Reimbursement of Gene Therapies in the UK – What Have We Learned So Far

With 16 gene therapies now approved for clinical use, industry is watching closely to see how these treatments fare when facing the reimbursement hurdle in the UK.[1] To date, difficulties have been expected due to high initial costs coupled with the typical challenges found in rare diseases (e.g. short trial follow-up and small populations), which lead to high levels of uncertainty.[2] However, the recent National Institute for Health and Care Excellence (NICE) highly specialised technologies (HST) recommendation of Novartis’ ￡1.79 million therapy Zolgensma? (onasemnogene abeparvovec) for the treatment of babies aged up to 12 months with Type 1 spinal muscular atrophy (SMA) is a landmark moment that could establish a new model for gene therapy reimbursement.[3, 4] The question now is what can industry learn from this case study to maximise the chances of patients being able to gain access to these life-changing therapies moving forwards.

One-off Payment with Substantial Discount

It is no surprise that price is critical with substantial confidential discounts to be expected for high-cost gene therapies. The Zolgensma? case study was no exception, and although the details of the discount agreed with National Health Service (NHS) England remain confidential, it has been reported to be substantial and the outcome of tough negotiations.[5] An interesting point to note, however, is that a one-off payment for Zolgensma? was accepted, suggesting that innovative pricing models such as annuity schemes and outcomes-based contracts are not necessarily required for these “curative” therapies, which may have yet to demonstrate the long-term outcomes they promise.

This example aligns with the general historic preference of NICE for simple discounts where possible. The proposed changes to the handling of commercial and managed access proposals, as detailed in the current NICE process consultation,[6] aim to increase clarity, promote earlier dialogue and ultimately reach agreement faster. NICE have proposed that the Patient Access Scheme (PAS) should be included in all commercial and manged access proposals, and companies should provide a summary of data gaps upfront to enable exploratory discussions about managed access. They do, however, leave the door open for increased commercial flexibility over and above a PAS if the need can be justified by the manufacturer.

Exceptional Significant Benefit in a Certain Age Group

Novartis have commented that the high price of Zolgensma? is justified by the clinical data it has gathered.[4] This is supported by NICE reporting that the exceptional benefit to young babies, with Zolgensma? potentially allowing them to reach normal developmental milestones, means that treatment can be recommended for use on the NHS despite the high cost.[3]

In order to demonstrate exceptional significant benefit, it is highly likely that the disease area must first have significant unmet need. This was very much the case for Zolgensma?, where SMA Type 1 is the most severe form of SMA with symptoms arising typically before six months and most children dying before the age of two years of age when treated with best supportive care. The only other active treatment available for SMA in the UK is Spinraza? (nusinersen), which is not routinely commissioned and recommended through a managed access agreement (MAA). As such, the primary comparison in the NICE HST evaluation was to natural history data from the NeuroNext study, whereby the chances of demonstrating an exceptional significant benefit were higher.[7] It is critical to note that the approach to Spinraza? has differed between health technology assessment (HTA) bodies.[8]

Ultimately, the reimbursed population was tightly restricted to the subpopulation where there was considered to be the most robust clinical data and greatest certainty surrounding the clinical benefit. For reference, babies with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of Type 1 SMA are only eligible if they are six months or younger, or if they are aged 7–12 months and treatment is agreed by the national multidisciplinary clinical team. The decision to apply additional restrictions on the 7–12 months age group allowed the risks associated with the more limited trial data in this subpopulation to be managed. In light of this, manufacturers may consider suggesting additional steps or services that could be put in place to manage the risk of uncertainty and allow a wider population to gain reimbursement.

In support of the early benefit offered by this treatment, it has been interesting to see the NHS being ready to fast-track the introduction of the gene therapy prior to NICE final guidance being issued.[5] This further demonstrates the exceptional level of benefit thought to be offered by Zolgensma?, and the options that can be available, should there be sufficient evidence of earlier treatment being beneficial for patients. The NICE process review has demonstrated NICE’s keenness to move to a faster, more flexible and responsive approach across programmes.[6] Should these changes be effective, time to patient access should be reduced and hopefully avoid the need for products to be fast-tracked ahead of NICE final guidance being issued.

