A review of the challenges and proposals for improving patient access to advanced therapeutic medicinal products in Germany

Executive Summary

RARE IMPACT is a multi-stakeholder initiative working to improve patient access to advanced therapy medicinal products (ATMPs). This patient-focused initiative aims to assess challenges and propose actionable solutions to concerns regarding access to these transformative rare disease treatments in Europe. Through engagement with health technology assessment (HTA) agencies, regulatory bodies, payers, patient groups, clinicians, manufacturers and other experts across Europe, RARE IMPACT partners identified challenges and have proposed solutions for better access to ATMPs in Europe.

This report aims to stimulate multi-level stakeholder discussions on patient access to ATMPs and is not intended to capture all challenges to patient access to ATMPs. The RARE IMPACT initiative was launched at the European Conference on Rare Diseases and Orphan Products in 2018.

Currently, ATMPs have been assessed positively in Germany and patients have received good access to these treatments in recent years

Affordability has not been a major impediment to patient access and the health system has managed to secure ATMP access within existing protocols for assessment and reimbursement. However, with more ATMPs due to be launched in the coming years, there are potential barriers to sustainable patient access to ATMPs for which there is now an opportunity to address.

The primary challenge to ensuring sustainable patient access to ATMPs relates to the assessment at the national level

The Arzneimittelmarkt-Neuordnungsgesetz (AMNOG; English translation: Pharmaceuticals Market Reorganisation Act) process is highly structured and emphasises methodological consistency and rigour. There is relatively little flexibility to account for the particular characteristics of ATMPs that place constraints on trial design and evidence availability at launch. The challenges concern the greater evidential uncertainty due to single arm or synthetic control arm studies, small patient numbers in trials, the use of surrogate endpoints and a lack of established comparators.

The most direct response to this challenge would be to allow more flexibility in the AMNOG assessment methodology to reflect the challenges of evidence generation for ATMPs in small populations. This would be especially beneficial in respect to indirect comparisons with appropriate comparator and extrapolation of surrogate data to downstream outcomes. Greater methodological flexibility could be permitted in accordance with the relative paucity of existing data on the disease, endpoints and current standard of care.

Under new legislation the Gemeinsamer Bundesausschuss (G-BA; English translation: Federal Joint Committee) can now request additional data collection for orphan products with conditional approval. The change will introduce a data collection period of 18 months post-launch and enable the Gesetzliche Krankenversicherung (GKV; English translation: Statutory health insurance) to trigger a price negotiation if the G-BA deem the additional data collected to be unsatisfactory. This may pose a challenge in that there is a very limited opportunity to collect meaningful data within an 18-month period. It is therefore necessary for the G-BA to provide guidance on real-world evidence generation needs at early scientific advice meetings, rather than at the time of assessment. It is also important that the process of evidence generation and price negotiation is adaptive and iterative to accurately reflect the cumulative weight of evidence over time.

For these reforms to be effective the quality of data collected needs to be maximised. There is a need for German health authorities to consider how healthcare providers can be encouraged to generate the data required, given no current obligation to participate in data collection

Similarly, patient education is required on the importance of post-treatment follow-up to ensure data collection is meaningful. This is particularly important for potentially curative treatments where patients may not feel the need to continue attending clinic.

Innovative funding schemes, such as outcome-based payment agreements, are likely to be an important part of this new process. Such agreements have already been developed for CAR-T in Germany, in which the manufacturer agreed to a rebate for some of the treatment cost if the survival outcomes of the therapy are not met. It should be noted that this model was agreed with a single coalition of payers (Gesellschaft für Wirtschaftlichkeit und Qualität für Krankenkassen) and further encouragement should be given to extend the participation for future ATMPs.

Given the particular characteristics of ATMPs in rare diseases, and the implications for the assessment of benefit, it is particularly important that the patient perspective is incorporated into the assessment process. Greater input would be helpful in understanding the burden of disease, interpreting novel endpoints and the magnitude of benefit, and understanding the impact on quality of life. Patient involvement in determining evidence requirements post-launch and interpreting evolving data would be very valuable and might assist with optimising patient compliance with follow-up assessments.

While affordability is currently not an issue, future funding challenges for ATMPs in Germany relate to the ability of existing structures to allow sustainable reimbursement strategies for ATMPs, which in many cases require large one-time payments

Annuity payments have been recognised as being a potential solution to the problem of large upfront costs and uncertain long-term outcomes. While such arrangements are conceptually attractive, they face practical challenges. Clarification should be sought from sick funds and accounting standards bodies if the concern about annuity payments is a legal/regulatory constraint or institutional preference. If the former, further engagement with accounting bodies and government financial regulators may be necessary to understand the opportunity for exemptions for ATMPs or contractual structures that are compliant. If the latter, further dialogue is necessary with sick funds to help them appreciate the benefits of minimising health outcome uncertainty through risk-sharing contracts. In addition, it may be helpful to create standardised annuity contracts that can be used across sick funds to minimise institutional concern about these novel deal structures.

The distribution of patients requiring a high-cost ATMP and the ability of German patients to switch insurance raises some concerns amongst sick funds about the affordability of ATMPs in future. To mitigate against the risk of patient movement, a framework for risk-sharing could be proposed and utilised amongst a consortium of insurers, such has been done with CAR-T. Risk-sharing in the form of collectivisation, such as the use of ‘high-risk funds’, allows initial costs to be collectivised and insured. In this way, individuals’ freedom to choose their insurance company is not compromised, while at the same time the fund balances expenses and amortisation. In order to ensure access beyond an initial willing group of insurers, a standardised and expanded approach could be developed for individual ATMPs or groups of ATMPs.

To date, German patients have been able to travel to cross-border treatment centres to receive ATMPs that are not available in Germany. However, this access is funded by sick funds on a case-by-case basis meaning there is a risk of variable patient access to ATMPs. Currently the G-BA does not assess ATMPs provided outside of Germany through the AMNOG process. Were this to change it might provide assurances for sick funds on the benefit of the product regardless of its availability within Germany or in cross-border scenarios. Alternatively, developing guidelines for sick funds to standardise the approach to decisions on funding for cross border ATMPs would benefit patients and remove uncertainty over availability.

The interpretation of hospital exemption legislation in Germany may pose a challenge to patient access as it currently stands (although this issue tends to apply more to cell therapies), where treatments approved through the central authorisation process of the European Medicines Agency (EMA) may have to compete with products developed under the hospital exemption directive. To address this, internal guidance could be issued to treating centres on when treatments with Marketing Authorisation should supersede those developed under hospital exemption in order to protect the integrity of the regulatory and assessment processes of the EMA and the AMNOG process. As Germany are taking over the presidency of the European Council, there is the potential that clarification or amendments to the hospital exemption directive could be sought. Any amendment should provide clear direction on when treatments with Marketing Authorisation supersede treatments developed under hospital exemption.

Accessibility of treatments for patients in Germany is very good and poses only minor challenges to patient access. These primarily revolve around the issue that some potential aspects of ATMPs may lead to delays in access, such as the requirement for additional assessment if a novel procedure or diagnostic accompanies the ATMP. These delays could be mitigated with better clarity around assessment needs of a new product and stakeholder communication well in advance, which would allow for better preparation and streamlining of the complex process.

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