Background

Gene therapy offers people with haemophilia (PwH) the potential of a life free from prophylactic factor replacement therapy and spontaneous joint bleeding [1, 2]. The availability of gene therapy for haemophilia has, however, been constrained as it has only been available as part of a clinical trials programme. Restrictive inclusion and exclusion criteria including age (≥ 18 years), pre-existing or historical inhibitors, significant concomitant liver damage and pre-existing neutralising antibodies to the adeno-associated vector (AAV) used have also limited its availability [1, 3,4,5].

Two gene therapy products have now been granted marketing approval in Europe and the United States [6, 7] with more expected in the next 12 months [8]. While it is likely that many of the restrictive inclusion and exclusion criteria seen in the clinical trials will be maintained in the marketed product, a growing number of PwH will soon be able to access gene therapy. The hub and spoke model of care proposed by the European Haemophilia Consortium and the European Association of Haemophilia and Allied Disorders [9, 10], will mean that those centres not previously part of a trials programme will be able to access the specialist expertise necessary to facilitate access to gene therapy for the PwH in their care.

Qualitative studies have explored the impact of gene therapy on those who have had it [11,12,13] and those who were excluded from having it [14]. A number of studies have also examined what the wider haemophilia community thinks of gene therapy and whether it is a treatment they would consider [15, 16]. This sub-study, part of the larger Exigency study [17], seeks to build on this body of knowledge by investigating perceptions of and concerns about gene therapy among PwH in the United Kingdom (UK) who have not yet been able to access it, and to identify the barriers to access they perceive if and when it becomes a standard of care (SoC) treatment option.

Results

We approached 23 PwH and consented 14. One withdrew before interview. Recruitment was discontinued after 13 interviews (participant codes Exi201–Exi213) as we deemed data saturation had been achieved. The method described by Guest, Namey and Chen, was used to assess saturation [18]. Five data collection events were used to calculate the base size (105), with three data collection events per run length of two interviews. A < 5% new information threshold was used for the level of saturation confidence (see Table 1).

Table 1 Data saturation calculation
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The mean age of participants was 35.7 years (range 25–74 years). Eleven had haemophilia A; two had haemophilia B. All participants were on prophylaxis, two on standard half-life (SHL) factor products, five on extended half-life (EHL) products, four on a FVIII mimetic and one on a clinical trial product. Demographic and treatment details for the participants are given in Table 2.

Table 2 Biographical and treatment data
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All participants saw gene therapy as a positive development and one that had the potential to improve the quality of life (QoL) of PwH,

'I think its advancement in treatment. It's the next stage in treatment.'

[Exi204]

There's people who'd benefit from that [gene therapy] to give them a better quality of life.

[Exi207]

There were, however, four key barriers which they suggested might prevent them and others from having gene therapy:

  • Expectations: concerns about the process of gene therapy

  • Outcomes: uncertainty about the results

  • Access to treatment

  • Information: a lack of information about gene therapy.

Expectations

Despite having a limited understanding of all the processes involved in gene therapy, many participants were aware of some and had concerns about them. Ten were worried about possible side effects and associated consequences of having gene therapy. Three participants knew of people who had had gene therapy and required steroids to maintain factor expression. Their concerns centred on the side effects they had seen, including weight gain, insomnia and immunosuppression, a particular concern during the Covid-19 pandemic.

'I did some reading and then I also know just from social media what it was like to go through the process, and I just thought the process looked awful, really, to be honest.'

[Exi205]

'And granted, the circumstances of [the individual] but also when he went on it he had to go on immunosuppressants, which at the time of Covid and all that stuff it… Covid in itself was just another big issue.'

[Exi212]

Three participants were concerned about the level of commitment and engagement that gene therapy would involve. Two acknowledged that it had the potential to improve their overall QoL but believed it would also increase their treatment burden, particularly in the short term.

'The fact is I really enjoy the treatment I'm on. I chose this treatment because I can't be bothered dealing with haemophilia – I want to just treat and forget. And obviously, that's maybe one of the selling points of gene therapy, but not in its current formation when there's so much baggage attached to it.'

[Exi202]

'I just can't be bothered with the faff [inconvenience], to be honest.'

[Exi211]

Three participants thought that the commitment required for follow-up was manageable on a personal level, but two did not think their employers would be as accommodating, potentially impacting their ability to have gene therapy.

'For me, it would be fine. Whether my employer had the same sort of mindset.'

[Exi208]

Outcomes

Five participants expressed concerns about the outcomes of gene therapy, with two citing rumours that the factor levels achieved were not as good as they would wish:

'To be fair, if someone said to me, "Ok, we'll go for gene therapy, your levels are going to be 60," I'd jump at it now. But the fact of, "Ok, we don't know what's going to happen and how you're going to react to it," it's too much of a risk for me at this moment in time.'

