The patient gene therapy journey: Findings from qualitative interviews with trial participants at one UK haemophilia centre

In December 2019, participants were identified from among the 21 PwH treated to date with an investigational gene therapy product for haemophilia A or haemophilia B at the Royal Free Hospital. The choice of participants was based on availability rather than any pre-selected clinical criteria.

From December 2019 to January 2020, structured, qualitative, one-to-one interviews were conducted by a clinical nurse specialist involved in day-to-day care in the clinic and known to the people taking part. Participants were offered the choice of an in-person or telephone interview. The interview questions were provided to the participants ahead of time. All face-to-face interviews were completed within a scheduled clinic visit; none of the participants was asked to attend specifically for the purposes of the interview. No time limit was set for the interviews – participants were able to speak for as much or as little as they wanted.

The interviews consisted of a series of 13 open-ended questions about the participants’ gene therapy experience (Figure 1). They were free to give as much or as little information as they chose, and the interviewer did not press or probe for additional or specific answers. For the most part, no additional prompts were used; question 10, on the follow-up regimen, included prompts on alcohol consumption and family planning.

Figure 1

The interviews were audio recorded and later transcribed verbatim. From the transcripts, the responses were thematically analysed using a latent inductive approach ^[18]. This hermeneutic phenomenological method allowed us to examine the participants’ lived experience ^[19], their perceptions about their gene therapy journey, their motivations and fears, and their satisfaction with their decision to trial the treatment.

We were aware that the response to gene therapy would be an important factor in determining the patient experience of the treatment. However, as the patients are still within the study period and the results have not yet been published, this was not included as part of this study. We did not collect any data on efficacy outcomes for any particular investigational gene therapy product and did not attempt to stratify results by which product each patient had received.

Seven PwH who had received an investigational gene therapy infusion as part of a clinical trial at the Royal Free Hospital were invited to be interviewed to discuss their experience of the journey, and six agreed (anonymised here as R1–R6). The person who declined did so for logistical reasons. This interview group represents almost one third of the 21 patients treated to date with an investigational gene therapy product for haemophilia at the Royal Free Hospital. Four interviews were conducted in person, and two took place by telephone. On average, the interviews lasted for 10–15 minutes.

Four participants had haemophilia A and two had haemophilia B. Four participants were under the age of 40. The mean time out from their gene therapy infusion was 10 months (range 4–18 months). Three were HCV-positive and one was both HCV- and HIV-positive. Two participants had previously undergone joint replacement surgery. Prior to receiving the gene therapy infusion, all participants had been on prophylaxis, two with extended half-life products, and the range of annual bleeds reported in the year immediately preceding was 2–15. Participant demographics are shown in Figure 2.

Figure 2

Pre-infusion

Main questions and concerns prior to receiving gene therapy

Perhaps unsurprisingly, the main concern that people with haemophilia had prior to receiving gene therapy centred on potential side effects (Figure 3a). Of our six interviewees, all noted that pre-infusion they had been worried about some of the possible side effects of therapy. This appeared to form an important part of their decision-making process, although their concerns were not strong enough to prevent them being dosed. Specifically, one respondent mentioned cancer, one the impact on existing HIV, one referenced heart problems, and two remembered being afraid of needing to use steroids. One interviewee also mentioned some fears around the viral vector but had been reassured by staff in the centre. Other concerns pre-infusion related to the predicted long-term efficacy of gene therapy (3/6); only one participant remembered having questions about the patient experience of taking a gene therapy product.

“[I wanted to know about] the experience of other patients, I wanted to know about potential side-effects and benefits – everything really.” (R2)

“For me, [the] major concern was that I wouldn’t be able to have another gene therapy in the future if this trial one didn’t work. And then about side-effects – not the inconsequential ones, but more severe ones like heart problems. I was keen to take part, but worried about the timing.” (R4)

“Before I did it, it took a year to decide. I saw a patient advocate. I had made my mind up I was going to do it. But the advocate totally changed my mind – he went through a list of horrible potential occurrences that may or may not happen. Afterwards I spoke to my mum, dad, sisters, partner, and my best mate. It was my mate who turned me around again and said to give it a go… the patient advocate scared me, but I can’t remember half of it now.” (R5)

Figure 3

Key factors that encourage people to consider having gene therapy

The most important factor for participants was the impact that gene therapy would have on their lifestyle or quality of life (Figure 3b). Three highlighted the importance of not needing to worry about bleeding or injuries anymore, two mentioned never needing to inject again, and two referred to the potential efficacy. One mentioned travel as a key factor in their decision to have gene therapy, one stated that being able to put a stop to further joint damage was attractive, and one made reference to a career path that would open up to him if he was no longer classed as having haemophilia.

