• Shaista Nisar

Gene therapy: Can HTA capture the value of a potential cure?

Updated: Mar 31

Decades of research have resulted in several gene therapies successfully reaching the clinic and continued strong growth in the global market is forecast. However, there are considerable challenges ahead to ensure all eligible patients have access to potentially life-changing treatment. Healthcare budgets remain under economic strain and spending needs to be prioritised, but is conventional HTA the right tool for the job?

by Shaista Nisar, PhD – Senior Analyst at RJW&partners

30 years on from the first gene therapy clinical trial, there are now seven gene therapies approved for use in Europe (Table 1). Despite a slow start, several gene therapies have come to market over the last two years including those that employ ex vivo gene editing (Zynteglo® for β-thalassaemia and the CAR-T cell therapies Kymriah® and Yescarta®) and in vivo therapies in which a viral vector carrying the therapeutic gene is directly administered to the patient (Luxturna® & Zolgensma®). Two further market authorisation applications for gene therapies are currently under review (BioMarin’s Roctavian® and Orchard Therapeutics’ OTL-200).

2018 was widely viewed as a historic milestone and the FDA is predicting between 10-20 cell and gene therapy approvals per year over the next five years (1).

Alongside the curative potential of gene therapies, the headlines have unsurprisingly focussed on price: in the EU Zolgensma® is expected to cost an estimated €2 million per patient, whilst Zynteglo® has a list price close to €1.6 million per patient.

Does existing HTA need to be adapted?

The costs associated with gene therapies arise principally from the substantial R&D investment required, and to a lesser extent from complex manufacture and storage. These costs must be recouped from a single treatment in often a limited number of eligible patients. The industry argues that despite high upfront prices, gene therapies offer value for money due to a life-time benefit and management costs avoided in the long-term. Whilst this may be true, especially when considering the wider indirect cost savings to the economy, the problem of affordability for payers remains.

These pressures have led to the tool used to prioritise spending – health technology assessment (HTA) – to come under increasing scrutiny.

Table 1: EMA-approved gene therapies

*Source: Adapted from Federal Gazette, Paul-Ehrlich-Institut

The list of medicines contains the products that have a current valid marketing authorization

Industry and lobby groups argue that existing HTA processes are not fit for evaluating the value of gene therapies as they do not accurately capture societal benefits and long-term savings associated with a potential cure delivered in a single treatment (2).

Whilst payers have thus far shown a willingness to engage with manufacturers to ensure timely access for gene therapies, the pressure to change the system (for example acceptance of indirect comparisons and alternative surrogate endpoints2) has largely been resisted. Instead, most therapies approved to date have been evaluated under pathways for orphan drugs indicated for debilitating or life-threatening conditions (Table 2), which in general have more lenient criteria than non-orphan drugs. For example, the G-BA in Germany automatically assigns orphan drugs an ‘additional clinical benefit’ and, in the UK, the NICE highly specialised technology (HST) appraisal pathway used for rare and debilitating conditions has a higher willingness to pay threshold than the standard single technology appraisal (STA).

Table 2: Gene therapy HTA outcomes in the EU5

Regenerative Medicine (2019). Recommendations for Timely Access to Advanced Therapy Medicinal Products (ATMPs) in Europe (2).

Uncertainty in the data

Like other orphan drugs, gene therapies are difficult for payers to assess with confidence due to lack of robust data arising from small populations, and the demands for randomised controlled trials (RCT) - often not available or ethical - with appropriate comparators are not new. These concerns were demonstrated in the HTA evaluations for Kymriah® and Yescarta® which focussed on the lack of a comparative trial arm and immature survival data.

The evaluations resulted in reimbursement via outcomes-based deals in Germany, Spain and Italy in which payment is linked to ongoing treatment success3. Managed access via the cancer drugs fund in the UK stipulates the requirement to gather real-world data to inform further decision making. Several HTA bodies (French Transparency Committee, NICE) require a reassessment when further data on CAR-T cell therapies are available (3).

Long-term durability of response is a key concern for payers given that gene therapies are priced assuming a lifetime benefit and clearly the curative potential of a therapy cannot be proven definitively on the basis of relatively short-term clinical trial evidence. For example, the data available for Luxturna® at the time of assessment showed improvements were sustained at 7.5-year follow up (phase 1 open-label study), however the NICE committee accepted an assumed 40-year treatment effect cost-effectiveness evaluation whilst acknowledging the “substantial uncertainty” of the long-term benefits (4).

