oral, intravenous, subcutaneous)
	Dose frequency	The number of times a treatment is administered within a specific time period (e.g., twice per week, once per year)
	Duration of administration	The amount of time needed to complete one administration (e.g., 15 min, 1 h)
	Dosage strength	The strength of a treatment, which indicates the amount of active ingredient in each dosage (e.g., concentration of factor, concentration of vectors)
	Place of administration	The geographical place where the treatment is administered (e.g., at home, hospital)
	Ease of administration	The degree of ease to perform an administration
	Ease of product storage	The degree of ease to store a treatment (e.g., the amount of storage space needed, temperature requirements)
Follow‐up	Frequency of monitoring	The number of times a patient has to visit a physician for follow‐up on the effect of the treatment within a specific time period (e.g., once per month, once per year)
Benefits	Effect on factor level	The effect on the amount of working clotting factor in the blood, delivered via factor replacement therapy or produced by the patient after gene therapy (often expressed in percentage, %, of normal levels)
	Effect on annual bleeding rate	The effect of the treatment on the number of bleeding events per year
	Probability that prophylaxis can be stopped after treatment	The chance that use of prophylactic factor replacement therapy can be stopped after treatment (expressed in percentage, %, of patients that can stop prophylaxis)
	Uncertainty regarding long‐term benefits	The degree of uncertainty that the effect of the treatment will be maintained after administration of the treatment (uncertainty may exist because of limited time that patients were followed‐up after treatment administration, or because of limited numbers of patients treated with the treatment)
Quality of Life	Impact on daily life	The impact of the treatment on daily activities
	Impact on participation in physical activity	The impact of the treatment on the performance of physical activity (sports)
	Possibility to undergo major surgery	The impact of the treatment on the possibility to undergo major surgery
Risks	Probability that liver inflammation will develop	The chance that liver inflammation develops after treatment (expressed in percentage, %, of patients that develops liver inflammation)
	Uncertainty regarding long‐term risks	The degree of uncertainty regarding the side effects that can occur after administration of the treatment (uncertainty may exist because of limited time that patients were followed‐up after treatment administration, or because of limited numbers of patients treated with the treatment)
Spontaneously mentioned elements

Interview number

Date

Location

Name interviewer

Supervisor

Starting time

Ending time

Categories	Elements	Definition	Ranking
Nature of treatment	Mechanism of action	The specific process through which a treatment produces its effect (e.g., through delivering a gene to liver cells in the case of gene therapy; or through delivering factor to the body in the case of factor replacement therapy)
Administration	Route of administration	The path by which a treatment is administered to the body (e.g., oral, intravenous, subcutaneous)
	Dose frequency	The number of times a treatment is administered within a specific time period (e.g., twice per week, once per year)
	Duration of administration	The amount of time needed to complete one administration (e.g., 15 min, 1 h)
	Dosage strength	The strength of a treatment, which indicates the amount of active ingredient in each dosage (e.g., concentration of factor, concentration of vectors)
	Place of administration	The geographical place where the treatment is administered (e.g., at home, hospital)
	Ease of administration	The degree of ease to perform an administration
	Ease of product storage	The degree of ease to store a treatment (e.g., the amount of storage space needed, temperature requirements)
Follow‐up	Frequency of monitoring	The number of times a patient has to visit a physician for follow‐up on the effect of the treatment within a specific time period (e.g., once per month, once per year)
Benefits	Effect on factor level	The effect on the amount of working clotting factor in the blood, delivered via factor replacement therapy or produced by the patient after gene therapy (often expressed in percentage, %, of normal levels)
	Effect on annual bleeding rate	The effect of the treatment on the number of bleeding events per year
	Probability that prophylaxis can be stopped after treatment	The chance that use of prophylactic factor replacement therapy can be stopped after treatment (expressed in percentage, %, of patients that can stop prophylaxis)
	Uncertainty regarding long‐term benefits	The degree of uncertainty that the effect of the treatment will be maintained after administration of the treatment (uncertainty may exist because of limited time that patients were followed‐up after treatment administration, or because of limited numbers of patients treated with the treatment)
Quality of Life	Impact on daily life	The impact of the treatment on daily activities
	Impact on participation in physical activity	The impact of the treatment on the performance of physical activity (sports)
	Possibility to undergo major surgery	The impact of the treatment on the possibility to undergo major surgery
Risks	Probability that liver inflammation will develop	The chance that liver inflammation develops after treatment (expressed in percentage, %, of patients that develops liver inflammation)
	Uncertainty regarding long‐term risks	The degree of uncertainty regarding the side effects that can occur after administration of the treatment (uncertainty may exist because of limited time that patients were followed‐up after treatment administration, or because of limited numbers of patients treated with the treatment)
Spontaneously mentioned elements