[Exi206]

Others had heard that the treatment was not as durable as they would hope. One reported he would sooner 'wait until there was more longevity data available’ [Exi208] before being ready to decide to have gene therapy.

Four participants stated that gene therapy would impact their independence and lead to an increased reliance on their treatment centre:

'I knew exactly how to look after myself, for lack of a better term. It wasn't the best treatment for me because I was treating daily. However, I knew exactly how to play it, and I knew if I did my injection in the morning I was covered. When I moved to [FVIII mimetic], I went from treating every day to once a week and then to fortnightly, and I'll go away for a weekend or I'll go and do something and I get paranoid that I'm not covered because I'm so used to having that injection and knowing that I've topped my levels up and I can go and do this thing. So, I think taking gene therapy and taking the injections entirely out of the equation might be a little bit too much.'

[Exi206]

'Right now, I think, my life is quite settled in the sense of I'm treating every fortnight, I'm doing it on my own, I don't need to go to my treatment centre other than for my six-month check-up.'

[Exi212]

Three participants were concerned that rather than reduce their treatment burden, gene therapy would add an administrative burden to their lives they were unwilling to accept:

‘The biggest impact haemophilia has on me isn't the bleeding, it's not even the joint damage, it's all the paperwork, it's all the bureaucracy, the admin, managing hospital appointments, managing home deliveries that never quite go right. So, any more paperwork, like haemophilia admin […] I don't see the need to take on any more bureaucracy. I don't see what gene therapy is going to add to pay that value, pay that extra cost.'

[Exi202]

‘[There would be] a lack of independence because I’d have to ring my centre – “I’ve got a bleed. What do I do?” where I’ve spent so long being like, “I’ll do what I want. I’m going to do something stupid, so I’ll take an extra dose.”’

[Exi206]

'I think there's going to be so much health surveillance attached to it right now, compared to I do a subcut injection twice a month and have a five-minute clinic conversation once every six months. Why would I trade that in?'

[Exi207]

One participant even stated the treatment he received, as someone with severe haemophilia, was better than he would have after gene therapy as a person with mild haemophilia.

'I'm very much of the belief that because treatment's available to severe haemophiliacs I sometimes have a better quality of life than some with mild and moderate [Haemophilia]. So, I wouldn't want to go through all that to then become essentially a mild haemophiliac, if you will, when mine is much more manageable because the treatment is there.'

[Exi206]

Access

Eleven participants had concerns about who would decide which PwH would be offered gene therapy and on what grounds any decision would be made.

None of the participants in this sub-study were treated at centres involved in gene therapy clinical trials and they had, therefore, been unable to access gene therapy. Two acknowledged that their centre was not large enough to have been involved in gene therapy studies; however, three believed their centre was large enough to have been involved but had actively decided not to participate in the gene therapy clinical trials. They also thought their centre would be unlikely to offer gene therapy if and when it becomes available as a SoC treatment option.

'I think [my centre] has made a decision that "We're going to get all our patients we can onto [names product]".'

[Exi204]

'It's almost like you are steered towards a particular treatment or a particular brand of treatment.'

[Exi203]

Three participants stated that their care team made treatment decisions in good faith, based on benefit to the individual; for example, because they 'last longer in your system, you're getting fewer bleeds now’ [Exi203]. Three, however, said this was not always the case, and two said that despite having compelling reasons to switch treatment, their care teams were not always willing or able to consider it.

'The treatment that I am on, I had to argue heavily to get onto it. I'd spent a few years asking for an extended half-life, was getting told, "No, your current treatment's working for you." And it was working for me because I was fiddling the doses I was taking, and I told them that.'

[Exi206]

One described having never been aware that a choice was available, saying it had always been a case of,

'"this [treatment] is coming, we're about to sign a contract, this is the plan." So, it's more about, "This is the plan, this is what we're going to do, and at some point you'll move across to this."'

[Exi204]

Five were aware that, ultimately, cost drives treatment choice and availability of treatment.

'I know the NHS is always focused on this cost-price analysis about…you know, the utilitarian argument about how do we get the best gain with the smallest amount of money.'

[Exi205]

As a result, they felt that, in reality, they had little say over what treatments they could access. Most did not think the advent of gene therapy would change this due to its cost.

'Unfortunately, I personally believe it's always going to come down to cost as number one. And I know that might make me come across a bit bitter, but I think it will always be cost one, patient two.'

[Exi208]

'From everything I've heard about gene therapy, it costs a lot of money.

[Exi205]

Two participants thought the cost of gene therapy would be so prohibitive that it would be better to direct research into treatments that have the greatest impact on the greatest number of people with haemophilia.

Information

Though all the participants had been aware of gene therapy for more than a decade, seven said they were concerned about the lack of easily accessible and understandable information. Although four had searched for information about gene therapy online, one said the propensity for 'misinformation on the internet' [Emi210] made him reluctant to use it as a resource. Four participants stated that even when information was available, much of it was too complicated.

