Advanced therapy medicinal product manufacturing under the hospital exemption and other exemption pathways in seven European Union countries

Abstract

Background aims: As part of the advanced therapy medicinal product (ATMP) regulation, the hospital exemption (HE) was enacted to accommodate manufacturing of custom-made ATMPs for treatment purposes in the European Union (EU). However, how the HE pathway has been used in practice is largely unknown. Methods: Using a survey and interviews, we provide the product characteristics, scale and motivation for ATMP manufacturing under HE and other, non-ATMP-specific exemption pathways in seven European countries. Results: Results show that ATMPs were manufactured under HE by public facilities located in Finland, Germany, Italy and the Netherlands, which enabled availability of a modest number of ATMPs (n = 12) between 2009 and 2017. These ATMPs were shown to have close proximity to clinical practice, and manufacturing was primarily motivated by clinical needs and clinical experience. Public facilities used HE when patients could not obtain treatment in ongoing or future trials. Regulatory aspects motivated (Finland, Italy, the Netherlands) or limited (Belgium, Germany) HE utilization, whereas financial resources generally limited HE utilization by public facilities. Public facilities manufactured other ATMPs (n = 11) under named patient use (NPU) between 2015 and 2017 and used NPU in a similar fashion as HE. The scale of manufacturing under HE over 9 years was shown to be rather limited in comparison to manufacturing under NPU over 3 years. In Germany, ATMPs were mainly manufactured by facilities of private companies under HE. Conclusions: The HE enables availability of ATMPs with close proximity to clinical practice. Yet in some countries, HE provisions limit utilization, whereas commercial developments could be undermined by private HE licenses in Germany. Transparency through a public EU-wide registry and guidance for distinguishing between ATMPs that are or are not commercially viable as well as public-private engagements are needed to optimize the use of the HE pathway and regulatory pathways for commercial development in a complementary fashion.

Re-Envisioning Pharmaceutical Manufacturing: Increasing Agility for Global Patient Access

“…To operationalize EMA's strategic goals towards advanced manufacturing techniques, a revised guidance document was published in January 2021, which goes into effect in June 2021, to provide advice for assessing quality aspects of medicinal products containing genetically modified cells [100]. For personalized therapies, the EU uses a variety of point-of-care regulation pathways that help to support advanced therapy medicinal products (ATMP) that rely on patient specificity, including hospital exemption, named patient use, and compassionate use [101]. In particular, the hospital exemption (HE) regulation allows prescribing medical institutions to manufacture ATMPs at the point-of-care, outside of the clinical trial setting [101,102].…”

“…For personalized therapies, the EU uses a variety of point-of-care regulation pathways that help to support advanced therapy medicinal products (ATMP) that rely on patient specificity, including hospital exemption, named patient use, and compassionate use [101]. In particular, the hospital exemption (HE) regulation allows prescribing medical institutions to manufacture ATMPs at the point-of-care, outside of the clinical trial setting [101,102]. The HE regulation is, in theory, a critical pathway to help enable decentralized, bedside production of complex therapies.…”

“…The HE regulation is, in theory, a critical pathway to help enable decentralized, bedside production of complex therapies. However, there are few examples of HE's real-world usage due to financial limitations and lack of experience with requisite regulations and manufacturing techniques [101].…”

Reinforcing Collaboration and Harmonization to Unlock the Potentials of Advanced Therapy Medical Products: Future Efforts Are Awaited From Manufacturers and Decision-Makers

“…However, interpreting the definition (e.g., non-routine use) and the qualification criteria for HE rules varied significantly across different Member States. Some required that clinical data must be submitted prior to a HE license, while some others may grant it in the absence of any preclinical or clinical data ( 61 ). Such inconsistencies in the regulations of HE were scrutinized for jeopardizing the stringency of centralized market authorization and creating unfair competition for manufacturers of ATMPs, who made substantial investments in conducting clinical trials and addressing regulatory challenges ( 3 ).…”

“…Therefore, better harmonization of the HE regulation across the EU is urgently needed. This could be achieved by issuing EU-wide regulatory guidelines to outline the minimal quality, preclinical, and clinical data that are required for the grant of HE license ( 61 ).…”