Advanced Therapeutic Medicinal Products Research Articles

Issues, Challenges and Opportunities for Economic Evaluations of Orphan Drugs in Rare Diseases: An Umbrella Review.

There are significant challenges when obtaining clinical and economic evidence for health technology assessments of rare diseases. Many of them have been highlighted in previous systematic reviews but they have not been summarised in a comprehensive manner. For all stakeholders working with rare diseases, it is important to be aware and understand these issues. The objective of this review is to identify the main challenges for the economic evaluation of orphan drugs in rare diseases. An umbrella review of systematic reviews of economic studies concerned with orphan and ultra-orphan drugs was conducted. Studies that were not systematic reviews, or on advanced therapeutic medicinal products, personalised medicines or other interventions that were not considered orphan drugs were excluded. The database searches included publications from 2010 to 2023, and were conducted in MEDLINE, EMBASE and the Cochrane library using filters for systematic reviews, and economic evaluations and models. These filters were combined with search terms for rare diseases and orphan drugs. A hand search supplemented the literature searches. The findings were reported by a compliant Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Two hundred and eighty-two records were identified from the literature searches, of which 64 were duplicates, whereas five reviews were identified from the hand search. A total of 36 reviews were included after screening against inclusion/exclusion criteria, 35 from literature searches and one from hand searching. Of those studies 1, 27 and 8 were low, moderate and high quality, respectively. The reviews highlight the scarcity of evidence for health economic parameters, for example, clinical effectiveness, costs, quality of life and the natural history of disease. Health economic evaluations such as cost-effectiveness and budget-impact analyses were scarce, and generally low-to-moderate quality. The causes were limited health economic parameters, together with publications bias, especially for cost-effectiveness analyses. The results highlighted issues around a considerable paucity of evidence for economic evaluations and few cost-effectiveness analyses, supporting the notion that a paucity of evidence makes economic evaluations of rare diseases more challenging compared with more prevalent diseases. Furthermore, we provide recommendations for more sustainable approaches in economic evaluations of rare diseases.

Validation of analytical methods for the production of expanded γδ T lymphocytes useful for therapeutic purposes

The use of γδ T lymphocytes as advanced therapeutic medicinal product has attracted much interest in the last years. Indeed, such cells are an ideal tool for the reconstitution of the immune system in patients receiving hematopoietic stem cell transplantation, due to their MHC-independent anti-tumor and anti-viral activities. We have here setup a protocol for the production of pure and functional γδ T lymphocytes, expanded from healthy donors’ mononuclear cells, and validated the analytical methods to identify them and to analyze their potency. Next, we performed stability studies to ensure that the cell product (γδ T cells) can be used after freezing and thawing. Notably, such protocol can be promptly translated to GMP-facility, since it has been designed using only clinical grade reagents.

A Flexible Digital Twin Framework for ATMP Production – Towards an efficient CAR T Cell Manufacturing

This paper presents a flexible digital twin framework tailored for the biomanufacturing of advanced therapeutic medicinal products (ATMPs), particularly focusing on chimeric antigen receptor T cell (CAR T cell) therapy. CAR T cell therapies face significant challenges in the management of their personalized and complex biomanufacturing processes. To tackle these issues, we propose a novel software framework for a digital twin system aimed at digitalizing, monitoring, and managing the physical production processes. The framework has a hierarchical architecture that methodically organizes production into distinct abstraction levels: processes, tasks and skills, and microservices. This layered architecture simplifies the modeling of complex biomanufacturing production and ensures that each component can be individually updated without disrupting the overall system. Furthermore, the digital twin framework integrates both manual and automated operations within a unified system, accommodating varied requirements of diverse tasks in production. The framework’s flexibility enables easier adaptation to dynamic technological advancements and allows for swift modifications in production processes, making it a sustainable and resilient digitalization infrastructure for ATMP manufacturing.