'I think if there'd have been more communication, different communication, more layman's term communication, that would have enabled haemophiliacs to make a more informed choice on their treatment, that would have been great.'

[Exi203]

'The language [is] still very medically orientated and not for the layman.'

[Exi207]

One participant said that some healthcare professionals (HCPs) were bad at explaining the therapy’s complexities in an easily digestible form.

'I ask a question…a 30-second question and get a 25-minute answer. [my consultant] can be half an hour, 40 minutes, 50 minutes, and by that time… What I would love is simple stuff. Simple, just easy for me to break down, easy for me to understand, easy for me to make a decision on.'

[Exi203]

Two participants thought there was a lack of information simply because it was not known.

'I think they should be putting more information out, but I'd like to know if they actually have the information themselves. That's the thing I'm really curious about because I'm not so sure they do. I'm not sure they've potentially got this actual data to show us all yet.'

[Exi205]

Three participants said that clinicians at their centres did not have the time to provide information about gene therapy, meaning they lacked the knowledge needed to make any decision about gene therapy as a treatment option.

'I only have a five-minute conversation with my consultant anyway, about every six months. He phones me up and says, "Are you doing all right?" and I say yes. He says, "Have you had any bleeds?" and I say no. And that's it.'

[Exi201]

'I have briefly mentioned it over the phone and I don't think it sits right with my consultant at that moment in time – but since then there's been no discussions around it.'

[Exi208]

Further supporting quotes can be found in Table 3.

Table 3 Supporting quotes
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Discussion

All participants in this study saw gene therapy as a positive development in the treatment of haemophilia. However, they also expressed concerns that present barriers to gene therapy.

The most significant concern, related to the need for steroids following gene therapy and their potential side effects. Even though not all clinical trials necessitated the use of steroids [19, 20], there was a widespread perception that, following gene therapy, there would be a need to take of steroids for prolonged periods. The level of concern expressed about the side effects, particularly immunosuppression, may always be a general concern but may also have been heightened during the Covid-19 pandemic when the interviews were taking place. The concern may, therefore, decrease as the pandemic continues to wane. The prospect of further pandemics [21, 22] may, however, mean there will always be concern about immunosuppressive medication following gene therapy. Further research is needed to ascertain whether immunosuppression will remain a necessary feature of gene therapy or whether alternative strategies can be used.

In common with other studies [3, 23, 24], many participants had concerns about the outcomes of gene therapy. However, rather than focusing on factor expression and durability, these related more to the need for an increased level of engagement with clinical services in the first 6–12 months, and a perceived additional burden related to the treatment of bleeds.

The ability to treat bleeds quickly and effectively has been a key advantage of home treatment [25]. Participants appeared to be concerned that treating bleeds after receiving gene therapy would involve contact with or a need to attend their haemophilia centre, which represented a ‘backwards step’, even if bleed frequency was reduced.

Many participants also felt their current treatments did not significantly impact their lives and were, therefore, reluctant to consider a change that might increase the frequency of interaction with their treatment centre, even if it was only in the short term. Consequently, some said they would be hesitant to pursue gene therapy as a treatment option. Similar concerns were expressed in other Exigency sub-studies [13, 16]. This may highlight a genuine concern among PwH, but may also reflect another perceived barrier the participants discussed: a lack of accessible, patient-focused information.

A number of participants stated that the language used to discuss gene therapy was too complicated and not pitched at a level they could easily understand. As a result, some said they were unable to decide whether gene therapy would or would not be an appropriate treatment for them. There is, therefore, a need for gene therapy providers, haemophilia care teams and patient organisations to do more to enable all PwH to fully understand its nature and implications. This should include plain language summaries, patient education leaflets, visual materials and engagement events, with consideration given to individual communication needs [26].

Recent discussion about gene therapy, education and decision-making has focused on shared decision-making (SDM). The concept of SDM was first described in the late 1980s as a reaction against the paternalistic nature of decision-making [27, 28], but it was first used in the context of haemophilia care in 2014 [29]. SDM is based on a two-way exchange of information between patients and HCPs [30,31,32], and seeks mutual understanding and agreement between the medical knowledge of HCPs and the beliefs, preferences, and experiences of patients/caregivers [33,34,35]. There is a concern, however, that SDM may retain features of the paternalistic decision-making process it initially sought to resolve, including limiting the number of available options, framing and nudging [36,37,38], many of which seem to have been experienced by many participants in the study. Despite these concerns, the core concepts of SDM—active dialogue, mutual understanding and agreement—must remain central to the educational process to enable PwH to choose the most appropriate treatment option for them at any given time, whether gene therapy or another of the available therapies [39].

