Read the following attached article and answer the following four questions:
· Discuss how clinical development plays a role in reimbursement of gene therapies
· Discuss how regulatory requirements play a role in reimbursement of gene therapies
· Provide your opinion on if and how reimbursement of gene therapies should be provided.
· What process would you design to determine if a gene therapy should be reimbursed?
Market access of gene therapies across Europe, USA, and Canada: challenges, trends, and solutions Q4 Q5 Q6 Re vi ew s � K EY N O TE R EV IE W Drug Discovery Today �Volume 00, Number 00 �November 2020 REVIEWS Teaser This review can inform gene therapy developers on challenges that can be encountered when seeking market access. Moreover, it provides an overview of trends among challenges and potential solutions. Market access of gene therapies across Europe, USA, and Canada: challenges, trends, and solutions Eline van Overbeeke1, Sissel Michelsen1,2, Mondher Toumi3, Hilde Stevens4, Mark Trusheim5, Isabelle Huys1,z and Steven Simoens1,z 1Clinical Pharmacology and Pharmacotherapy, University of Leuven, Herestraat 49 Box 521, 3000 Leuven, Belgium 2Healthcare Management Centre, Vlerick Business School, Reep 1, 9000 Ghent, Belgium 3 Public Health Department, Aix Marseille University, 27 bd Jean Moulin, Marseille, France 4 Institute for Interdisciplinary Innovation in Healthcare (I3h), Université libre de Bruxelles, Route de Lennik 808, Brussels, Belgium 5Massachusetts Institute of Technology, 100 Main Street, Cambridge, MA 02139, USA A limited number of gene therapy medicinal products (GTMPs) have received marketing authorization (MA), of which some have been withdrawn, and even less have gained reimbursement. Many challenges that complicate GTMP market access can occur across multiple jurisdictions and decision-making contexts, but some reimbursement challenges are specific to jurisdictions. The importance of these challenges vary according to the specific therapy being developed, the country where market access is sought, and the efforts made by developers, regulators and payers to implement solutions to overcome these barriers. This review could alert developers to challenges associated with GTMP MA and how to address them. Introduction Gene therapies are innovative therapies that can result in permanent improvement of patients’ lives and might, for certain diseases, even provide a cure. An overlap in the definitions of gene ther apies and genetically engineered cell therapies is observed in literature [1–3]. Moreover, the European regulation (EC) No 1394/200 states that products that may fall under both definitions of somatic cell therapy medicinal product (sCTMP) or tissue-engineered products (TEP) and GTMP (see Glossary) shall be considered as GTMP in Europe. Therefore, the term ‘GTMP’ is also used here to refer to all types of gene therapies and genetically engineered cell therapies (see Glossary). GTMPs aim to address the cause of a disease by correcting the genetic material in the disease-causing cells of the patient, altering the genetic material of other autologous cells to counter-act the activities of the disease-causing cells (e.g., chimeric antigen receptor T cells; Eline van Overbeeke is a PhD student at the University of Leuven (Belgium), and has worked on the Patient Preferences in Benefit-Risk Assessments during the Drug Life Cycle (PREFER) project of the Innovative Medicines Initiative (IMI) since October 2016. During her PhD and the PREFER project, she led research that investigated preferences of patients regarding gene therapies. Given that market access of gene therapies is complex, Eline considers it important that solutions are developed in collaboration with all stakeholders, including the patient. Sissel Michelsen was awarded an MSc in biomedical sciences from the University of Leuven (Belgium). Since receiving a grant from the Research Foundation – Flanders (FWO), she has been a PhD student at the University of Leuven and Vlerick Business School, focusing on value-driven market access to gene therapies. As part of her PhD, she is investigating the implementation of novel payment structures, such as outcome-based spread payments, to mitigate unaffordability of gene therapies and the use of a value assessment framework suitable for the potential curative yet uncertain characteristics of gene therapies. Please cite this article in press as: van, E. et al. Market access of gene therapies across Europe, USA, and Canada: challenges, trends, and solutions, Drug Discov Today (2020), https://doi. org/10.1016/j.drudis.2020.11.024 Corresponding author: van Overbeeke, E. ([email protected]) z Joint last author. 1359-6446/ã 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). https://doi.org/10.1016/j.drudis.2020.11.024 www.drugdiscoverytoday.com 1 https://doi.org/10.1016/j.drudis.2020.11.024 https://doi.org/10.1016/j.drudis.2020.11.024 mailto:[email protected] http://creativecommons.org/licenses/by/4.0/ https://doi.org/10.1016/j.drudis.2020.11.024 C a d fr le w E P c fo t t If E C D T E is A fr a o t p li R DRUDIS 2857 1–17 2 Review s �K EY N O TE R EV IEW AR-T), or by providing allogeneic cells to counter-act the ctivities of the disease-causing cells. GTMPs are mainly being eveloped for cancers and monogenic rare disorders [4]. As regulators became aware that existing drug assessment ameworks might not fully address the characteristics and chal- nges of these complex novel therapies, specific approval path- ays for the regulatory evaluation of GTMPs were established. In urope, GTMPs are classified as Advanced Therapy Medicinal roducts (ATMPs), for which MA must be obtained through the entralized procedure. The evaluation of these products is per- rmed at the European Medicines Agency (EMA) by the Commit- ee for Advanced Therapies (CAT), which provides a draft opinion o the Committee for Medicinal Products for Human Use (CHMP). the CHMP adopts a positive opinion, MA is granted by the uropean Commission (EC) [5]. In