Interview number

Date

Location

Name interviewer

Supervisor

Starting time

Ending time

Categories	Elements	Definition	Ranking
Nature of treatment	Mechanism of action	The specific process through which a treatment produces its effect (e.g., through delivering a gene to liver cells in the case of gene therapy; or through delivering factor to the body in the case of factor replacement therapy)
Administration	Route of administration	The path by which a treatment is administered to the body (e.g., oral, intravenous, subcutaneous)
	Dose frequency	The number of times a treatment is administered within a specific time period (e.g., twice per week, once per year)
	Duration of administration	The amount of time needed to complete one administration (e.g., 15 min, 1 h)
	Dosage strength	The strength of a treatment, which indicates the amount of active ingredient in each dosage (e.g., concentration of factor, concentration of vectors)
	Place of administration	The geographical place where the treatment is administered (e.g. at home, hospital)
	Ease of administration	The degree of ease to perform an administration
	Ease of product storage	The degree of ease to store a treatment (e.g., the amount of storage space needed, temperature requirements)
Follow‐up	Frequency of monitoring	The number of times a patient has to visit a physician for follow‐up on the effect of the treatment within a specific time period (e.g. once per month, once per year)
Benefits	Effect on factor level	The effect on the amount of working clotting factor in the blood, delivered via factor replacement therapy or produced by the patient after gene therapy (often expressed in percentage, %, of normal levels)
	Effect on annual bleeding rate	The effect of the treatment on the number of bleeding events per year
	Probability that prophylaxis can be stopped after treatment	The chance that use of prophylactic factor replacement therapy can be stopped after treatment (expressed in percentage, %, of patients that can stop prophylaxis)
	Uncertainty regarding long‐term benefits	The degree of uncertainty that the effect of the treatment will be maintained after administration of the treatment (uncertainty may exist because of limited time that patients were followed‐up after treatment administration, or because of limited numbers of patients treated with the treatment)
Quality of Life	Impact on daily life	The impact of the treatment on daily activities
	Impact on participation in physical activity	The impact of the treatment on the performance of physical activity (sports)
	Possibility to undergo major surgery	The impact of the treatment on the possibility to undergo major surgery
Risks	Probability that liver inflammation will develop	The chance that liver inflammation develops after treatment (expressed in percentage, %, of patients that develops liver inflammation)
	Uncertainty regarding long‐term risks	The degree of uncertainty regarding the side effects that can occur after administration of the treatment (uncertainty may exist because of limited time that patients were followed‐up after treatment administration, or because of limited numbers of patients treated with the treatment)
Spontaneously mentioned elements

Spontaneously mentioned attributes
Lifespan of efficacy of gene therapy
Level of knowledge and research on gene therapies
Family opinions on gene therapy
Impact on working life
Management of patient post‐intervention
Viral shedding
Alcohol consumption
Additional treatments after intervention (e.g., steroids)
Underlying conditions
Patient lifestyle
Patient adherence
Costs associated with gene therapy
Certainty of risks/outcomes/duration
Emotional and identity changes