SDM to support access to haemophilia gene therapy, however, may be impacted by another concern raised by the participants: cost. Aware that treatment for haemophilia is expensive, and that their access to treatment has always been limited by its cost, many participants were anxious that haemophilia gene therapy may be yet more expensive. They were concerned that gene therapy might not be considered cost-effective and that, as a result, its availability would be limited or even prohibited, as has been seen in other conditions [40]. Indeed, at the time of writing, draft guidance from the National Institute for Health and Care Excellence (NICE) has not recommended the first gene therapy product as a treatment option in the UK [41]. It may be that until more long-term data regarding expression, durability, and efficacy is available, many PwH will remain unable to access gene therapy. Until such time that access is available to all, some commentators have suggested that stakeholders—patients, patient advocacy groups and clinicians—should seek to evidence the everyday realities and difficulties of living with haemophilia, including treatment burden and anxiety induced by the ongoing fear of potential bleeds [42].

Strengths and limitations

Some aspects of this study may affect the generalisability of its findings. These relate to the size and structure of the study sample, the study setting, and the qualitative aspect of its methodology.

Participants in the study were under the care of centres not involved in gene therapy clinical trials. However, as this means they would have had less access to the information about gene therapy, the authors believe this makes them more representative of the majority of PwH in the UK. The sample included fewer people with haemophilia B than people with haemophilia A. This was not seen as a concern as the majority of the issues raised related to gene therapy processes, outcomes, education and access, and were not therefore, therapy or condition specific.

That the study was conducted in a high-income country where access to factor prophylaxis is readily available. Findings therefore may not be representative of the views of PwH in lower and middle-income countries. Further research should be undertaken in other economic territories to address this.

The nature of qualitative research makes it difficult to generalise any data collected. Its strength lies in the ability of qualitative inquiry to provide meaning and deeper understanding in specific situations [43, 44]. Through both meta-analyses and syntheses, qualitative sources can have application beyond their immediate context [45, 46]. This paper, therefore, should not be seen in isolation but within the growing body of qualitative haemophilia gene therapy studies [11, 13, 15, 47].

Conclusion

This Exigency study subgroup sees gene therapy as a positive treatment development that promises a greatly improved QoL. However, four significant issues were identified that could present barriers to participants considering gene therapy as a treatment option: the processes involved, the outcomes of gene therapy, access to gene therapy, and the availability of information. If the promise of haemophilia gene therapy is to be realised, these barriers need to be acknowledged and addressed by HCPs, patient organisations, and gene therapy providers. If, however, it is not possible to resolve these barriers fully, it is essential that PwH are enabled, through a SDM process, to access an available treatment option that offers the QoL they seek.

Material and methods

Design

Exigency is a mixed methods study designed to explore the opinions of PwH and their families in the UK about gene therapy [17]. This sub-study focuses on PwH who have not yet had the opportunity to participate in a gene therapy programme because they are under the care of a centre not currently involved in ongoing clinical trials.

Following a brief indicative literature review, the study team and a patient representative designed a semi-structured interview schedule (See Additional file 1: Appendix 1). The guide addressed issues including the participant's condition, their treatment history, their understanding of gene therapy for haemophilia, why they think they have not yet been offered the possibility of taking part in a gene therapy study, and how gene therapy might be accessible in the future as a treatment option (18). The guide was used as a template for the interviews, but the interviewer (Principal Investigator) was free to explore any of the issues raised in more depth. He we also encouraged to explore any issue discussed in a previous interview if it had been discussed (unprompted) on at least two previous occasions.

Recruitment

Participants were recruited through participant identification centre referral, social media advertising and word-of-mouth referral. The eligibility criteria allowed for the recruitment of all people with either haemophilia A or B who could give written informed consent and had a good command of English. All participants and a family member, if available, took part in a single one-hour semi-structured interview using a video conferencing platform. All interviews were carried out by the principal researcher (SF). Three of the 13 participants were known to the principal researcher prior to their participation in the study. Video conferencing was used during the Covid-19 pandemic as a social distancing strategy. It was continued post-pandemic as it was convenient and popular and has been shown to provide rich qualitative data [48,49,50].

Data collection

Analysis

At consent, each participant was assigned an individual study number. All interviews were recorded (audio and video), transcribed, and thematically analysed inductively. NVivo for Mac (version 12) was used to facilitate the coding process. Field notes were made following each interview. All interviews were coded within five working days by the principal investigator. Seven of the interviews were randomly re-coded by a second investigator (KK) and both investigators met once a month to discuss all completed interviews to ensure the reliability of the interview process and code generation. Previously created field notes were also be reviewed to provide added context to the discussion. This process was continued until saturation was achieved and the interviews discontinued. Upon completion of the interviews, the study team reviewed all the emergent codes, refined them further, and identified the final themes (see Table 4).

Table 4 Coding diagram
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