HTA and Affordability for Innovative Therapies in Germany, Perspectives on Advanced Therapy Medicinal Product (ATMP) Pathway
HTA QUARTERLY | WINTER 2020
HTA and Affordability for Innovative Therapies in Germany: Perspectives on Advanced Therapy Medicinal Product (ATMP) Pathway
The Way to Market in Germany
Marketing authorization granted via the European Medicines Agency (EMA) centralized process or by the German regulatory agency—the Paul-Ehrlich-Institut (PEI)—is a mandatory condition for launch and reimbursement of an advanced therapy medicinal product (ATMP) in Germany. The pharmaceutical manufacturer can ask for guidance from EMA’s Committee for Advanced Therapies (CAT) on the classification of their product as an ATMP. The different types of ATMPs are gene therapy medicinal products, somatic cell therapy medicinal products, tumor vaccines, and tissue-engineered products. Pharmaceutical manufacturers can request an accelerated assessment procedure, which is decided on by CAT. If a conditional marketing authorization is granted, renewal applications have to be submitted yearly until regular market authorization is granted. Some ATMPs may also be eligible for the Priority Medicines (PRIME) scheme by EMA, where enhanced regulatory support is provided.
In Germany, all ATMPs, except tissue-engineered products, that are approved by EMA need to undergo the benefit assessment procedure according to Arzneimittelmarktneuordnungsgesetz (AMNOG) (§35a SGB V Paragraph 1b). For tissue-engineered products, the Federal Joint Committee (G-BA) first categorizes the ATMP either as a drug or a treatment method. If the ATMP has pharmacologic properties and the outcome of the therapy is generally not dependent on the skills of a healthcare professional, it is categorized as a drug. If the administration of the ATMP or the required skill set is complex and crucial for the treatment effect, the ATMP is categorized as a treatment method without a need to undergo the AMNOG assessment. Manufacturers can ask G-BA and PEI for advice regarding the categorization and subsequently the reimbursement prior to the benefit assessment.
Most of the tissue-engineered products and the tumor vaccine have been approved at the national level by PEI. For these ATMPs, special regulations exist for national authorization according to § 4b Medicines Law (Arzneimittelgesetz) in Germany; manufacturers must report if new data on efficacy and safety for assessment of the product become available. As well as the EMA, PEI can give a conditional approval if there is insufficient data to comprehensively assess the product. The maximum duration of the approval is determined by PEI for each case individually and can be revoked, if the conditions of the law are no longer met.
Nineteen ATMPs so far have been granted a marketing authorization, 9 of these are known to have an orphan status, 11 were approved by EMA, and 8 by PEI. Of these 19 ATMPs, 10 are tissue-engineered products, 7 are gene therapeutics, 1 is a somatic cell therapeutic, and 1 is a tumor vaccine.
For 2 ATMPs, the EMA approval has been withdrawn after marketing authorization (Table 1). The 2 chimeric antigen receptor T-cell (CAR-T) products—Kymriah® and Yescarta®—were the first ATMPs brought to market through EMA’s PRIME scheme.
Table 1: Overview of Authorization Details of the 19 ATMPs Approved in Germany (status August 2020)
|Brand name||Authorization Status||Authorization Date||Authorization Holder||Orphan Designation|
|Glybera®||EMA (withdrawn)||10.25.2012||uniQure biopharma||Yes|
|Imlygic®||EMA (active)||12.16.2015||Amgen Europe||No|
|Kymriah®||EMA (active)||08.23.2018||Novartis Europharm||Yes|
|Luxturna®||EMA (active)||11.22.2018||Spark Therapeutics Ireland||Yes|
||08.23.2018||Kite Pharma EU||Yes|
|Somatic cell therapeutics|
|CIK-Cells||PEI (active)||06.13.2014||German Red Cross, blood donation service in Baden-Wuerttemberg and Hesse||No|
|co.don chondrosphere||PEI (active)||12.12.2013||co.don AG, Teltow||No|
|Holoclar||EMA (active)||02.17.2015||Chiesi Farmaceutici||Yes|
|Obnitix||PEI (active)||08.24.2016||Medac Gesellschaft für klinische Spezialpräparate mbH||Yes|
|MACI||EMA (withdrawn)||06.27.2013||Genzyme Europe||No|
|MukoCell||PEI (active)||12.23.2013||MukoCell GmbH||No|
|NOVOCART 3D||PEI (active)||08.29.2014||TETEC AG||No|
|NOVOCART Inject||PEI (active)||06.27.2016||TETEC AG||No|
|Spherox||EMA (active)||07.10.2017||co.don AG, Teltow||No|
|t2c001||PEI (active)||03.31.2014||t2cure, Frankfurt||No|
|Key: ATMP – advanced therapy medicinal product; EMA – European Medicines Agency; PEI – Paul-Ehrlich-Institut.
