In January, the Alliance for Regenerative Medicine (ARM)’s Cell and Gene State of the Industry briefing earmarked 2022 as a record year for approval of gene therapies for rare diseases. This has not transpired. As of September, only three gene therapies from the ARM list have received European Medicine Agency (EMA) approval so far, with three expected to reach the market in 2023 (see Table 1).
Developing, manufacturing, and getting a gene therapy to a patient is complex and expensive. Gene therapies are associated with a high cost of goods and require a price reflective of their curative value. For ultra-orphan and orphan diseases, the small numbers of patients who will benefit mean high prices are needed to ensure profitability and these have proven challenging to achieve.
While the industry remains active in developing advanced therapies (including gene therapies) within the rare disease space, including haematological disorders and eye disorders, there is an increasing shift from the advanced therapy sector as a whole to more prevalent diseases (see Table 2).
According to the ARM, just 59% of the 2,405 advanced therapy clinical trials (both industry and academic/government sponsored) are focused on diseases defined by ARM as ‘prevalent’, as outlined in Graph 1.
The economic challenges associated with commercialisation of a gene therapy for an ultra-orphan disease were once again underscored by the July 2022 decision by Italy’s non-profit organisation, Telethon Foundation, about Strimvelis for Adenosine Deaminase severe combined immunodeficiency. The Foundation decided to take sole responsibility for commercialising Strimvelis after current license holder Orchard Therapeutics opted to withdraw from this programme due to lack of economic viability. Figure 1 signposts the chequered past of cell and gene therapies.
The Strimvelis development follows the high-profile decision of US firm Bluebird Bio to cease operations in Europe after two years of failed discussions with reimbursement authorities over its beta thalassemia gene therapy, Zynteglo.
Failure to achieve appropriate value recognition for Zynteglo, and the inability to identify a commercialisation partner, led the company to also withdraw its regulatory marketing authorisation for gene therapy Skysona for cerebral adrenoleukodystrophy from Europe. Skysona was the only gene therapy approved by the EMA in 2021.
When the Telethon Foundation stepped in to ‘rescue’ Strimvelis, it echoed the thoughts of many developers, stating that scientific advances have not been matched by an adequate evolution of regulatory and market access processes for gene therapies, considering their unique characteristics compared to traditional drugs.
Gene therapies face a range of evidence-generation challenges, including uncertainties regarding the magnitude and duration of treatment effects, poorly defined patient populations, limitations in trial duration and size, and reliance on single-arm trials and surrogate endpoints.
The challenges associated with characterising value made us curious about HTA body and payer preparedness to deal with the imminent influx of gene therapies with an inherently high sticker price. From our global network, we reached out to seven payers with gene therapy expertise in the UK, France, Germany, Spain, and Italy to get their views.
Most respondents believe that RWE is ‘somewhat important’, however, a French payer emphasised that this depends on the objective and the context. Haute Autorité de santé’s (HAS’) latest evaluations of gene therapies make requests of RWE collection as part of reassessments, including monitoring data as part of early access programmes.
The German payer highlighted that the G-BA selects which EMA conditionally approved products and orphan drugs must be part of a mandatory RWE data collection registry. Although only expected for selected products, the registry requirement aims to help overcome the uncertainty associated with weak evidence at launch. After the first test case, Zolgensma for spinal muscular atrophy, Roctavian for haemophilia A is the next gene therapy to be subjected to a registry.
Only three respondents, including two from France, do not expect it to have an impact. One French payer underscored that Zynteglo was granted an ASMR rating III for patients aged over 12 to less than 35 years by HAS. This meant it was in a good position to obtain a high price from CEPS until negotiations stopped due to the marketing authorisation withdrawal.
The German payer considered Zynteglo’s list price of €1,575,000 as one of the main reasons for its demise. During the AMNOG’s Arbitration Board process, this price could not be justified, considering its very low cost-comparator, i.e., annual blood transfusions. The Board was convened after Bluebird Bio could not agree a final reimbursement price with the National Association of Statutory Health Insurance Funds, GKV-SV. According to the European Confederation of Pharmaceutical Entrepreneurs (EUCOPE), this was not the fault of the G-BA, but the tough line taken by the GKV-SV in not recognising performance-based guarantees.
In Germany, outcome-based models have been used by individual sickness funds for the gene therapies commercialised so far. At the GKV-SV level, it has been more common to use one-time payment with evidence development via the mandatory registry data collection.
