Exploring patient and clinician perspectives on the benefits and risks of emerging therapies for the treatment of haemophilia: a qualitative study

The responses across participant groups brought the concept of patients playing an active role in their healthcare and treatment decisions into focus, particularly the ability of clinicians to influence decisions and if patients can choose to proactively delegate treatment decisions. This was important to understand, given the study objectives to assess clinician-patient communication on new therapeutic options in haemophilia.

Clinicians were reflective on the topic of bias and acknowledged that they brought unconscious bias into the clinic when discussing benefit-risk associated with treatments. It was stressed that this was often personality driven and that the clinical scenarios observed in the clinic could be complex. It was seen as challenging for clinicians not to let their external influences or past experiences impact decisions, and this was exacerbated with chronic conditions such as haemophilia where clinicians got to know patients over time.

“I think that clinicians need to accept they influence patients, but it is then as soon as you accept that you influence patients, then comes an additional responsibility of actually moving to how do you then make sure you are able to get your patient around to thinking from a different perspective? How to control the disease?” – Consultant Haematologist 2

Clinicians were aware they had the potential to, and actively did influence patient therapeutic choice. A range of opinions were expressed on the topic: some clinicians were bold about their ability to influence patients and utilise their clinical expertise to drive health outcomes. These clinicians felt that by diluting this approach they would be taking away part of what defined them as clinicians. It was highlighted that if a clinician took a less directive stance, this might actually increase the anxiety of a patient if they are unable or unwilling to make a decision. Other clinicians adopted a more balanced approach and felt that as long as the patient had capacity to make the decision they were happy to support this, even if they recommended an alternative approach.

Clinicians also acknowledged that with experience, knowledge and influence came a deep responsibility to inform patients and advise them to achieve the best possible medical outcome. It was considered perfectly legitimate for a patient to choose to be passive and allow the doctor to make recommendations.

“It's OK for patients to have different attitudes and different levels of involvement. It's OK for patients to not engage as much as you think they should engage, or listen as much as you think they should listen.” – Consultant Haematologist 2

Clinicians highlighted that patients often bring in lists of questions, but that these tended to be unstructured and focused on short-term issues. It was reported that very few patients email clinicians in advance to highlight what they would like to discuss at a consultation.

“I've not had many people emailing in advance… A few come with lists of questions, but they tend to be more kind of abstract questions.” – Consultant Haematologist 4

Clinicians unanimously agreed that requests for second opinions were rare, and some estimated this occurred with less than 1% of their patients. The clinicians interviewed were more regularly involved as providing a second opinion. Overall, there was a view that requesting second opinions was perfectly acceptable and this became more comfortable over time as clinicians gained clinical experience.

Conversely, the patients interviewed had all requested a second opinion and felt comfortable doing so if they disagreed with a decision. There was an acknowledgement that this could potentially be difficult for clinicians, as experts, to accept. Clinicians were considered to be open to embracing challenge, however it was acknowledged that this might not be universal.

“Yeah, I've done a second opinion, because in previous hospitals I sought a second opinion because I just felt like my doctor was actually trying to force me down routes and I just wasn't happy at being forced down the route at all.” – Patient 3

The patients affiliated with The Haemophilia Society highlighted the importance of taking an active role in consultations with doctors. It was stressed that patients had a responsibility to communicate issues clearly to doctors to enhance treatment and care decisions. Participants all gave examples of where they had actively engaged or tried to manage interactions with consultant haematologists. It was highlighted that doctors could not know everything related to care and therefore actively challenging them was beneficial to ensure the patient perspective was fully taken into account.

“Last year, and it sort of was a bit of an eye opener, I kind of learnt what I have access to if I speak loud enough, which wrongly or rightly, it is what it is.” – Patient 2

Patient respondents who were not affiliated with The Haemophilia Society were generally less active than their Haemophilia Society-affiliated counterparts. However, these patients did give examples of being active in their consultations, either via being an advocate for gene therapy, proceeding with surgery or resisting attempts from clinicians to switch them to particular therapies. At the centre of decision-making was trust and experience of care, which shaped their desire to be active or passive in treatment decisions.

“I think you have to put trust in your doctors. You have to, because they're the ones that know and they know their jobs. And if you're gonna turn up there because you've read an article somewhere in Google about gene therapy and now you think you know everything, it's not right.” – Patient 6

Patients associated with The Haemophilia Society said they often ‘pre-loaded’ consultations by emailing or speaking to clinicians in advance regarding issues they would like to discuss. It was felt that this approach was helpful as time with consultants was often limited and this could facilitate optimal engagement. This was in contrast to patients who were not affiliated with The Haemophilia Society, who were generally less active in the pre-consultation phase.