HPR65 Pricing and Reimbursement Mechanisms for Advanced Therapeutic Medicinal Products in 20 Countries

HPR65 Pricing and Reimbursement Mechanisms for Advanced Therapeutic Medicinal Products in 20 Countries

Redefining informed consent form in cell and gene therapy trials.

Informed consent is a foundation of the ethical conduct of research involving human participants. Based on the ethical principle of respect for persons, the goal of informed consent is to ensure that participants are aware of the risks and potential benefits and make a voluntary decision about participating in clinical trial research. The extraordinary scientific advances happening globally, have demonstrated the potential of regenerative therapies in transforming the health of the nation by providing a therapeutic option for diseases that were previously considered incurable. These therapies, which include cells and gene therapy (GT) labeled as Advanced Therapeutic Medicinal Products globally, have complex mechanisms of action. Owing to their highly personalized and intricate nature of these therapies, developing the latter often presents unique challenges above and beyond those encountered for small molecule drugs. We recently looked through some cell and GT clinical trials and realized the lacunae in the informed consent form (ICF) provided by the investigators. Especially in a country like India, where the general understanding and perception of patients is limited regarding clinical trials, it is felt that any lapses in the consent process may jeopardize the informed decision-making and safety of the participants and tarnish the reputation of India globally. The present article highlights the need for appropriate patient and public education on the various aspects of cell and gene therapies and aims to address all the elements of ICF in light of the challenges associated with these innovative therapies.

Recent Advancement in Ocular Drug Delivery System: A Systematic Review

Recent scientific and technological advancements have made ophthalmology a top priority for the study of therapeutic products, including the creation, preclinical testing, and clinical evaluation of novel medications, medical devices, and drug-medical device combinations. In order to decrease metabolism and elimination and increase residence time in ocular tissues and compartments, sustained-release drug delivery systems such as liposomes, micelles, nano-emulsions, nanoparticles with colloidal structures, and intraocular implants have been developed. Research is also being conducted in the area of cutting-edge medicines, including those based on gene or cell systems, both of which are considered high-risk products because to their intricate structures. Regarding the definition of drug (medicinal product) and recent changes in regulation, this article reviews recent advancements in ophthalmic drug, gene, and cellular delivery systems and related goods as well as breakthroughs in advanced therapeutic medicinal Products.

Chromatographic Purification of Viral Vectors for Gene Therapy Applications.

Chromatography has been a mainstay in the downstream processing and purification of biopharmaceutical medicines. Until now, this has largely involved the purification of protein products such as recombinant enzymes and monoclonal antibodies using large-scale column chromatography methods. The development of advanced therapeutic medicinal products (ATMP) is heralding in a new era of therapeutics for a range of indications. These new therapeutics use diverse substances ranging from live stem cell preparations to fragments of nucleic acid enclosed in a viral delivery system. With these new technologies come new challenges in their purification. In this chapter, the challenges faced in producing and purifying viral vectors capable of delivering life-altering gene therapy to the patient will be discussed. Current methods of chromatography capable of adaptation to meet these new challenges and advancements that may be needed to increase the purification capabilities for these new products will also be discussed.

The Evolving Landscape of Potency Assays.

There is a "goldilocks" aspect to potency assays. On the one hand, a comprehensive evaluation of the cell product with detailed quantitative measurement of the critical quality attribute/s of the desired biological activity is required. On the other hand, the potency assay benefits from simplification and lean approaches that avoid unnecessary complication and enhance robustness, to provide a reproducible and scalable product. There is a need to balance insightful knowledge of complex biological healing processes with straightforward manufacture of an advanced therapeutic medicinal product (ATMP) that can be administered in a trustworthy cost-effective manner. While earlier chapters within this book have highlighted numerous challenges facing the potency assay conundrum, this chapter offers a forward-looking perspective regarding the many recent advances concerning acellular products, cryopreservation, induced MSC, cell priming, nanotechnology, 3D culture, regulatory guidelines and evolving institutional roles, that are likely to facilitate potency assay development in the future.