“Key factors were overall improvement of day-to-day life; not having to worry as much about hurting myself. Being able to do more. A general better quality of life. I guess additionally, from a more empathetic side, it could help a lot of other people like me. Selfish and an unselfish reason. But both made sense.” (R5)

“If you don’t try these things, no one benefits. I was confident it would work, and if it made me a mild phenotype that would be an advantage to me and my lifestyle, just by no longer needing prophylaxis.” (R3)

“The main thing was the idea of not having to be on prophylaxis or have the worry of carrying treatment or injuring myself. But knowing what damage has already been done, to put a potential stop on that – even temporary – that's the main thing for me.” (R2)

Sources of information prior to treatment

The main source of information was the treatment centre and the health care professionals working there. Only two respondents had proactively looked elsewhere for information to support their decision – both had researched online, and one had talked to people who had previously had gene therapy. Although our sample is small, we were interested to see if there was a difference in how people in different age groups behaved. Those in the youngest and oldest age groups (20–30 and 60–70) were content to rely entirely on the centre for information; those who searched for additional information fell into the two middle categories (30–40 and 50–60 years of age). Of the two interviewees who had looked for information online, one stated that it was hard to find the right information, and that a lot of what was available was not suitable for patients.

“[I had] lots of information from [the] centre, previous patients, and did some research online – but a lot of the information online is aimed at health care professionals, so it wasn’t the right thing for me. Reading online wasn’t very useful, and it was hard to find relevant information.” (R2)

“I had a number of discussions with doctors; I had more meetings and discussions than for any other trial or treatment in the past.” (R1)

“Centre information, nothing from outside. Didn’t speak to any other patients.” (R6)

First awareness of gene therapy

All respondents said they had heard about gene therapy from the treatment centre, though one indicated they had also seen news articles and were aware of the technology from the media.

The role of patient support networks

Four participants had not spoken to any other patients about their experience of gene therapy prior to their own infusion. One had used a group on social media (Facebook) that they had found helpful, although they did not elaborate on how they used it, nor whether it was geared solely towards discussing gene therapy or was a general haemophilia community group. Although not directly addressed in their responses to this question, participant R5 mentioned talking to a patient advocate.

“I didn’t speak to any other patients – not before having the gene therapy. Although possibly as I was preparing the week before there was someone who had already had it who reassured me – but it was a very surface interaction.” (R5)

Family considerations

The main considerations for family members were potential risks and side-effects. Two respondents said their families were excited for them to take part, and most (5/6) responses indicated that families were supportive of the decision.

“My wife was concerned about some of the risks.” (R1)

“[My family] were excited at the prospect of a potential cure and not having to inject. But then they were worried that the side effects were unknown, and potentially big. They are not so connected to the disease as me, and the thought something could go wrong 10 years down the line was scary for them.” (R2)

“My brother was keen for me to go for it. My wife was encouraging as long as I was confident in it.” (R3)

“My parents were excited for me. It was overwhelming for them – they needed as much counselling as I did. My partner came to the centre with me to discuss it. Once I made my mind up that I wanted to do it, it couldn’t come quick enough.” (R4)

“My mum didn’t really question it, she said to go for it. My dad had a lot more concerns. He was very dubious about it. Ultimately the decision lay with me.” (R5)

“[My family] wanted to me do it. There were concerns about effect on liver/cancer, but overall they weren’t worried.” (R6)

Compared to our colleagues in Germany, our interview group was a much wider age range, with higher rates of bleeding reported in the year prior to treatment, and represented more than one investigational product – yet some of our findings are very similar, especially around people reporting that a key advantage to life after gene therapy is not having to worry about injection^[17]. When asked about their feelings about the future, most of our interviewees expressed hopeful, optimistic, yet pragmatic and open-minded views. Up to 18 months post-infusion, none of our interviewees regret their choice to take part in the trials of investigational gene therapy products for haemophilia. When thematically analysing the responses, we concluded that altruism was one of the driving forces in decision making, with half of our interviewees indicating that they felt taking part in gene therapy trials would give something back to the haemophilia community. Interestingly, altruistic reasoning was more common in the older age categories (>50 years), while the majority of younger people were more focused on lifestyle factors and benefits that could accrue to them personally. This may reflect the higher expectations of younger people with haemophilia and is an important facet to consider when introducing the idea of novel therapies. Our analysis also indicated a sense that siblings and parents of PwH are more open to gene therapy than spouses or partners. This may reflect the greater number of years that haemophilia has been a feature of their lives, or a heightened understanding in families who may have experienced the disease over many generations.

One issue that becomes clear from talking to PwH in this way is that we can do more to prepare gene therapy candidates ahead of their infusion. Although PwH are often well-informed – and there is a dynamic community – our selection of interviewees generally had low awareness of gene therapy prior to joining the trials. They were not motivated to do their own research and content to rely almost entirely on health care professionals at the treating centre for information, with four out of six participants making their decision to have gene therapy based solely on this. Similar findings have been reported elsewhere ^[21,22,23]. However confident we are in our own staff and our knowledge as a trial centre, when extrapolated this is an important finding. Results of a large-scale international survey published in 2020 ^[24] show that among physicians directly involved in haemophilia care, 35% lack the ability to explain the science of adeno-associated viral (AAV) gene therapy (which may become a more common concern for PwH considering gene therapy going forward, given heightened public awareness due to the coronavirus pandemic), and 40% are not comfortable answering patient questions about gene therapy for haemophilia based on clinical trial results to date. As gene therapy moves into the mainstream, there is a critical need for ongoing education programs for all staff involved in the care of PwH to ensure their preparedness to offer up-to-date information to candidates and their families. Undertaking gene therapy is a big decision that should not be taken lightly, and requires clear education and support, with consistent language ^[25]. We should not assume PwH will have access to materials that would enable them to learn about gene therapy and should be aware of the existence of misinformation in the public domain ^[23]. Patient advocates are already known to play a role in ensuring that PwH participating in gene therapy trials are informed and aware of the risks ^[26], reflecting the experience of one respondent who described being informed of ‘horrible potential occurrences’ and being scared of what he was told. Treating centres may also find it useful to build networks of experienced patients who are willing to offer support to new candidates on the journey.

