HTA and Affordability for Innovative Therapies in Germany, Perspectives on Advanced Therapy Medicinal Product (ATMP) Pathway

By Xcenda

The integration of new and innovative treatments into the healthcare system is a challenge for regulatory agencies, HTA authorities as well as the manufacturers. In this article, we present the path into the German market for new state of the art treatments, advanced therapy medicinal products (ATMPs). For these products, there are exceptions to the standard procedure to consider.


HTA and Affordability for Innovative Therapies in Germany: Perspectives on Advanced Therapy Medicinal Product (ATMP) Pathway

By: Ulrike Kuchenbecker, PhD, Mareike Konstanski, Corinna Templin, MPH

Updated September 4, 2020

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
Gene therapeutics
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
Strimvelis®a EMA (active) 05.26.2016 GlaxoSmithKline Yes
Yescarta® EMA (active)
08.23.2018 Kite Pharma EU Yes
Zynteglo® EMA (active)
05.29.2019 bluebird bio Yes
Somatic cell therapeutics
Alofisel® EMA (active) 03.23.2018 TiGenix Yes
Tumor vaccines
CIK-Cells PEI (active) 06.13.2014 German Red Cross, blood donation service in Baden-Wuerttemberg and Hesse No
Tissue-engineered products
BioSeed-C PEI (active)
06.04.2014  BioTissue Technologies 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) 
Gene therapeutics
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.

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