Cost-Effectiveness Considerations

It is interesting to note the manufacturer’s conservative decision to lead with the 3.5% reference case discount rate for costs and health benefits in its base case. The alternative would have been to suggest a discount rate of 1.5%, which may be used, for example, when treatment restores people to full or near-full health when they would otherwise die or have severely impaired lives. After much consideration, ultimately the NICE Committee concluded that a 1.5% discount rate was suitable, interestingly opting for a more favourable assumption to be used in decision making than the manufacturer.[7]

That being said, the NICE Committee did determine that the quality-adjusted life year (QALY) modifier suggested by the manufacturer (1.86 based on an undiscounted QALY gain of 18.62 in the most plausible scenario) included too much uncertainty and was therefore reduced. In doing so, the Committee reduced the weight applied to the ￡100,000 QALY limit, effectively lowering the willingness-to-pay threshold applied in decision making as compared to that originally proposed by the manufacturer. Although the revised QALY weight remains confidential, it is made clear that the final incremental cost-effectiveness ration (ICER), including the confidential discount, was considered to be within the range NICE normally considers an effective use of NHS resources for HSTs.[7]

The shift towards a more general severity modifier, as proposed in the current NICE methods consultation,[9] suggests that the application of a QALY modifier in HST evaluations has been considered a success. This is further supported by the outputs of the NICE modifiers task and finish group, which explored modifiers as a method for capturing societal values by adjusting QALYs to reflect specific populations, disease areas or technologies.[10] This proposed change to NICE programmes allows a more flexible approach to the categorisation of diseases, better reflecting the spectrum of severity across both rare and common conditions.

Patient Voice

The role of the patient advocacy groups in the Zolgensma? example has been clear throughout its clinical development programme, with SMA REACH previously playing a key role in the UK’s response to the controversial early access programme lottery model proposed by AveXis in December 2019.[11] The NICE Committee meeting included data collected by SMA UK/MNDA UK capturing caregiver opinion on Zolgensma?. Furthermore, patient experts spoke to the future long-term benefits, highlighting that Zolgensma? could make it possible for children with SMA Type 1 to attend school and interact with the wider community; a hugely valuable opinion considering the current absence of long-term data.[7] The pivotal role of patients as experts in rare diseases should never be understated, and the critical role patient advocacy groups can play in addressing uncertainty inherent to the dataset, and collecting insights across both patients and caregivers, can contribute enormously to the process.

The greater emphasis on patient involvement in the NICE process consultation, for example, via the introduction of a summary of information for patients (SIP) and assignment of a dedicated relationship manager for patient and carer organisations, supports further moves towards these insights becoming a fundamental requirement of a thorough appraisal process.[6]

Take Home Message

The Zolgensma? case study has demonstrated a willingness from all stakeholders to find a solution that can rapidly bring life-extending treatments to patients with the highest unmet need. Moving forwards, it is evident that the NICE HST programme is adapting to the increasing numbers of gene therapies coming through. For example, NICE propose to remove the criteria that require the technology to have the potential for “life-long use” and that “the condition is chronic” in order to enable one-off treatments such as gene therapies to be considered more routinely by HST.[6] As such, further recommendations are likely to follow on from Zolgensma?, allowing gene therapies to become more established as a viable treatment option in the UK and support the aims of the NHS long term plan to introduce treatment possibilities that a modern health service should “rightly be providing”.[12]

The simple one-off payment approach, coupled with a substantial confidential discount offered by the manufacturer of Zolgensma?, allowed the price to become feasible from the perspective of NICE. This, plus the significant unmet need in the disease area and the convincing clinical data in a subpopulation, ensured that a positive reimbursement decision could be reached. As expected, compromises were reached along the way. For example, it was interesting to see the Committee decided upon a less conservative discounting approach but a more conservative QALY weighting than suggested by the company. For manufacturers, the lessons seem to be to simplify the decision where possible, both in terms of costs and the population with the most certain and significant clinical benefit. As always, a willingness to be flexible and open to discussion regarding assumptions is required to bring negotiations to a conclusion, whilst erring on the side of conservative when selecting a base case and actively seeking patient input is likely to be beneficial. 

Many thanks to Andrew Olaye (Senior Director, Market Access EMEA at Orchard Therapeutics) for his review of and contribution to this article.

