Patients should be at the centre of the development and evaluation of cell and gene therapies, according to Eric Low and Sally-Anne Tsangarides
Cell and gene therapies may have enormous potential benefits for individuals and society, but their implementation is hampered by challenges related to assessment, reimbursement, and service delivery. In addition to in-service challenges, there is insufficient evidence to support the potential value of gene therapies at present. Specialised Commissioning asked Eric Low, Independent Healthcare Consultant, and Sally‑Anne Tsangarides, General Manager UK, AveXis, to explain the development and appraisal process, barriers to implementation, and measures necessary to unleash the power of cell and gene therapies.
What are the challenges around the implementation of cell and gene therapies, and what can be done to address them?
Sally-Anne Tsangarides: Cell and gene therapies have the potential to transform lives, but their implementation in the healthcare system can bring additional challenges around diagnosis, service delivery, and payment.
Cell and gene therapies are likely to provide the best patient outcomes, and thus the best value, if they are used early in the course of a disease. However, in rare inherited disorders, diagnosis is often delayed, which limits both who can benefit from these therapies and by how much. To treat people earlier and unlock the maximum value from these products, efforts must be made to accelerate diagnosis—for example, through education of healthcare professionals, and through screening programmes such as the pilot project to sequence the whole genomes of 20,000 babies recently announced by Genomics England, which may enable accelerated diagnosis of severe genetic conditions.1
As with genetically modified organisms, robust systems must be put in place for the distribution, storage, and use of cell and gene therapies. Additionally, the radically different treatment paradigm of cell and gene therapies compared with the treatments they replace may necessitate substantial changes to patterns of service delivery. Although the net outcome may be positive, the transition may be complex and disruptive to healthcare teams.
Most healthcare systems around the world are not set up to assess the potential value of therapies that may provide a lifetime of benefit following a single administration. The cost of conventional treatments can run into millions of pounds spread over many years, whereas the cost savings associated with a single-use therapy will accrue over a patient’s lifetime. To address this, we need new models of assessment to properly evaluate these novel therapies, together with new approaches to payment when value accumulates over a lifetime. These may include the option to pay in instalments over several years, and the possibility of refunding payments if the treatment doesn’t meet a predetermined definition of success.
Few companies have experience of obtaining scientific advice from NICE for gene therapies. How does the support given to the development and appraisal of cell and gene therapies differ from that given to other therapies?
Sally-Anne Tsangarides: Cell and gene therapies introduce new challenges around assessment, reimbursement, and service delivery. As such, it is essential to ensure a joined‑up approach between companies and NICE as early as possible in the process. In my experience, constructive, early engagement has been very positive, from the early advice obtained prior to and during scoping, to advice gained from the Office for Market Access2 and at various stages during the appraisal. Because the underlying science is evolving so rapidly, flexibility on both sides is essential, and companies including AveXis have experienced this to date in dealings with NICE.
Cell and gene therapies are likely to provide the best patient outcomes … if they are used early in the course of a disease.
What is the importance of considering the patient perspective in scientific advice and during the development and appraisal of a cell or gene therapy?
Eric Low: Companies, as well as health technology assessment (HTA) and commissioner archetypes, need to have a laser-sharp focus on what matters most to patients when considering the potential benefits and risks of a new treatment. Knowing this will give companies the opportunity to account for patient priorities in their evidence development programme, and provide a context to help NICE shape their scientific advice.3 Defining the potential value of a treatment through the lens of patient experience is the most important part of assessing and evaluating the clinical benefit and cost‑effectiveness of a new treatment.
Many new gene therapies are in the pipeline, but uncertainty exists about their value because of a lack of clinical experience and long‑term follow-up data. How can NICE and industry work together to ensure long-term data collection, and why is this important?
Sally-Anne Tsangarides: Advanced treatments have huge potential health benefits, but also some significant areas where long-term evidence simply doesn’t exist yet. We could ask how certain do we need to be of the persistence of benefit over time? And how long is ‘long enough’, particularly for conditions where patients rarely live beyond a few years under the current paradigm of care?