“I have a pretty similar technique to him, preload the appointment and say here are my problems…..Also yeah, keep pretty good notes of when things go wrong.” – Patient 3

Advanced nurse practitioners (ANPs) highlighted the difficultly for patients to challenge clinicians on treatment decisions, a situation exacerbated when centres adopt blanket policies towards treatment. ANPs felt empowered to challenge treatment decisions they felt were wrong or were influenced by bias, however it was hinted that this environment might not be universally applied across NHS treatment centres.

“I don't know of a centre where one consultant will do one thing and then another would do another, so it's not like you can even swap consultants. That is the centre's policy because the centre director's policy is what they think.” – Advanced Nurse Practitioner 2

ANPs highlighted that patients often have very high opinions of consultant haematologists and that they might therefore find it disconcerting when healthcare professionals admit to being unsure about the long-term outcomes of a treatment such as gene therapy.

Health literacy was a key theme identified during the research and a central pillar for understanding how benefits and risks were communicated and understood for existing and new therapeutic options in haemophilia.

Clinicians universally acknowledged the challenge of comprehension and that what was articulated in consultation may not have been fully understood by patients. They were reflective on this and often used subsequent consultations to check back on a patient’s understanding.

“I mean it's well known that what you tell people and what they perceive and what they take in, it can be very different.” – Consultant Haematologist 7

Clinicians observed that patients often suffer from poor concentration, struggle to remember key details or have challenges dealing with complex topics such as ATMPs. They highlighted that health literacy and education varied widely in the patient population, ranging from the highest level of academic achievement to some patients not being able to read or write. Understanding health literacy was considered not only crucial to establish the level of information delivered to the patient, but also for the patient to be able to articulate to the doctor about their clinical and life scenario, and any challenges with current therapy.

Clinicians stated that they tailored their language to the individual, with the main driver for this being education and health literacy. Other key factors included age, family history and specific acute concerns.

“So the way I speak to someone and kind of what I say, yes, I do individualise it – but within that, I don't think it's based on age, I think it's based on their level of education and a level of medical understanding.” – Consultant Haematologist 6

There was clear evidence of using analogies, drawings or simple examples to try and communicate trial data results, benefit-risk and highlight uncertainty. It was stressed that the majority of patients did not want detailed statistical information.

“I do end up drawing quite a lot in clinic – I think that everyone responds really differently. But certainly for something like factor levels and different products, I find like a graph just where I can scribble.” – Consultant Haematologist 6

It was acknowledged that patients also research treatment elements by themselves, and clinicians therefore provided leaflets or directed patients to websites to help facilitate this. The challenge of educating patients and their parents over a long time period was stressed; lifelong learning was considered essential and, ideally, knowledge given to parents would then be passed on to children as they grew up.

ANPs were cognisant of the need to account for health literacy and how messages were communicated to patients, and they adapted their approach accordingly. Individual patient comprehension of the message communicated could be quite different and therefore repetition was important to reinforce key advice. Ensuring that comprehension of key messages happened early in patient engagement was considered important to avoid any misunderstandings which could take patients on a trajectory that becomes harder to influence over time.

“You know they can often go away and have conversations in their own head and come back with a completely different idea of what has been said. They take a bit of information and then they build their own story, their own narrative around that. And sometimes it's quite hard to rein that back in if they've got it wrong.” – Advanced Nurse Practitioner 3

ANPs linked confidence to talk about benefit-risk of therapies to patients with knowledge and experience. The rapidly evolving treatment pipeline and novel mechanism of actions were considered to be challenging to explain to patients, parents and families without a medical background.

Patients associated with The Haemophilia Society highlighted the advantages of being involved with the national patient organisation in terms of access to information and networks. They felt better informed and more empowered regarding treatment decisions. Interestingly, as a result of this position, they felt a greater responsibility to share knowledge with the haemophilia community.

“I think I have a responsibility now, taking on a role to actually get better informed and speak to those who are actually impacted.” – Patient 1

Clinicians highlighted how they were aware that patients are influenced by external factors in their lives, which in turn will impact consultations. This could include family issues, employment or other elements which impact mood and affect. Understanding the influence of this was vital for the study objectives on both the perception of and communication of benefit-risk.