a Strimvelis® is only applied in a hospital in Milan, Italy as the only approved manufacturing site is located there and shelf-life of the medicinal product is 6 hours.
Because tissue-engineered products and tumor vaccines have a unique status and only limited information is available, this section will focus on gene and somatic cell therapeutics to give an overview of the reimbursement situation for ATMPs in Germany.
Benefit Assessment According to the AMNOG Regulation
According to Social Law (§35a SGB V), G-BA assesses the medical added benefit of every newly authorized drug in the benefit dimensions mortality, morbidity, and health-related quality of life and weighs that information with available data on safety and/or side effects the new technology may have. The result of the benefit assessment, for which a manufacturer must submit a dossier with all relevant clinical data, serves as the basis for price negotiations between the manufacturer and the National Association of Statutory Health Insurance Funds (GKV-Spitzenverband). For non-orphan drugs, these data must show a comparison to an appropriate comparator that was previously set by the G-BA. For orphan drugs, the additional benefit is already set by law and the G-BA only decides on the extent or magnitude of the additional benefit. When, after launch, the moving annual total in sales of the assessed drug exceed 50 Mio Euro, the pharmaceutical company has to submit a new dossier with comparative clinical data.
The magnitude of the additional benefit is defined by the following categories: major, considerable, minor, non-quantifiable, no additional benefit, or less benefit. The number, quality, and characteristics of studies provided, the reliability of results, and the observed effects determine the G-BA grading of the submitted evidence (“proof,” “indication,” or “hint”).
Most of the approved ATMPs are orphan drugs and due to small patient population sizes and the oftentimes accelerated authorization, only limited evidence is available to determine the long-term value of these products. Many times, these circumstances are the reason for an additional benefit being categorized as “non-quantifiable” (Table 2). For Strimvelis, a benefit assessment was not performed even though a market authorization exists because the product is only available in Italy. To diminish the uncertainty regarding the clinical value due to the limited long-term efficacy and safety data, G-BA can set a fixed term for a mandatory reassessment usually in the range of 1 to 3 years, if additional clinical evidence is to be expected then. This was the case for the majority of ATMPs assessed so far. During this time, the manufacturer must collect further data to be able to submit new evidence for the reassessment by G-BA.
Table 2: Outcome of Benefit Assessments for ATMPs That Have Been Approved in Germany (August 2019)
|Brand Name||Indication||Orphan Status||No. of Patients
According to G-BA Assessment
|Start of AMNOG Procedure/
Date of Market Entry
|Result of AMNOG Assessment||Term Set by G-BA (duration)
|Glybera®||Familial lipoprotein lipase deficiency||Yes||-||11.01.2014||Not quantifiable||Yes (2.5 years after extension)|
|Imlygic®||Unresectable melanoma||No||375–670||06.15.2016||No additional benefit||No|
|Kymriah®||ALL, DLBCL (lymphoma)||Yes||440–700||09.15.2018||Not quantifiablea||Yes (1 year)|
|Luxturna®||Innate vision loss||Yes||189–290||04.15.2019||Considerable||Yes (2 years)|
|Yescarta®||DLBCL (lymphoma)||Yes||475–709||11.01.2018||Not quantifiable||Yes (3 years)|
|Zynteglo®||TDT||Yes||49–53||11.15.2019||Not quantifiable||Yes (5 years)|
|Somatic cell therapeutics|
|Alofisel®||Stem cell transplantation||Yes||90–230||06.01.2018||Not quantifiable||No|
Key: ALL – acute lymphocytic leukemia; AMNOG – Arzneimittelmarktneuordnungsgesetz; ATMP – advanced therapy medicinal product; DLBCL – diffuse large B-cell lymphoma; G-BA – Federal Joint Committee; TDT – transfusion-dependent β-thalassemia.
a Result of new G-BA middle of September 2020.