Continuing long-term follow up and data collection is important for cell and gene therapies, and particularly for rare disease treatments. Populations of patients with rare conditions are small and there is often a lack of accepted alternative treatments. Placebo‑controlled trials may not be considered ethical in conditions with a very high risk of serious morbidity or mortality. As a result, treatment outcomes may be compared with the projected natural history of the condition obtained from various sources, where this is available. When requesting and receiving scientific advice from NICE, companies can assess potential evidence gaps and consider gathering long-term follow‑up data, more confident that they will meet the expectations of NICE and NHS England.
What changes must be put in place to ensure that the maximum value of cell and gene therapies is achieved, and how will this benefit the NHS and society?
Eric Low: The promise of cell and gene therapies has yet to be backed up by evidence—namely, evidence of positive risk/benefit profiles, of clinical effectiveness, and that they actually deliver on their theoretical potential. Companies, therefore, need to think carefully about their evidence development programmes. Specifically, they need to clearly define the patient population most likely to benefit, and ensure that their outcome measures, the number of patients enrolled in their trial(s), and the follow‑up period are adequate to show sustainability of effect over time and reduce uncertainty under HTA/commissioner scrutiny.
They must ensure that research questions on patient preference and quality of life are built into their evidence development programme, so that they are able to express a value proposition in the context of potential patient benefits and risks of treatment, both in the short and long term. There should also be a requirement to ensure that adequate support and information is in place at the time of treatment decision making and consent.
Our view is that HTA assessment and evaluation methods and thresholds remain adequate, but that commissioners may need to think about creative approaches to pricing, such as milestone payments, and ensure that systems are in place to track and monitor patients over the long term. Commissioners should also have the means to perform horizon scanning to prevent all the value going to an early treatment, thereby exhausting available resources.
For their part, patients, patient organisations, and patient advocates should invest in the collection of patient data using validated methodologies to ensure that they can provide evidence for and clearly articulate what matters to patients.
What are the potential risks to the patient of consenting to receive gene therapies, and what can be done to mitigate them?
Eric Low: Despite the potential benefits of cell and gene therapies, there are also significant potential risks and unknowns. Consequently, there is a need for comprehensive, independent informed consent and holistic needs assessment processes to be put in place.
The best way to support patients in making an informed decision on whether to consent to treatment is to ensure that they have access to high‑quality evidence, including real‑world data, together with support to understand and interpret it.
It is important that the clinician is not the only person to be involved in this. One could argue that cell and gene therapy specialist nurses should be available. Patients, and their families, should also have access to high-quality, independent information.
Do you have any concluding remarks?
Cell and gene therapies have potential benefits for individuals, the NHS, and society. We believe that there is broad support across many stakeholders for the appropriate development and implementation of these technologies, with the UK a potential leader in their research, development, and manufacture. It is vitally important that patients in the UK can participate in shaping product development programmes, regulatory reviews, and HTAs, so that they can in turn benefit from access to potentially transformational therapies.
Very few cell and gene therapies have so far completed a reimbursement process in the UK; we must learn from every example, and work together to continuously improve our research, clinical trial design, and evidence generation generally, to ensure that we are ready for the future that is already here. Most importantly, we need to put patients firmly at the centre of research and development, as well as involving them in the assessment and evaluation of cell and gene therapies. Furthermore, it is imperative that patients have access to the high‑quality independent advice and support they need to make informed decisions about their treatment and care choices throughout the course of their disease.
AveXis is an Ethical Medicines Industry Group (EMIG) member company. This article was based on the EMIG–NICE webinar, Opportunities and challenges with cell and gene therapies: an interactive discussion with NICE and industry, which took place on Tuesday 24 September 2019 as part of a collaboration between NICE and EMIG to promote the services of NICE Scientific Advice, the Office of Market Access, and other NICE departments. This article does not necessarily reflect the position of NICE on cell and gene therapies.
- Reynolds J. DNA testing at birth will be available for everyone. www.thetimes.co.uk/article/dna-testing-at-birth-will-be-available-for-everyone-wbmn0zjwz# (accessed 11 November 2019).
- NICE. Office for Market Access. www.nice.org.uk/about/what-we-do/life-sciences/office-for-market-access (accessed 11 November 2019).
- NICE. Scientific advice. www.nice.org.uk/about/what-we-do/life-sciences/scientific-advice (accessed 11 November 2019).