In both Germany and France, annuity payment models, which would allow the high upfront cost of gene therapies to be split over multiple years, could be on the cards. As of March 2022, there was debate in Germany around amending the GKV-FKG act’s 2021 risk pool mechanism for high-cost therapies, which eliminates incentives for entering instalment-based payment contracts. In France, the CEPS-innovative drug industry association LEEM framework agreement of March 2021 included contractual amendments that may now split payment over several years, but they are yet to be implemented into legislation.
This pathway is emerging as a key market access route for products for severe genetic and ultra-rare diseases that require specialist centres of excellence, due to complexity in patient management and needed clinical expertise. Despite Brexit, in February 2022, Orchard Therapeutics announced that patients will be able to take advantage of cross-border pathways to get access to its gene therapy Libmeldy from a UK site (one of five centres across Europe).
Despite manufacturers like Orchard using this framework, the industry does not believe it is fit for purpose. Key barriers are the complexity and the opaque discretionary approval process, particularly for products without favourable P&R outcomes in patients’ home countries.
There also seems to be a need for better planning: in our research only two out of seven payers (a German and a French respondent) said their countries were very prepared to manage the pathway.
Interestingly, the payers surveyed do not expect the EU’s new joint clinical assessment, which will be starting for advanced therapies in 2025, to help the cross-border pathway to realise its full potential. A French respondent emphasised that this is because P&R decisions will continue to be done nationally.
The Strimvelis case also underscores the need for a policy environment supportive of the advances made in gene therapy for rare diseases. This requires a recognition of the challenges of economics of this space, which has implications for pricing. It is important that the promise of gene therapy can be met in orphan indications although the ultimate value may reside more with indications for prevalent diseases.
In pursuing these indications, gene therapy commercialisation represents a perfect storm as the issue of economic sustainability becomes acute. Besides the potential high budget impact, the unmet needs for diseases like beta-thalassemia and haemophilia are not deemed as high versus, for example, spinal muscular atrophy where Zolgensma commanded a high price. Moreover, in these conditions the comparators are typically much lower priced.
This means that HTA bodies and payers will continue to demand more data to justify reimbursing such gene therapies. Therefore, it will be important for manufacturers to seek early feedback from these stakeholders on data requirements and expectations, as underscored by a UK respondent surveyed. This feedback should be on a range of aspects including their clinical trial design, economic modelling plans, additional data collection requirements, and suitable payment models.
To improve HTA/P&R outcomes at launch, it will be key to strengthen evidence generation plans to show potential lifetime durability of efficacy and capture additional elements of value. Commitments to longer-term ongoing submissions of post-marketing data, follow-up pivotal clinical trial data, and RWE collection can support in this regard. A direct measure of health-related quality of life in the clinical trial could also help demonstrate a quality-of-life improvement.
Continued HTA body and payer education is needed to change mindset, particularly when it comes to therapies for prevalent diseases. This would help increase willingness to pay and support with pushing for greater HTA/P&R process adaptations, whilst reducing concerns about budget impact, health system sustainability, and administrative burden.
Innovative payment models, such as outcome-based and annuity models, are potential solutions to ensure the collection of pertinent data to reduce payers’ long-term uncertainty regarding these therapies’ effectiveness, whilst providing a reasonable return on investment. However, the development and implementation of such models are complex. Payers could also manage affordability/budget impact concerns by spreading their costs across several years linked to outcome demonstration, but this requires greater flexibility and legislative change. All eyes are now on how Roctavian will succeed in navigating the EU P&R landscape, having just received conditional approval from the EMA.
Tania Rodrigues is a senior consultant in Research Partnership’s market access division.
Tania manages qualitative global market access projects in varied therapeutic areas, with a particular interest in cell and gene therapies (CGTs). Recent projects have ranged from understanding payer perceptions of the clinical value, HTA, and pricing potential of CGT product profiles, to providing guidance on key policy considerations to inform pricing, and payment model decisions in the CGT space.
Research Partnership is now a member of Inizio Advisory, the consulting business unit of Inizio, a strategic partner for health and life sciences with a full suite of medical, marketing, advisory, and engage services. As the market insights specialist of this curated group of companies, we collaborate with clients from the global pharmaceutical, medtech, and biotech industries, providing research intelligence and strategic recommendations that elevate healthcare brands and help them thrive in a complex and challenging environment.
Our specialist market access service supports the world’s leading manufacturers in market access, pricing, and reimbursement. To find out more please visit: