Europe’s complex reimbursement process puts access to ATMPs at risk
A potential crisis with advanced therapy medicinal products (ATMPs) is looming in Europe. Concerns over reimbursement in the EU were brought to a head when bluebird bio announced it would withdraw its gene therapy Zynteglo from the EU after failing to secure the reimbursement it sought in the key German market. Several other companies have also withdrawn their marketing authorizations from Europe for commercial reasons[i].
Now that an FDA advisory committee have given unanimous endorsement to three of bluebird’s gene therapies, it looks likely patients in the U.S. will have access to medicines that won’t be readily available to patients in Europe. Zynteglo – or beti-cel in the U.S. – is a gene therapy for patients with beta-thalassemia, an inherited blood disorder.
The situation is an extremely complex one. While the therapies could potentially be life-changing for patients, they are expensive and as yet there is not yet enough real-world data to determine how long patients will benefit from cell and gene therapy. These products are often approved with limited data, making pricing and reimbursement decisions and long periods of follow-up are required for both safety and efficacy. Nor are these treatments without risk, since they can impact on hematopoietic and immune reconstitution with a risk of malignancy due to bone marrow reconstitution or integration of the vector into chromosomal sites, potentially later leading to cancer.
Nevertheless, the decision by bluebird bio and other ATMP developers means patients in Europe will potentially miss out on life saving and one-time treatments with only patients having participated in clinical trials being able to access the therapies. Furthermore, some European clinicians have said they are not willing to have their patients participate in clinical trials if pricing and reimbursement challenges mean the treatment won’t be made available for their patients after regulatory approval.
Adding to the situation is that international migration to Europe has meant conditions that, in the past, affected tiny numbers of European citizens are becoming more prevalent. For example, beta-thalassemia, which bluebird’s Zynteglo treats, is more widespread in parts of Asia, and, with migration, this prevalence is spreading. As more patients qualify for cell and gene therapy, there is an impact on health budgets.
The issue of reimbursement in Europe is complicated, because it means working with 27 different countries to negotiate a price. Even if some countries do agree to the price sought, others are not able to do so. Regulatory approvals for rare and ultra-rare diseases are often granted on the basis of limited data sets, with agreement on the generation of real world data following approval to supplement the existing registration package. Often payers have other needs than the regulators when it comes to demonstrating the value and efficacy associated with a new gene therapy product. This is further complicated by incomplete patient records used to generate historical data on disease progression to develop a baseline for the evolution of a given disease.
Regulators in Europe have been open about their concerns. Ana Hidalgo-Simon, the European Medicines Agency’s head of advanced therapies, said in an address to the Cell and Gene Meeting on the Mediterranean in April that marketing authorization withdrawals in Europe needed to be addressed, adding that one important step would be to have greater alignment between regulators, health technology assessment (HTA) bodies and payers before the regulatory decisions are taken.
Similarly, Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), referred to reimbursement as the 800-pound gorilla in the room, adding that accelerated approvals “make people shudder because of concerns” about pricing and risk-sharing models.
Addressing access to ATMPs
While Europe was highly competitive early on and was faster to approve cell and gene therapies than the U.S., the issue of who will pay for these innovative treatments sets the EU back. According to some estimates, there may be as many as 70 cell and gene products approved in the U.S. in the next five to eight years. Investments in China are also increasing, and today the country holds 56% of global cell and gene therapy patent registrations.
Europe remains highly innovative at a research level, but as EFPIA Director General Nathalie Moll has said: “Innovation only matters if it reaches patients.”
Various payment models are being considered. Some approaches include pay-for-performance and risk-sharing agreements that are outcomes-based, which help payers deal with the uncertainty over the long-term benefits of ATMPs, although these do still present challenges.
There are already some cross-country collaborations aimed at optimizing and harmonizing HTA capabilities in an effort to simplify the assessment process and reduce time to patient access. For example the Beneluxa initiative that brings together The Netherlands, Belgium, Luxembourg, Austria and Ireland, or FINOSE, Finland, Norway and Sweden have already delivered a number of joint assessments
One proposal put forward by the European Confederation of Pharmaceutical Entrepreneurs is for an EU fund to enable cross-border treatment.
The European Federation of Pharmaceutical Industries and Associations has proposed equity-based tiered pricing (EBTP), where medicine prices would be determined by a country’s ability to pay. In this way, lower income EU countries could access innovative treatments while still ensuring incentives to invest in new medicines. However, because EBTP would only be effective if certain commitments are adhered to (such as having member states commit to good practices in external reference pricing and limit parallel trade between high- and low-income countries) EFPIA has said more discussion is needed.
While there is no silver bullet to this complex situation – especially given the huge costs involved with gene therapy products — there is a need for European regulators, HTAs and companies to work together early on. The EMA is now offering consultations in parallel with the European Network for Health Technology Assessment (EUnetHTA) 21 consortium, allowing developers to get both regulatory and reimbursement feedback early on, with the goal of generating robust feedback for both regulators and HTA bodies. The ILAP process in the UK also integrates Scottish Medicine Consortium and NICE feedback into the Target Development Profile of a new drug to ensure that the data package generated for this product meets requirements for both regulatory and reimbursement hurdles.
Cell and gene therapies hold the potential to not only improve or save lives, but also enable caregivers, in particular parents, to go back to work. And for children with neurocognitive disorders, treatment can ensure greater participation in daily life.
For healthcare systems, it potentially means not having to provide life-time care for patients with debilitating disorders.
“What we need is a holistic approach to take into account the benefits not only for the patient but also for the healthcare system, and for the caregivers,” Susana Solís Pérez, a member of the European Parliament’s Renew Europe group, said at a recent Alliance for Regenerative Medicine event.
About the authors:
Emma Cheesman-Ungstrup is Director of Development Consulting and Scientific Affairs at Biopharma Excellence and Alberto Rubio is Senior Director Market Access & Digital Health Solutions at PharmaLex.
[i] Other product withdrawals include: Glybera from uniQuire, for the treatment of reverse lipoprotein lipase deficiency; Dendreon’s Provenge for asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer; Zolmed’s Zalmoxis, an add-on treatment in adults who have received a haematopoietic stem cell transplant; TiGenix’s ChondroCelect, for repair of symptomatic cartilage lesions of the femoral condyles of the knee; and Vericel’s MACI, for the repair of symptomatic single or multiple full-thickness cartilage defects of the knee
[ii] Key factors to improve drug launches, Deloitte, https://www2.deloitte.com/us/en/insights/industry/life-sciences/successful-drug-launch-strategy.html