Issues with Tissues: Trends in Tissue-Engineered Products in Clinical Trials in the European Union.

Tissue-engineered products (TEPs) consist of engineered cells or tissues produced to regenerate, repair, or replace a dysfunctional, diseased, or absent human tissue. TEPs make up <5% of all advanced therapeutic medicinal products (ATMPs) in clinical trials and received 5.1% of ATMP-designated funding in trials in the European Union (EU) in 2019, highlighting the relatively low proportion of TEPs being developed. The realization of TEPs being marketed has yet to be fulfilled, with few products being approved. Since 2009, 90 TEP-based clinical trials have been undertaken in the EU. Of these 90, 25 were Phase I/II trials, 35 were Phase II, 28 were Phase III, and two were Phase IV trials. This review provides an overview of TEPs in development, identifying musculoskeletal, cardiovascular, and skin/connective tissue disorders as the main therapeutic areas of interest. Commercial sponsors have funded most trials, and a significantly higher proportion of late-phase trials. Furthermore, this study has identified a shift toward the use of allogeneic cells in TEPs and increased activity in the proportion of early phase trials listed. This indicates a renewed interest in TEP development as sponsors adapt to the new regulation, with prospects of more TEP market authorization applications in the future. Impact Statement Tissue-engineered products (TEPs) consist of engineered cells or tissues produced to regenerate, repair, or replace a dysfunctional, diseased, or absent human tissue. This article evaluates the regulatory landscape of TEPs and identifies the trends in clinical trial activity in the European Union (EU) since the introduction of Regulation (EC) No 1394/2007. This article identifies trends in TEP development, highlighting the most active member states, commercial involvement, a shift toward the use of allogeneic cells and a renewed interest in TEP development in recent years.

Needle to needle robot-assisted manufacture of cell therapy products.

Advanced therapeutic medicinal products (ATMPs) have emerged as novel therapies for untreatable diseases, generating the need for large volumes of high‐quality, clinically‐compliant GMP cells to replace costly, high‐risk and limited scale manual expansion processes. We present the design of a fully automated, robot‐assisted platform incorporating the use of multiliter stirred tank bioreactors for scalable production of adherent human stem cells. The design addresses a needle‐to‐needle closed process incorporating automated bone marrow collection, cell isolation, expansion, and collection into cryovials for patient delivery. AUTOSTEM, a modular, adaptable, fully closed system ensures no direct operator interaction with biological material; all commands are performed through a graphic interface. Seeding of source material, process monitoring, feeding, sampling, harvesting and cryopreservation are automated within the closed platform, comprising two clean room levels enabling both open and closed processes. A bioprocess based on human MSCs expanded on microcarriers was used for proof of concept. Utilizing equivalent culture parameters, the AUTOSTEM robot‐assisted platform successfully performed cell expansion at the liter scale, generating results comparable to manual production, while maintaining cell quality postprocessing.

Advanced therapeutic medicinal products (ATMPs) in Ischemic Stroke; novel therapeutic modalities from financial perspective

Advanced therapeutic medicinal products (ATMPs) in Ischemic Stroke; novel therapeutic modalities from financial perspective

Can cell and gene therapies improve cognitive symptoms in Parkinson's disease?

Advanced therapeutic medicinal products (ATMPs), including cell and gene therapies, are in development for Parkinson's disease (PD). In many cases, the goal is to replace the lost dopamine (DA), which is anticipated to improve motor dysfunctions associated with DA loss. However, it is less clear the extent to which these therapeutic interventions may impact on the wide range of cognitive symptoms that manifest as the disease progresses. Although the accepted perception is that cognitive symptoms are predominately non-DAergic in origin, in this commentary, it is argued that several, specific cognitive processes, such as habit formation, working memory and reward processing, have been reported to be DA-dependent. Furthermore, there is evidence of DAergic medications modulating these behaviours in PD patients. Finally, the potential for cell and gene ATMPs to influence these symptoms is considered. It is concluded that DA replacement through ATMPs is likely to improve certain DA-dependent symptoms, but only sparse clinical data are currently available and the ability to precisely titrate DA transmission is likely to be complex.