For both assessed CAR-T products, the benefit assessment was based on non-comparative, single-arm studies with a small number of participants. The additional benefit was rated as “non-quantifiable” and the G-BA has set a term for mandatory reassessment. Based on this, hospitals that want to use the products must meet specific requirements regarding their expertise in the indication of the drug, cell therapy, and existing special qualifications of treating healthcare professionals. Furthermore, the manufacturers are required to provide educational material for healthcare professionals and patients to inform them about side effects. According to a survey of the German Society for Haematology and Medical Oncology (Deutsche Gesellschaft für Hämatologie und medizinische Onkologie), 26 centers in Germany entered a contract with at least one of the CAR-T manufacturers as of May 2020.
Quality audits and monitoring activities by the manufacturer are required to ensure quality of manufacturing and administration. Patients treated with CAR-T cell therapy will be continuously monitored to collect data regarding previous treatments, adverse drug effects, time and duration of response to treatment, follow-up treatment, and overall survival. A post-authorization safety study was initiated as non-interventional regular follow-up until December 2038. These data will be collected by special registries: the German Registry for Stem Cell Transplantation, Paediatric Registry for Stem Cell Transplantation, or the registry of European Society for Blood and Marrow Transplantation.
Now regulated by the law effective August 2019 (Gesetz für mehr Sicherheit in der Arzneimittelversorgung), the G-BA is authorized to request the collection of additional post-authorization data by the pharmaceutical company. Documenting and reporting of adverse reactions that are not subject to approval, is going to be mandatory, which will create additional challenges for the manufacturers and product marketing.
Implications for Manufacturers
Pharmaceutical manufacturers should request guidance from authorities to determine whether their product must go through the AMNOG procedure or not. Furthermore, it is important to consider the possibility that the G-BA may request a collection of additional post-authorization data. In the case that additional data collection is planned by the manufacturer, it may be advisable to ask the G-BA for consultation. For strategic planning, it will be important for manufacturers to understand the outlook for ATMP pricing and reimbursement within Germany, and the negotiation process. This will be further explored in the next edition of HTA Quarterly.
The article should be referenced as follows:
Kuchenbecker U, Konstanski M, Templin C. HTA and affordability for innovative therapies in Germany, perspectives on advanced therapy medicinal product (ATMP) pathway. HTA Quarterly. Fall 2020. https://www.xcenda.com/insights/htaq-winter-2020-hta-affordability-innovative-therapies-germany
- Bundesministerium für Gesundheit. Mehr Sicherheit in der Arzneimittelversorgung 2019 https://www.bundesgesundheitsministerium.de/gsav.html.
- Cassel D, Ulrich V. AMNOG-Daten 2018 – Funktionsweise und Ergebnisse der Preisregulierung für neue Arzneimittel in Deutschland: Bundesverband der Pharmazeutischen Industrie e. V. (BPI). 2018. https://www.bpi.de/fileadmin/user_upload/Downloads/Publikationen/AMNOG-Daten/AMNOG-Daten-2018.pdf.
- Detela G, Lodge A. EU Regulatory Pathways for ATMPs: Standard, Accelerated and Adaptive Pathways to Marketing Authorisation. Mol Ther Methods Clin Dev. 2019;13:205-232.
- European Medicines Agency (EMA). Marketing-authorisation procedures for advanced-therapy medicinal products. 2020. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/marketing-authorisation-procedures-advanced-therapy-medicinal-products.
- EMA. Supporting medicine developers. 2020. https://www.ema.europa.eu/en/documents/leaflet/ema-supporting-medicines-development_en.pdf.