Annabel is Head of Rare Diseases at Costello Medical, a global healthcare consultancy providing scientific support in the analysis, interpretation and communication of clinical and health economic data. Due to growing demand across an increasing range of service offerings and geographies, Costello Medical has grown organically since its foundation in 2008 to a global team of over 200 based in Europe, Asia and North America. Alongside our evolving technical and creative capabilities, we remain committed to our core values of high-quality scientific work coupled with exceptional customer service at competitive and transparent prices. Our talented team has experience with a variety of leading pharmaceutical and device companies across an extensive range of therapy areas and geographies, including Europe, Asia Pacific and North America. For more information on our services, please visit our website. If you would like any further information on the content presented above, or our experience in gene therapies and rare diseases, please contact Annabel Griffiths.

References

1.        American Society of Gene + Cell Therapy. Gene, Cell, & RNA Therapy Landscape. Q1 2021 Quarterly Data Report. 2021. Available from: https://www.asgct.org/global/documents/asgct-pharma-intelligence-quarterly-report-q1-2021.aspx. Last accessed: 16.04.2021.

2.        PharmaTimes. Bluebird Bio’s Beta-Thalassaemia Gene Therapy Rejected by Nice. 2021. Available from: https://www.pharmatimes.com/news/bluebird_bios_beta-thalassaemia_gene_therapy_rejected_by_nice_1363220?utm_campaign=pt+daily+news+alert&utm_medium=email&utm_source=PT+Daily+Newsletter. Last accessed: 07.04.2021.

3.        NICE. Nice Approves Life-Changing Gene Therapy for Treating Spinal Muscular Atrophy. 2021. Available from: https://www.nice.org.uk/news/article/nice-approves-life-changing-gene-therapy-for-treating-spinal-muscular-atrophy. Last accessed: 07.04.2021.

4.        PharmaPhorum. Novartis Says ￡1.8m Zolgensma Is Model for Gene Therapy Pricing. 2021. Available from: https://pharmaphorum.com/news/novartis-e1-9m-zolgensma-is/?utm_source=pharmaphorum+Daily+Newsletter&utm_campaign=a375f52f17-EMAIL_CAMPAIGN_2019_09_24_10_10_COPY_01&utm_medium=email&utm_term=0_a54496134b-a375f52f17-444759141. Last accessed: 07.04.2021.

5.        NHS. Nhs England Strikes Deal on Life-Saving Gene-Therapy Drug That Can Help Babies with Rare Genetic Disease Move and Walk. 2021. Available from: https://www.england.nhs.uk/2021/03/nhs-england-strikes-deal-on-life-saving-gene-therapy-drug-that-can-help-babies-with-rare-genetic-disease-move-and-walk/. Last accessed: 07.04.2021.

6.        NICE. Reviewing Our Process for Health Technology Evaluation: Consultation. 2021. Available from: https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/reviewing-our-process-for-health-technology-evaluation--consultation. Last accessed: 07.04.2021.

7.        NICE. Onasemnogene Abeparvovec for Treating Spinal Muscular Atrophy Type 1 [Id1473] - Project Documents. 2021. Available from: https://www.nice.org.uk/guidance/indevelopment/gid-hst10026/documents. Last accessed: 14.04.2021.

8.        SMC. Onasemnogene Abeparvovec 2 × 1013 Vector Genomes/Ml Solution for Infusion (Zolgensma?) - Detailed Advice. 2021. Available from: https://www.scottishmedicines.org.uk/media/5813/onasemnogene-abeparvovec-zolgensma-final-feb-2021-amended-010321docx-for-website.pdf. Last accessed: 16.04.2021.

9.        NICE. Reviewing Our Methods for Health Technology Evaluation: Consultation. 2021. Available from: https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/chte-methods-consultation. Last accessed: 14.04.2021.

10.      NICE. CHTE Methods Review: Modifiers. 2021. Available from: https://www.nice.org.uk/Media/Default/About/what-we-do/our-programmes/nice-guidance/chte-methods-consultation/Modifiers-task-and-finish-group-report.docx. Last accessed: 14.04.2021.

11.      TreatSMA. Update on Avexis’s Global Managed Access Programme for Zolgensma. 2020. Available from: https://www.treatsma.uk/2020/03/update-on-avexiss-global-managed-access-programme-for-zolgensma/. Last accessed: 07.04.2021.

12.      NHS. The NHS Long Term Plan. 2019. Available from: https://www.longtermplan.nhs.uk/wp-content/uploads/2019/08/nhs-long-term-plan-version-1.2.pdf. Last accessed: 16.04.2021.