Evolution of Mesenchymal Stem Cell Therapy as an Advanced Therapeutic Medicinal Product (ATMP)-An Indian Perspective.

Stem cells can be defined as the cells that have the capacity to both self-renew and give rise to differentiated cells. Under the right conditions and signals, depending on their origin and bio-plasticity, stem cells can differentiate into multiple cell lineages and develop into various mature cells. Stem cell therapy is a fast-developing branch of medicine that includes the most innovative regenerative therapies for the restoration of cell and tissue function in individuals with severe diseases. Stem cell research has resulted in the emergence of cell-based therapies for disorders that are resistant to conventional drugs and therapies, and they are considered under the category of an Advanced Therapeutic Medicinal Product (ATMP). The FDA and the European Medicines Agency (EMA) devised a new strategy in 2017 with the aim of unifying the standards for development of ATMPs such that it is easy to exchange information at the international level. In this review, we discuss the evolution of mesenchymal stem cell-based therapy as an ATMP in the global and Indian scenarios, along with the guidelines governing their usage and clinical application of these therapeutics.

Reported Challenges in Health Technology Assessment of Complex Health Technologies

ObjectivesWith complex health technologies entering the market, methods for health technology assessment (HTA) may require changes. This study aimed to identify challenges in HTA of complex health technologies. MethodsA survey was sent to European HTA organizations participating in European Network for HTA (EUnetHTA). The survey contained open questions and used predefined potentially complex health technologies and 7 case studies to identify types of complex health technologies and challenges faced during HTA. The survey was validated, tested for reliability by an expert panel, and pilot tested before dissemination. ResultsA total of 22 HTA organizations completed the survey (67%). Advanced therapeutic medicinal products (ATMPs) and histology-independent therapies were considered most challenging based on the predefined complex health technologies and case studies. For the case studies, more than half of the reported challenges were “methodological,” equal in relative effectiveness assessments as in cost-effectiveness assessments. Through the open questions, we found that most of these challenges actually rooted in data unavailability. Data were reported as “absent,” “insufficient,” “immature,” or “low quality” by 18 of 20 organizations (90%), in particular data on quality of life. Policy and organizational challenges and challenges because of societal or political pressure were reported by 8 (40%) and 4 organizations (20%), respectively. Modeling issues were reported least often (n = 2, 4%). ConclusionsMost challenges in HTA of complex health technologies root in data insufficiencies rather than in the complexity of health technologies itself. As the number of complex technologies grows, the urgency for new methods and policies to guide HTA decision making increases.

Comprehensive Study Identifies a Sensitive, Low-Risk, Closed-System Model for Detection of Fungal Contaminants in Cell and Gene Therapy Products.

The U.S. Food and Drug Administration (FDA) regulates manufacturing and testing of advanced therapeutic medicinal products (ATMPs) to ensure the safety of each product for human use. Gold-standard sterility testing (USP<71>) and alternative blood culture systems have major limitations for the detection of fungal contaminants. In this study, we evaluated the performance of iLYM (lactic acid-fermenting organisms, yeasts, and mold) medium (designed originally for the food and beverage industry) to assess its potential for use in the biopharmaceutical field for ATMP sterility testing. We conducted a parallel evaluation of four different test systems (USP<71>, BacT/Alert, Bactec, and Sabouraud dextrose agar [SDA] culture), three different bottle media formulations (iLYM, iFA Plus, and Myco/F Lytic), and two incubation temperatures (22.5°C and 32.5 to 35°C) using a diverse set of fungi (n = 51) isolated from NIH cleanroom environments and previous product contaminants. Additionally, we evaluated the effect of agitation versus delayed-entry static preincubation on test sensitivity and time to detection (TTD). Overall, delayed entry of bottles onto the BacT/Alert or Bactec instruments (with agitation) did not improve test performance. USP<71> and SDA culture continued to significantly outperform each automated culture condition alone. However, we show, for the first time, that a closed-system, dual-bottle combination of iLYM 22.5°C and iFA Plus 32.5°C can provide high fungal sensitivity, statistically comparable to USP<71>, when tested against a diverse range of environmental fungi. Our study fills a much-needed gap in biopharmaceutical testing and offers a favorable testing algorithm that maximizes bacterial and fungal test sensitivity while minimizing risk of product contamination associated with laboratory handling.

