Reimbursement of ATMPs in Germany: Challenges, opportunities and key initiatives
Liron Sarid-Krebs Associate Principal Consultant and Team Lead at Biopharma Excellence.
Carolin Denzinger Director, Head of Market Access Germany.
Zaklina Buljovcic Director, Principal Consultant, Development Consulting & Scientific Affairs
Advanced therapy medicinal products (ATMPs) offer new opportunities to treat disease or injury, and in some cases even have curative potential. Two distinct hurdles that these therapies must overcome to reach patient access are marketing authorization (MA), where risk vs. benefit is evaluated, and market access and reimbursement, where cost vs. benefit is assessed.
Unlike the centralized procedure for ATMPs to gain MA, when it comes to pricing and reimbursement (P&R) discussion for market access, companies have to handle negotiations separately with each country.
Most P&R negotiations have been based on more traditional treatments to manage chronic conditions, where payment is spread over time. However, ATMPs are very often single treatments that offer life-changing potential but frequently require specialist treatment and long-term follow-up. This requires a radical shake-up of the P&R framework.
Establishing the price
International reference pricing, also known as external reference pricing, is commonly used to compare the price of drugs and set a benchmark price. As a higher-price country with a large market, Germany is often one of the first countries that companies seek to launch in to establish reference pricing. At the same time, innovators need to consider various factors that can affect pricing, including different healthcare systems, economic constraints and different priorities in each market.
Nevertheless, while there are exceptions, many companies that are unable to reach their price in Germany choose to take their drug off the German market and not to pursue other EU or European Economic Area (EEA) markets. The impact of this has been felt with several companies choosing to remove or not bring their products to the EU market after being unable to reach a satisfactory P&R agreement in Germany.
Understanding the German market
Germany’s health technology assessment (HTA) procedure is largely based on the “AMNOG” (Arzneimittelmarktneuordnungsgesetz) process to determine the benefit of the drug and the reimbursement. After a company has received marketing authorization, it submits an HTA dossier to the Federal Joint Committee (Gemeinsamer Bundesausschuss or G-BA) to demonstrate the benefit of the product in comparison to any other treatment on the market for that therapeutic category. The dossier should include clinical trial data and amongst others all information gathered from physicians and patients early on to demonstrate patient-related need.
The G-BA determines the benefit of the therapy based on the dossier submitted, after which the German National Association of Health Insurance Funds (Spitzenverband Bund der Krankenkassen or GKV) sets the reimbursement price after negotiation with the manufacturer. ATMPs that have received marketing approval can be made available to patients in the ambulatory setting (outpatient) for the first year – when the AMNOG process takes place – at a reimbursement price set by the manufacturer.
From a social law perspective, it was previously problematic to establish whether certain ATMPs were considered as a medicinal product or a method, since in the case of a method no AMNOG procedure had to be carried out, but rather a method assessment procedure (BSG, 2004). However, as a result of a recent change in the law, it has now been clarified that ATMPs (with the exception of biotechnologically processed tissue, or tissue-engineered products like chondrocytes for knee cartilage treatment) are to be assigned to the AMNOG procedure even if they are predominantly to be classified as a method. This is defined under Section 35a (1b) of the German Social Code, Book V (SGB V). As such, the reimbursement price for approved ATMPs – unless they are tissue-engineered products – is determined in the “AMNOG” procedure.
One pathway open to developers of innovative products such as ATMPs is Hospital Exemption (HE) which allows patients to receive treatment that hasn’t been granted marketing authorization under specific circumstances and controlled conditions. This pathway only applies in the hospital setting for non-routine treatments and for individual patients when no centrally authorized treatment or clinical trial is available. Funding for HE products in Germany as well as centrally authorized tissue-engineered products is classified through Diagnosis Related Groups (DRGs), which establishes a fixed rate per case.