It was stressed that body language was important and both consultant haematologists and ANPs reacted accordingly to this when undertaking consultations and tailored sessions.

Clinicians highlighted the influence of family, friends and peer networks. All of the respondents were able to cite examples of where this had directly occurred when switching therapy.

“You know, it's a small community, often more than one person in the same family, often friends, and I think that has quite a big influence.” – Consultant Haematologist 7

Clinicians facilitated close contacts of patients attending clinics to provide patients with support, assist with questioning and add an additional layer of comprehension to the consultation outcome. They also mentioned bringing in additional staff members for potentially challenging clinics and to ensure robustness of follow-up.

Clinicians acknowledged the influence of a patient’s family and wider social network on treatment decisions. There were a number of elements linked to this including the family history with haemophilia, the number of haemophilia patients in the household, and broader social networks. It was flagged that a patient’s life and family scenario changes over time and that their attitudes were therefore likely to evolve accordingly.

“And then you've all of those other things that you know, cultural influences, whether you're talking to the mum, the dad, the granddad who's also got haemophilia? All those things come into play.” – Advanced Nurse Practitioner 2

It was stressed that mental health played a large role in patients’ treatment decision-making. ANPs highlighted that patients have general anxieties linked to the world around them, with work, economic, political and social issues all impacting their ability to make treatment decisions.

“I think mental health plays a huge factor in decision-making around treatment… they're anxious about climate change, they're anxious about the government, they're anxious about working life, they're anxious about COVID.

They're just generally anxious about the state of the world, and that completely detracts from any other decision they have to make.” – Advanced Nurse Practitioner 1

Patients were reflective on a number of external factors which influenced their treatment choice. The type of haemophilia was considered important, as the rarity of haemophilia B limited the number of other patients available to engage with.

“As someone with haemophilia B, to kind of get a message of what's out there… because there's just so few of us, trying to find another haemophilia B patient is like actually pretty difficult.” – Patient 3

Family, friends and social networks were considered vital; not only in managing treatment choice but also in tackling issues with ongoing care. Patient respondents associated with The Haemophilia Society stressed that being part of a patient organisation was considered influential in terms of hearing from world-leading doctors, engaging with other patients, and hearing active discussions on the latest treatment developments.

Clinicians and patients stressed the importance of the multidisciplinary team (MDT) in decision-making. It was felt that sometimes there is a barrier between the patient and the consultant, which other members of the MDT can overcome, allowing life and treatment issues that patients did not feel able to or want to talk to the consultant about to be raised. Members of the MDT might be in role longer than some of the clinical team, which facilitates a growing bond between staff members and patients.

“The patient might go off separately with a nurse to have bloods and then kind of do a more detailed thing with our physio and the conversation can kind of keep on going.” – Consultant Haematologist 6

Clinicians thought that the media had a relatively limited impact on therapeutic choice. However, they did acknowledge that the number of queries about new therapies increased when articles were published online. Clinicians saw social media as more of a networking source which had a marginal impact on treatment decisions.

Clinicians cautioned against the extremes of social media and how this polarised communication of outcomes and experience which was likely to be unhelpful in assisting decision-making. It was stressed that false information made social media a potentially dangerous place, and this has been previously observed with treatments such as emicizumab.

“Having social media is obviously quite influential in people, but the problem with social media is that it is uncontrolled, so you can talk to anybody and they just give you any opinion whatsoever really.” – Consultant Haematologist 7

Patients gave a wide range of evidential sources that they accessed for new treatments. This included undertaking pharmaceutical company surveys, engagement with clinicians, websites, and engagement through patient organisations. Participants were aware of the pitfalls of using social media and were clear that they did not exclusively use it to help them with treatment decisions. However, they did follow particular accounts for information and utilise internet sources to access information. It is likely that these resources indirectly influence decisions, even if patients are vigilant to the potential risks.

“The straight answer is no [I don’t use social media for information on therapeutic choice]… I think there's a lot of nonsense out there I believe.” – Patient 2

Understanding perspectives on gene therapy benefit-risk was a core study objective. Clinicians were cautious about using gene therapy and stressed the burden of delivering gene therapy and concerns about the requirements for long-term steroids or other immunosuppressants. It was felt that the logistical burden of monitoring patients would be high and that this would temper demand. The extensive monitoring and follow-up requirements may make gene therapy challenging with employment and lifestyle commitments.