IPSC-Derived Organoids as Therapeutic Models in Regenerative Medicine and Oncology.

Progress made during the last decade in stem cell biology allows currently an unprecedented potential to translate these advances into the clinical applications and to shape the future of regenerative medicine. Organoid technology is amongst these major developments, derived from primary tissues or more recently, from induced pluripotent stem cells (iPSC). The use of iPSC technology offers the possibility of cancer modeling especially in hereditary cancers with germline oncogenic mutations. Similarly, it has the advantage to be amenable to genome editing with introduction of specific oncogenic alterations using CRISPR-mediated gene editing. In the field of regenerative medicine, iPSC-derived organoids hold promise for the generation of future advanced therapeutic medicinal products (ATMP) for organ repair. Finally, it appears that they can be of highly useful experimental tools to determine cell targets of SARS-Cov-2 infections allowing to test anti-Covid drugs. Thus, with the possibilities of genomic editing and the development of new protocols for differentiation toward functional tissues, it is expected that iPSC-derived organoid technology will represent also a therapeutic tool in all areas of medicine.

Bringing Advanced Therapies for Parkinson's Disease to the Clinic: An Analysis of Ethical Issues.

Advanced therapies for Parkinson’s disease (PD) constitute a broad range of treatments, each presenting specific ethical challenges. Some of these therapies are established and in clinical use, like device-aided therapies, and others, based on advanced therapeutic medicinal products (ATMPs), are still in early stage of clinical trials. This paper focuses on some common ethical issues arising in these two categories of advanced therapies, especially challenges arising when advanced therapies are proposed to PD patients in the form of advanced care, under a clinical trial, or, in case of ATMPs, under the “hospital exemption” rule. The ethical issues covered here relate mainly to ensuring informed consent in these different contexts, to the stakeholder role of patient’s non-professional caretakers, such as family, and to patient safety in treatments under “hospital exemption”. To illustrate the points discussed in connection with “hospital exemption” rule, the example of the EU has been chosen. This paper does not claim completeness of ethical issues raised by bringing advanced therapies for PD to the clinic, but rather presents examples of ethical challenges in this context.

Price and reimbursement of advanced therapeutic medicinal products in Europe: are assessment and appraisal diverging from expert recommendations?

BackgroundAdvanced therapy medicinal products (ATMPs) represent an important cornerstone for innovation in healthcare. However, uncertainty on the value, the high average cost per patient and their one-shot nature has raised a debate on their assessment and appraisal process for pricing and reimbursement (P&R) purposes. This debate led experts providing for recommendations on this topic. Our primary objective is to investigate the ATMPs P&R process in the main five European countries and to understand if this process is consistent with published P&R expert recommendations. We also investigated the current ATMP pipelines to understand if future ATMPs will create challenges for their P&R process.MethodsP&R framework for ATMPs in the European Major five (EU5) countries was investigated through a literature search on PubMed, institutional websites of National Health Authorities and grey literature. The ATMPs pipeline database was populated from a clinical trial database (clinicaltrials.gov), relying on inclusion and exclusion criteria retrieved from the literature.ResultsReimbursement status of ATMPs is different across the EU5 countries, with the exception of CAR-Ts which are reimbursed in all countries. Standard P&R process in place for other medicinal products is extended to ATMPs, with the exception of some cases in Germany. List prices, where available, are high and, tend to be aligned across countries. Outcome-based Managed Entry Agreements (MEAs) have been extensively used for ATMPs. Extra-funds for hospitals managing ATMPs were provided only in Germany and, as additional fund per episode, in France. The accreditation process of hospitals for ATMPs management was in most countries managed by the national authorities. As far as ATMPs pipeline is concerned, ATMPs in development are mostly targeting non-rare diseases.ConclusionsExpert recommendations for ATMPs P&R were partially applied: the role of outcome-based MEAs has increased and the selection process of the centres authorized to use these treatments has been enhanced; additional funding for ATMPs management to accredited centres has not been completely considered and annuity payment and broader perspective in cost considerations are far from being put in place. These recommendations should be considered for future P&R negotiations to pursue rational resource allocation and deal with budget constraints.