If there is no existing DRG for an ATMP in the hospital setting (inpatient), a new examination and treatment method (NUB) payment application can be applied, which allows for limited time, case-by-case charge. Hospitals can use an individual reimbursement application while waiting for NUB approval, but this process is costly for all parties. NUB applications can be highly complex. They must be sent to the Institut für das Entgeltsystem im Krankenhaus (InEK) in a set period – from 1 September until 31 October – and must be submitted via the InEK portal and include specific information. Hospitals can get support from the manufacturer with the NUB application.
Navigating reimbursement in Germany
Given the complex nature of P&R negotiations, and particularly with ATMPs which have limited real-world evidence, companies should seek early advice from the G-BA to determine if the protocol and clinical data fits the needs of the HTA. Is the company using the right comparator? Are endpoints correct? Is the study length sufficient? Leaving discussion with the G-BA until after marketing approval could result in the committee determining that the study doesn’t demonstrate added benefit and doesn’t match the G-BA’s requirements, and therefore fails to achieve the expected reimbursement.
Companies should also consider seeking advice from physicians, particularly key opinion leaders in the relevant therapeutic area.
Pre- and post-treatment modalities and the associated costs are also important considerations with ATMPs. Unlike traditional therapies, where patients are given a pill or an injection, ATMPs require patients to be prepared in a specific way, for example, harvesting and processing the patient’s cells for CAR-T cell therapy, then delivering the treatment through intravenous infusion.
Another option open to companies is EUnetHTA, a European network for HTA evaluation that brings together member organizations across Europe to improve cross-border HTA collaboration. However, unlike the centralized regulatory approval process, harmonization between member states on P&R is yet to be realized as each country has its own position based on different healthcare systems, economic constraints, and patient population priorities.
Bridging the gap
While early discussion with the G-BA and other key stakeholders are important to the P&R process of ATMPs, there are still many issues to address for HTA bodies and innovator companies alike.
One initiative that is seeking to achieve greater harmonization and quality-assurance measures for the use of current and future ATMPs in Germany is the INTEGRATE-ATMP project[i]. The project brings together specialized German treatment centers to help achieve structured, interdisciplinary cooperation in the complex processes from the production of these therapies to the management of side effects, as well as addressing bureaucratic obstacles.
The consortium will examine economic care structures, including reimbursement, the creation of an ATMP register and implementing a telemedicine communication platform. The success of the therapies and any undesirable side effects will also be observed.
Another European endeavor is the PAtient REgistries iNTiatives (PARENT) Joint Action, which is a collaborative effort by the European Commission and some Member States with regards to patient registries in Europe. The objective is to “support member states in developing comparable and coherent patient registries in fields of identified importance … to rationalize and harmonize the development and governance of patient registries, thus enabling analyses of secondary data for public health and research purposes.[ii]”
From a P&R perspective, registry data can provide real-world evidence on the overall effectiveness of treatments. The better and more comprehensive the registry data, the more reliable it is during health economic evaluations[iii].
Early-phase modelling, which evaluates costs and expected outcomes of new and current treatments using assumptions and extensive sensitivity analysis should be performed as soon as possible in the product development process, when there is a need to understand opportunities and challenges from a health economic perspective.
There are still many uncertainties about ATMPs and undoubtedly cost must be considered in HTA decision-making. However, with greater real-world evidence and key initiatives, it is hoped there will be a more cooperative, harmonized approach to all issues relevant to ATMPs – from production, to quality, to data on adverse events, to longer-term outcomes data and to inevitable shifts in the HTA process as the patient and economic benefit is better understood.
- INTEGRATE-ATMP, https://innovationsfonds.g-ba.de/projekte/neue-versorgungsformen/integrate-atmp-integrierte-versorgung-neuer-therapien-durch-telemedizin-empowerment-gentherapeutika-registeretablierung-arzneimittelsicherheit-therapiepfaden-und-erstattung.510
- EUnetHTA, https://www.eunethta.eu/parent/
- Patient Registries as Instruments for HTA Outcomes Research: A European Perspective, ISPOR, https://www.ispor.org/docs/default-source/publications/value-outcomes-spotlight/january-february-2016/vos-patient-registries-as-instruments.pdf?sfvrsn=aca51b6_2