- EMA. Provenge® (autologous peripheral-blood mononuclear cells activated with prostatic acid phosphatase granulocyte-macrophage colony-stimulating factor [sipuleucel-T]). 2019. https://www.ema.europa.eu/en/medicines/human/EPAR/provenge.
- EMA. Kymriah® (tisagenlecleucel). 2019. https://www.ema.europa.eu/en/medicines/human/EPAR/kymriah#.
- EMA. Yescarta® (axicabtagene ciloleucel). 2019. https://www.ema.europa.eu/en/medicines/human/EPAR/yescarta.
- EMA. Human medicines highlights. 2018. https://www.ema.europa.eu/en/documents/report/human-medicines-highlights-2018_en.pdf.
- EMA. Guide to information on human medicines evaluated by EMA – What the Agency publishes and when. 2015. https://www.ema.europa.eu/en/documents/other/guide-information-human-medicines-evaluated-european-medicines-agency-what-agency-publishes-when_en.pdf.
- First two CAR-T cell medicines recommended for approval in the European Union [press release]. 06.29.2018. https://www.ema.europa.eu/en/news/first-two-car-t-cell-medicines-recommended-approval-european-union.
- Gemeinsamer Bundesausschuss. Tragende Gründe zum Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage XII – Beschlüsse über die Nutzenbewertung von Arzneimitteln mit neuen Wirkstoffen nach § 35a SGB V – Axicabtagen-Ciloleucel. 2019. https://www.g-ba.de/downloads/40-268-5741/2019-05-02_AM-RL-XII_Axicabtagen-Ciloleucel_D-406_D-416_TrG.pdf.
- Gemeinsamer Bundesausschuss. Tragende Gründe zum Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage XII – Beschlüsse über die Nutzenbewertung von Arzneimitteln mit neuen Wirkstoffen nach § 35a SGB V – Tisagenlecleucel (diffus großzelliges B-ZellLymphom). 2019. https://www.g-ba.de/downloads/40-268-5622/2019-03-07_AM-RL-XII_Tisagenlecleucel-DLBCL_D-375_TrG.pdf.
- Gemeinsamer Bundesausschuss. Verfahren der Nutzenbewertung nach § 35a SGB V. 2019. https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/.
- Gen-, Zell- und Gewebetherapie sollen der Nutzenbewertung unterliegen. Deutsches Ärzteblatt [Internet]. 2020. https://www.aerzteblatt.de/nachrichten/109232/Gen-Zell-und-Gewebetherapie-sollen-der-Nutzenbewertung-unterliegen.
- Greiner W, Witte J, Gensorowsky D, Storm A. AMNOG-Report 2019 – Nutzenbewertung von Arzneimitteln in Deutschland. Schwerpunkt: Höchstpreise für ein Mehr an Lebensqualität? 2019.
- Jørgensen J, Kefalas P. Reimbursement of licensed cell and gene therapies across the major European healthcare markets. J Mark Access Health Policy. 2015;3:10.3402/jmahp.v3.29321.
- National Institute for Health and Care Excellence. Strimvelis for treating adenosine deaminase deficiency–severe combined immunodeficiency. 2018. https://www.nice.org.uk/guidance/hst7/resources/strimvelis-for-treating-adenosine-deaminase-deficiencysevere-combined-immunodeficiency-pdf-1394905926085.
- Onkologie DGfHu. CAR-T-Zelltherapie – Qualitätsgesicherte Durchführung in Deutschland. 2020.
- Paul-Ehrlich-Institut (PEI). Arzneimittel für neuartige Therapien (ATMP). 2019. https://www.pei.de/DE/arzneimittel/atmp-arzneimittel-fuer-neuartige-therapien/atmp-arzneimittel-fuer-neuartige-therapien-node.html.
- PEI. Arzneimittel für neuartige Therapien (ATMP). 2012. Advanced Therapy Medicinal Products – Regulatorische Anforderungen und praktische Hinweise Langen.
- Theidel U, von der Schulenburg J-M. Benefit assessment in Germany: implications for price discounts. Health Econ. Rev. 2016;6(1).