Defining a Regulatory Strategy for ATMP/Aerosol Delivery Device Combinations in the Treatment of Respiratory Disease.

Advanced Therapeutic Medicinal Products (ATMP) are a heterogenous group of investigational medicinal products at the forefront of innovative therapies with direct applicability in respiratory diseases. ATMPs include, but are not limited to, stem cells, their secretome, or extracellular vesicles, and each have shown some potential when delivered topically within the lung. This review focuses on that subset of ATMPs. One key mode of delivery that has enabling potential in ATMP validation is aerosol-mediated delivery. The selection of the most appropriate aerosol generator technology is influenced by several key factors, including formulation, patient type, patient intervention, and healthcare economics. The aerosol-mediated delivery of ATMPs has shown promise for the treatment of both chronic and acute respiratory disease in pre-clinical and clinical trials; however, in order for these ATMP device combinations to translate from the bench through to commercialization, they must meet the requirements set out by the various global regulatory bodies. In this review, we detail the potential for ATMP utility in the lungs and propose the nebulization of ATMPs as a viable route of administration in certain circumstances. Further, we provide insight to the current regulatory guidance for nascent ATMP device combination product development within the EU and US.

TRUST4RD: tool for reducing uncertainties in the evidence generation for specialised treatments for rare diseases

BackgroundMany treatments developed for rare diseases will have an Orphan Medicinal Product (OMP) designation, indicating that they are likely to deliver benefit in an area of high unmet need. Their approval may be based on a small or uncontrolled trial, as randomised controlled trials (RCTs) of sufficient size are often difficult to conduct, or repeat, as a result of the rarity of the condition, sparsity of patients, or for ethical reasons. Furthermore, many products are given a conditional marketing authorisation, requiring additional evidence to be collected after product launch. This is even more challenging with the advent of advanced therapeutic medicinal products, which use novel scientific approaches like gene or somatic cell therapy.IssueGiven the high unmet need associated with these products, there is pressure for Health Technology Assessment (HTA)/reimbursement bodies to enable rapid access to effective treatments. However, there is often only limited evidence available for assessment.MethodsTRUST4RD proposes an approach to identify uncertainties of most concern for decision-makers by developing an iterative and informed dialogue amongst stakeholders (including manufacturers, clinicians, patients, regulatory- and HTA agencies and payers), so that potential approaches to resolution can be discussed. As evidence is generated, uncertainties are reviewed and prioritised, and evidence-generation plans revised or clarified accordingly. The aim is to develop – both pre- and post HTA submission – a better understanding of evidence requirements versus evidence-generation trade-offs as an evidence base grows and the potential value of a product becomes clearer.ConclusionTRUST4RD presents guidance on defining uncertainties and evidence gaps in the assessment of value and value for money of specialised treatments for rare diseases. It also provides guidance on the potential of Real World Evidence (RWE) to help address such uncertainties, including the typology of evidence uncertainties, the importance of different uncertainties and the data sources available to address them before and after HTA submission. In making use of the guidance, authorisation and reimbursement discussions on such treatments can be embedded in an evidence-rich context, thereby ensuring value to all parties, particularly to patients.