Clinicians highlighted that precise adoption rates were difficult to predict for gene therapy, but they anticipated uptake to be relatively modest and slow. It was highlighted that negative patient experiences could significantly impact early adoption, particularly the clinical burden of care.

“I think it will be really interesting to see how many people take it up because I think we're in a really different situation with longer acting therapies and novel therapies now compared to ten years ago.” – Consultant Haematologist 6

Clinicians were concerned about the durability of gene therapy and variability of patient response. The efficacy of gene therapy for haemophilia B was expected to be more durable than the efficacy of gene therapy for haemophilia A. The significant impact of emicizumab in haemophilia A, which had framed the decision to potentially proceed with gene therapy, was also highlighted.

“I don't think it's a straightforward decision at all and that's particularly true for haemophilia A, where there are big question marks about the durability of the effect.” – Consultant Haematologist 5

Clinicians were also unsure about future therapeutic options (including gene therapy) for patients if gene therapy efficacy waned or failed and aired concerns about the irreversibility of the treatment in comparison to existing therapeutic options.

There was a concern from clinicians about long-term unknown adverse effects with gene therapy, and that in some areas of research there is evidence that gene therapies may increase the risk of tumorigenesis via integration. There was a general feeling that using the word ‘cancer’ in a consultation would be a powerful motivation for patients not to progress with therapy.

“If you mention cancer, that's the end of the conversation.” – Consultant Haematologist 7

The patients who were not affiliated with The Haemophilia Society were much more positive towards gene therapy than their Haemophilia Society-affiliated counterparts. They had all heard of gene therapy from various sources (internet resources, social media, face-to-face consultations) and, fuelled by reporting in the media, had very high expectations for it. The main advantage that patients associated with gene therapy was convenience; it would allow them to be free from regular treatment and give them confidence to go on holidays without the worry of transporting treatment.

“I mean it's the Holy Grail, isn't it? It's just as good as we're gonna get.” – Patient 6

The Haemophilia Society-affiliated patients interviewed were negative towards gene therapy; there was a concern the technology was immature and potentially unsafe. There was also apparent mistrust, reflecting the ongoing scars left by the infected blood scandal.

“Two weeks ago at a conference, someone presented on stage saying we're all a bunch of guinea pigs and he wouldn't trust it with a barge pole and especially haemophilia A … And yeah, I don't wanna be the guinea pig.” – Patient 4

They highlighted their concern about the lack of data with gene therapy, which made them nervous about the long-term effects (efficacy and safety). This ranged from an increased risk of cancer to having negative outcomes from overexpression of clotting factor. They were aware of the expected financial impact of gene therapy and the high cost associated with the technology. It was suggested that funds could be better spent on optimising and expanding existing services, rather than on gene therapy. There was an anxiety that gene therapy might not provide the confidence and flexibility to fit into lifestyles.

Both patient groups articulated the physical and mental burden the process of gene therapy would put on them, their families and friends, which was considered to be underrepresented in current conversations about gene therapy. It was stressed that the burden was likely to be unacceptable to many patients, who would be unable or unwilling to put their life on hold for it. There was a concern about the lack of widespread expertise in UK centres when it came to delivering these technologies.

“Yeah, it would take six months and it might not even work. See, you've gone through all of that stress. You've put your family and friends, loved ones through that stress as well. And it might not even work.” – Patient 2

“The kind of heartache of not getting on the previous gene therapy was kind of like, I don't want anything for a good couple of years.

I was like, I don't want anything to do with haemophilia anymore. It was my life – it broke me.” – Patient 7

During the 1970s and 1980s, people with haemophilia (and other blood disorders) were infected with viruses including hepatitis and HIV via contaminated blood products. A statutory inquiry in the UK was set up in 2017 to investigate the infected blood scandal and is anticipated to conclude in May 2024. It was therefore vital to understand the impact of the infected blood scandal on participant’s risk appetite, and how this impacted treatment decision-making and patient-clinician relationships.

Clinicians were clearly influenced by the current infected blood inquiry, expressing caution around risk communication and being more diligent with recording conversations, particularly about unknown risks. There was acknowledgement that uncertainty should have been communicated better in the past and more consideration given to patient comprehension. Clinicians flagged that generational attitudes, practice and technology all played a role in the contaminated blood scandal.

“I am scarred, the patients certainly are scarred and I'm having a lot more conversations with my patients about it because they've been retraumatised by the inquiry.” – Consultant Haematologist 5

It was felt that the trauma caused by the infected blood scandal could be deep-rooted within individual patients and families and could impact therapeutic choices. Adverse effects of therapies to deal with the consequences of infected blood (e.g. Hepatitis C) were acutely remembered and clearly impacted therapeutic choice. ANPs referenced the negative impact of subcutaneous injections, which was mentioned frequently as a barrier for starting emicizumab.

