Authored by: Tania Rodrigues
Having attended the 2022 World Evidence, Pricing and Access Congress in Amsterdam (Netherlands) with my colleagues Rachel Howard and Rebeca Nana Barrantes earlier this year, I continue to reflect on some of the specific sessions and roundtables I attended where the hot topics related to advanced therapies were discussed. Here I recap on those topics and consider the market access implications for pharmaceutical companies.
Germany: First launch market in Europe or not?
I partly attended the advanced therapies sessions thinking that the elephant in the room would be the 2021 high-profile decision of US firm, bluebird bio, to cease operations in Europe after two years of failed discussions with reimbursement authorities over their beta thalassemia gene therapy, Zynteglo (betibeglogene autotemcel).
However, according to the European Confederation of Pharmaceutical Entrepreneurs (EUCOPE), there were lessons learnt in Germany from the Zynteglo negotiations in which innovation was not rewarded. EUCOPE’s Secretary General believes this was not the fault of the HTA body, G-BA, but the tough line taken by the National Association of Statutory Health Insurance Funds, GKV-SV, not recognizing performance-based guarantees.
According to Tresja Bolt, a senior healthcare advisor and former employee at bluebird bio who spoke during the Q&A, another challenge was dealing with a very low-cost comparator, since Zynteglo was compared to blood transfusion and iron chelation. In contrast, a previous gene therapy evaluated by the G-BA was Zolgensma for spinal muscular atrophy (SMA), which benefited from having the already relatively expensive Spinraza (nusinersen) as a comparator.
EUCOPE believed that the German landscape remained positive for advanced therapies with orphan status, provided annual revenues realized with the Statutory Healthcare Insurers were below the €50 million annual threshold. As a result, manufacturers are free to set reimbursement prices for 12 months unless the threshold is surpassed. However, in July 2022, the German cabinet finally approved the text of the Statutory Health Insurance Finance Stabilization Bill, which includes a change to a €20 million annual threshold and limits the free pricing period to 6 months. This cost-containment package is still subject to several rounds of Parliamentary hearings; hence it will be important for those of us working in market access to continue monitoring.
Cross-border healthcare needs to be improved
As the speaker of a separate session on optimizing cross-border pathways, Tresja Bolt also mentioned Zynteglo in the context of joint HTA evaluation and price negotiation collaborations. This session focused on the EU cross-border reimbursement pathway, whereby EU citizens have the right to access healthcare in any EU country and to be reimbursed for care abroad by their home country.
In fact, for its now-withdrawn gene therapy, Skysona (elivaldogene autotemcel), for cerebral adrenoleukodystrophy, bluebird bio looked at cross border pathways as an emerging key route for treatments for severe genetic and ultra-rare diseases that can only be treated in centres of excellence. Skysona’s withdrawal was driven by the Zynteglo debacle coupled with a failure to identify a commercialization partner.
Although the UK is no longer part of the EU, as there are only five centers across Europe providing Libmeldy (autologous CD34+ cells encoding ARSA gene) for metachromatic leukodystrophy, UK firm Orchard Therapeutics announced in February 2022 that patients will be able to take advantage of cross-border pathways to get access to its gene therapy.
The session by Bolt and by manufacturer Santen highlighted that the EU cross-border framework is not fit for purpose for advanced therapies since it was created for chronic non-specialized treatment. Key barriers are the complexity and the non-transparent discretionary nature of the approval process, particularly those that have not received favorable HTA/P&R outcomes in patients’ home countries.
Continued friction over the Hospital Exemption route
Having touched upon the potential threat of CAR-Ts manufactured through the controversial hospital exemption (HE) route in my recent white paper “Are we prepared for the influx of CAR-Ts?”, I experienced first-hand the tension this topic is causing during one of the roundtable discussions.
The HE allows an institution to manufacture autologous advanced therapies without centralized European Medicines Agency (EMA) approval if on a non-routine basis and in the same member state, to mainly address an unmet need or a rare disease.
During the discussion, there was a clear difference in views between a Novartis representative and a Hospital Clinic de Barcelona representative. The Hospital Clinic created ARI-001, the first CAR-T approved in the European Union (EU) through the HE pathway in February 2021. While Novartis was the first manufacturer to have launched a CAR-T in Europe via the standard EMA procedure in August 2018, Kymriah (tisagenlecleucel) for blood cancers.
According to the Hospital Clinic delegate, competition between the conventional EMA approval and HE route is not in equilibrium, whereas the Novartis representative believes that the motivation to use HE is mainly driven by cost. Although there is expectation that payer evidence requirements will be the same, HE-approved products are expected to exert a downward pressure on price. ARI-0001 has a list price of merely €89,270 in Spain, about 3.5 times less than industry manufactured CAR-Ts.
Outlook and implications
The EU’s pharmaceutical legislation is currently up for review by the European Commission as part of the new EU Pharmaceutical Strategy, whereby several key aspects of how drugs are regulated in the EU could be affected, from pricing and reimbursement to incentives and more. The pharmaceutical industry needs to embrace this remarkable opportunity to continue advocating for a discussion on the future use of the hospital exemption route that needs to be strictly regulated and harmonized across member states.
The review should also be used to lobby for the creation of a ‘one-stop shop’ to help with transparency and understanding and ease navigation of the complex cross border healthcare framework. To promote timely cross-border access, the idea of a European fund for advanced therapies for ultra-orphan diseases could also be floated.
Pharmaceutical industry advocacy is also required to push for a softening of the harsh cost-containment measures envisaged in the German bill, which is still up for discussion with several stakeholders. If implemented, which is likely, manufacturers of advanced therapies for rare diseases need to start preparing sooner rather than later for a HTA process if annual revenues exceed €20 million. The pharmaceutical industry must also assess the potential implications for other markets where the reimbursement price in Germany may be referenced.
The withdrawal of Zynteglo shows that the European HTA/payer landscape is going to be challenging for gene therapies as we move to more prevalent rare diseases. Besides greater budget impact, diseases like beta-thalassemia and haemophilia have relatively lower cost standards of care like blood transfusions and clotting factor replacements. Although there is still an unmet need, it is not considered as high as in diseases such as SMA, which means HTA bodies and payers are still demanding more data to justify reimbursing gene therapies instead of the standard of care.
With a considerable amount of gene therapies anticipated to be approved by the EMA annually over the coming years, there is need for a greater change in payer mindset and HTA evaluation methodologies to address the unique characteristics of advanced therapies whilst recognizing innovation. Gene therapies in development for delayed onset diseases (such as Huntington’s disease) are the next type expected to have tricky pricing negotiations as the benefit is only likely to be measurable with surrogate clinical endpoints and there are typically no disease modifying therapies.
Therefore, it will be important to continue educating payers and policy makers to help them recognize the value of these potentially curative therapies and inherent evidence challenges faced in this space. This is particularly important before the joint EU HTA for advanced therapies becomes operational in 2025. But ultimately, as P&R decisions will remain national decisions, it will be equally critical to explore innovative contracting beyond current pricing models and continue exploring the use of real-world evidence to help manage the uncertainties.