Moving on from orphan indications

Looking ahead, the gene therapy market is set to move beyond orphan indications. Whilst there are incentives for developing drugs for very rare diseases, including less stringent criteria and rapid regulatory approval, overall, it is not economically viable if there are too few patients to begin with, and less over time as they are cured.

Indeed, the commercial failure and subsequent withdrawal of the first gene therapy (Glybera for familial lipoprotein lipase deficiency) resulted, in part, from extremely limited patient numbers (1 per million people worldwide). Similarly, Strimvelis® is indicated for a form of severe combined immunodeficiency that affects only about 14 people per year in Europe and there are an estimated 86 eligible patients in England with the form of inherited retinal disease treated by Luxturna® (4). In contrast, gene therapy clinical trials are underway to treat dry age-related macular degeneration which is the most common form of blindness in the Western world and affects up to 600,000 people in the UK (5). Gene therapies are also in advanced development for sickle cell disease, a condition that can affect up to 2-3% of the population in some countries, and Haemophilia A which affects 1:5000 male births.

Whilst larger population sizes will produce more robust trial data, and prices may come down in response to more eligible patients and competition with existing treatments, payers will likely continue to face issues of affordability and cost management.

Learnings for the industry

It is clear that HTA for gene therapies will not reward innovation alone and will continue to demand robust clinical evidence and value for money. The introduction of therapies for diseases with higher prevalence and existing treatments available will lead to gene therapies being evaluated via the same processes as conventional medicines. For example, manufacturers may be able to prove cost-effectiveness versus existing management for haemophilia gene therapies currently in development due to the high costs of current replacement factors. For diseases that do not have effective treatments, the example of Luxturna® shows it is possible to instil confidence in payers by investing in long-term data generation and including a best supportive care control trial arm.

The issue of long-term effectiveness is being addressed on a number of levels including a collaboration between the EMA and HTA bodies via the EMA and EUnetHTA joint work plan (6) on strategies to collect high-quality real-world evidence, suggesting that payers are recognising the need to look beyond the gold standard of RCT data. A pilot EMA-HTA consultation was conducted for Kymriah® (7) and a joint HTA and price negotiation for Zolgensma® has recently been announced by Belgium, the Netherlands and Ireland under the Beneluxa initiative (8).

As most countries appear to favour market access agreements linked to performance, the generation of unbiased registry data over the long-term will be critical for the ongoing success of gene therapies.

For HTA to adequately capture the value of gene therapies, manufacturers need to address concerns about data uncertainty by investing in well-designed trials and strategies to collect high-quality real-world data, alongside effective communication of the wider societal and patient benefits.

About RJW&partners

RJW&partners works in the biotech and pharmaceutical sector globally. We provide expert market access advice, including pricing strategy, value proposition development, evidence support planning and payer negotiation training.

Contact us to find out how we can help at info@rjwpartners.com



  1. US FDA (2019). Statement from FDA Commissioner Scott Gottlieb, M.D. Accessed May 2020, https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics

  2. Alliance for Regenerative Medicine (2019). Recommendations for Timely Access to Advanced Therapy Medicinal Products (ATMPs) in Europe. Accessed May 2020, http://alliancerm.org/wp-content/uploads/2019/07/ARM-Market-Access-Report-FINAL.pdf

  3. Jorgensen J, Hanna E & Kefalas P. Outcomes-based reimbursement for gene therapies in practice: the experience of recently launched CAR-T cell therapies in major European countries. Journal of Market Access & Health Policy 2020, 8:1, 1715536

  4. NICE (2019). Voretigene Neparvovec for Biallelic RPE65-Mediated Retinal Disease: Final Evaluation document. Accessed May 2020, https://www.nice.org.uk/guidance/hst11/documents/final-evaluation-determination-document-2

  5. Nuffield Department of Clinical Neurosciences, University of Oxford (2020). Gene Therapy for Age-Related Macular Degeneration. Accessed May 2020, https://www.ndcn.ox.ac.uk/research/clinical-ophthalmology-research-group/trials/amd-gene-therapy

  6. European Medical Agency (2020). Health technology assessment bodies. Accessed May 2020, https://www.ema.europa.eu/en/partners-networks/health-technology-assessment-bodies

  7. Seimetz D, Heller K & Richter J. Approval of First CAR-Ts: Have we Solved all Hurdles for ATMPs? Cell Med 2019;11: 1-16

  8. Beneluxa Initiative on Pharmaceutical Policy. Joint HTA assessment of Zolgensma. Accessed June 2020, https://beneluxa.org/news3