“So lots of talk about emicizumab when it came in about actually the ease of sub- cut[aneous] injections versus IV injections, but for many of our adult patients, they'd had hepatitis C treatment and the side effects of sub-cut[aneous] hepatitis C treatment were horrific.” – Advanced Nurse Practitioner 1

Three of the patient participants were directly impacted by the infected blood scandal via receiving contaminated blood. It has had a lasting impact on their lives, and they still live with the effects day-to-day. Key issues such as survivor’s guilt, the shame and stigma of having haemophilia and the impact of the medications required to clear hepatitis C were all stressed.

“I had quite a bit of survivor guilt frankly, so that when in 1993-94, they said you've got hepatitis, and here's what you've got to do. And I was just thinking, I've got something you know, I didn't get off scot-free, that makes me feel a little bit better if anything.”

– Patient 4

Participants highlighted that due to the infected blood scandal, there was a mistrust with the healthcare system and government. However, patients flagged that trust with clinicians was built up over time and highlighted the importance of personal relationships in their ongoing care.

“I mean, my cousin, he had his windows smashed at his house and things like that… some people might say, oh, you know, just try and put it out your mind. You can't put it out your mind..... You can't have a day off, you have it everyday. It's as simple as that.” – Patient 5

The study has a number of limitations. The majority of patients (six out of seven) in the study had severe haemophilia A. Although this split is reflective of the disease epidemiology ^[47], there is the potential for bias in the results, given the difference in anticipated clinical outcomes for gene therapy between the two diseases. The sample focused on severe adult male patients with haemophilia. Whilst ATMPs are currently being developed for severe adult male patients, the broader haemophilia community will have extensive views on the topic of benefit-risk communication. The clinicians interviewed pointed out that a minority of patients requested a second opinion, yet all patients in the study had done so. This could highlight that the patient sample is not representative of persons with haemophilia more generally. The sample comprised UK-based participants and views from the international community with different healthcare structures, treatments and patient scenarios would add further granularity and depth to the research results. Finally, there was a need to utilise both qualitative one-to-one interviews and focus groups to accommodate participant availability. Whilst using two qualitative methodologies enriched the dataset by expanding participation, it made analysing the data more methodologically challenging ^[48]. The focus groups and qualitative interviews ran concurrently and the authors aimed to counteract confirmation bias by following topic guides to ensure that information arose independently and that similar topics were covered, regardless of the methodology employed.

This study and associated dataset have identified a number of areas which warrant further research.

The exploration of the balance in patient-clinician decision-making for complex technologies such as gene therapy is required. Whilst there is a clear direction of travel for patients to be engaged in consultations to positively shape health outcomes ^[46], the research reported here uncovered examples where patients were content to delegate treatment decisions to expert clinical decision-makers, particularly for complex and irreversible treatment decisions as with gene therapy. Given the range of opinions expressed, and the uncertainty associated with gene therapy, this topic would merit further exploration.

The impact of the infected blood scandal is unique to haemophilia and the research concludes that this adds an additional layer of complexity to treatment decision making. With gene therapies being developed in oncology, other blood disorders and rare conditions ^[49], research on unique, therapy area specific drivers of treatment decision-making, and a subsequent cross-therapeutic area comparison, would help in understanding decision-making in more depth.

There was a clear difference in patient attitudes between those who were associated with The Haemophilia Society and those who were not. A deeper assessment of the motivations and membership of national patient organisations would support further understanding of the vital role they can play in being a trusted source of information, and also if potential attitudes of patients to new treatments are linked to membership.

Social media was identified as a polarising phenomenon, and despite scepticism about its value in treatment decision-making, there is no doubt that these platforms have the ability to reach large numbers of patients. Understanding the potential of social media to enhance access to high-quality, balanced information for gene therapy and novel treatments, whilst tackling the pitfalls of misinformation and abuse, would be a fertile area of research.

Finally, the role mental health and broader life influences play in treatment decision-making needs to be explored further. The decision to proceed with an irreversible treatment such as gene therapy is a pivotal one; and therefore understanding how mental health and wellbeing influences treatment decision-making, and the psychological impact before and after gene therapy, particularly if the outcome is sub-optimal, will be important to explore.