At present in the UK, people with haemophilia are usually looked after in comprehensive care centres or haemophilia treatment centres ^[27,28]. Care is frequently delivered by a multidisciplinary team coordinated by specialist nurses ^[27], which for optimal care should include a haematologist, physiotherapist, orthopaedic practitioner, occupational therapist, psychologist, social workers, a counsellor and nurses ^[15,29]. The need to fully understand gene therapy is therefore not limited to haematologists and research teams but must extend to the full multidisciplinary team. Our interviews were conducted by a clinical nurse specialist involved in day-to-day care. Nurses in particular are critical and already play a central coordinating role in delivering comprehensive care for PwH and helping to promote adherence ^{[16,27,28,30,31]}. It is well known that nurses are able to foster good relationships with patients, and that patients are often more candid with nurses than they may be with doctors. Nurses can empower people to make the right choice for them. and offer ongoing support and counselling, in addition to playing a key role in comprehensive care ^[30]. One of the major benefits provided by nurses is education ^[31]. In the future, nurses will be critical in helping PwH to understand the decisions they make around gene therapy, and to prepare them mentally and physically for the infusion and what lies beyond. It is important to emphasise that it is not just specialist or research colleagues who need to know about gene therapy. PwH may canvass opinion from staff at all levels within the haemophilia centre, or from link nurses they come into contact with in other medical wards. We therefore believe that all members of the multidisciplinary team and all staff within a haemophilia treatment centre should be armed with the knowledge and confidence to answer questions about gene therapy. At present, health care professionals have clear gaps in knowledge related to gene therapy ^[24,32,33]. Education programs should target understanding of the fundamentals of gene therapy in general, and specifically how gene therapy is being developed as a treatment approach for haemophilia A and B ^[24].

Successful gene therapy will likely reduce the level of care that people with haemophilia need ^[34]. At present, and influenced by the Covid-19 pandemic, much of haemophilia care is delivered outside the centre, with the nurse playing a key role in supporting people remotely by phone or email, or through liaison with local services ^[28,35]. We might expect this same pattern to hold for people undergoing gene therapy after the initial monitoring period. However, not all people with haemophilia will be eligible for gene therapy ^[1,34], and it will be important to manage expectations – from very early in the discussions, and throughout the pre-infusion journey ^[36].

Nurses will have an important role to play in mental support and counselling for those who desire gene therapy but are ineligible, as well as for those who embark on the treatment and may struggle to come to terms with the change, or who find the initial follow-up period difficult. Although not couched as a concern, when discussing their concerns and questions around infusion day, the responses of two participants raised the possibility of a need for greater counselling in advance of having gene therapy to help PwH deal with its potentially life-changing nature. Before gene therapy, many PwH plan their lives around their disease, but afterwards they have to learn to adapt to live without it. When analysing the responses relating to the impact of gene therapy on daily life, the three participants with more recent infusions (up to eight months previously) expressed greater degrees of caution in their response than those who were 10 or more months out from their gene therapy infusion. This may be indicative of a wariness early on and during the follow-up periods, giving way to a growing sense of confidence as more time passes.

Our respondents also indicated that the frequency of follow-up appointments is inconvenient. While we acknowledge that all were participating in clinical trials of investigational gene therapy products, which inherently require much more follow-up and monitoring than may be required in normal clinical practice, nurses may be well-positioned to help provide support during the follow-up period. It has already been demonstrated that a key barrier to adherence to current prophylaxis is a lack of understanding about the underlying disease ^[31]. Again, education is key to driving optimal outcomes. Ensuring long-term follow-up and adherence to the monitoring regimen for gene therapy will therefore become an important part of the nurse workload as people with haemophilia transition to new care patterns post infusion.

As with any new therapy, there is a need to make shared decisions to proceed with gene therapy ^[23]. All health care professionals working with people considering gene therapy should make it clear that research is ongoing, and that there are remaining evidence gaps ^[36]. Although the participants in this study had generally positive perspectives with regard to their experience of receiving gene therapy, there remains a need for education and support. As more people with haemophilia undertake gene therapy, it will be important to continue to analyse their experiences to help support them at all steps in the journey. Nurses will play a pivotal role in the delivery of gene therapy for haemophilia; they are a key and trusted source of information for PwH and are well positioned to offer general counselling and support. All health care professionals within the haemophilia treatment centre should be armed with the knowledge and confidence to answer questions about gene therapy from PwH and their families.