the USA, GTMPs are called ellular and Gene Therapy Products and are regulated under the ivision of Cellular and Gene Therapies (DCGT) of the Office of issues and Advanced Therapies (OTAT) at the Center for Biologics valuation and Research (CBER) of the US Food and Drug Admin- tration (FDA) [2,6]. In addition, the Tissue and Gene Therapies dvisory Committee (CTGTAC) can provide the FDA with advice om external experts. In Canada, the Biologics and Genetic Ther- pies Directorate of Health Canada is responsible for the regulation f GTMPs. A ‘regulatory sandbox’ has been created in Canada for he regulatory review of advanced therapeutic products to evaluate In contrast to the novel pathways that are put in place by regulators to ensure appropriate assessments of these novel thera- pies, most health technology assessment (HTA) bodies and payers have not adapted distinct assessment pathways for GTMPs [3]. In Europe, HTA is usually performed and payer decisions are reached at the national level by the Member States. Although efforts have been made to align assessments across European countries (e.g., EUnetHTA core model), criteria and techniques used to assess therapies and processes to ensure access still vary widely, as do payer decisions as a result. In the USA, no specific governmental institute performs centralized HTAs. US payers include ten federal government programs*, 50 state employee plans, numerous private health insurers, and employers with self-insured employer plans. These payers internally decide on reimbursement (i.e., coverage) decisions through Pharmacy and Therapeutics (P&T) committees and economic negotiations; in this process, some payers consider recommendations from the Institute for Clinical and Economic Review (ICER), which has specifically adapted its methods for these products [8,9]. All US payers have to organize reimbursement separately and coordina- tion among private payers is prohibited by anti-trust law. Al- though US private health insurers are obliged to reimburse medically necessary FDA-approved therapies, including GTMPs, self-insured plans regulated under the Federal ERISA law have more freedom to define benefits and might not reimburse GTMPs. In Canada, HTA is conducted by two organizations: at the federal level by the Canadian Agency for Drugs and Technologies in Health (CADTH), and by the Institut National d’Excellence en Santé et Services Sociaux (INESSS) for the region of Quebec. By contrast, reimbursement decisions are made by the 19 different payers representing the ten provinces and three territories, and six federal programsy [10]. To date, nine GTMPs have received MA in Europe, five in the USA, and two in Canada (Table 1). However, these GTMPs have gained reimbursement in few countries and two (Glybera1 and Zalmoxis1) have since been withdrawn from the market. Chal- lenges to obtaining market access (covering both MA and reim- bursement) and meeting postmarketing requirements to maintain conditional MA are likely to have contributed to the withdrawal of these products [11,12]. Furthermore, the limited number of au- thorized GTMPs and lack of reimbursement might indicate the existence of barriers. Previous research has focused on explaining some of these challenges in-depth. However, in this systematic review (the methods of which are described in File I in supple- mental information online), we identify and discuss challenges that can be encountered when GTMP developers try to gain market access in Europe, the USA, and Canada. Moreover, we describe trends among main challenges, and potential solutions. Challenges We identified 95 publications reporting on challenges in gaining market access for GTMPs (File II in supplemental information online). Data extraction from these publications resulted in the identification of 30 challenges (Table 2). For the purpose of this research, a challenge was defined as any issue originating from quality, clinical, and health economic studies and evidence, or EVIEWS Drug Discovery Today �Volume 00, Number 00 �November 2020 GLOSSARY Allogeneic cells cells derived from another person’s body (donor). Autologous cells cells derived from the patient’s own body. Chimeric antigen receptor T cells (CAR-T) genetically engineered T cells that can produce an artificial T cell receptor that can be used in onco-immunotherapy. Discounting mathematical procedure that calculates the current value of future costs and the health outcomes related to a product. Gene therapy medicinal product (GTMPs) a biological medicinal product that has the following characteristics: (a) contains an active substance that contains or comprises a recombinant nucleic acid used in or administered to humans with a view to regulating, repairing, replacing, adding, or deleting a genetic sequence; (b) its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence. Gene therapy medicinal products do not include vaccines against infectious diseases (Directive 2001/83/EC). Good Clinical Practices (GCP) international ethical and scientific quality standard for the conduct of clinical trials in humans. Good Manufacturing Practices (GMP) international quality standard for the manufacturing of products in a consistent and controlled manner. Health technology assessment (HTA) process that systematically compiles the medical, social, and economic evidence as well as ethical issues related to the use of a health technology. roducts in collaboration with healthcare stakeholders and estab- sh new regulatory pathways [7]. Please cite this article in press as: van, E. et al. Market access of gene therapies across Europe org/10.1016/j.drudis.2020.11.024 www.drugdiscoverytoday.com from assessment practices, procedures, and the organization of healthcare that can affect evaluations of GTMPs by regulators, , USA, and Canada: challenges, trends, and solutions, Drug Discov Today (2020), https://doi. https://doi.org/10.1016/j.drudis.2020.11.024 https://doi.org/10.1016/j.drudis.2020.11.024 DRUDIS 2857 1–17 Q1 Re vi ew s � K EY