Marketing Regulatory Oversight of Advanced Therapy Medicinal Products in Europe.

Advanced therapy medicinal products (ATMP) in the European Union (EU) are regulated by Regulation 1394/2007 and comprise gene and cell therapy and tissue-engineered products. Under this framework, ATMP are authorised by the centralised procedure, coordinated by the European Medicines Agency (EMA), whereas clinical trial authorisations remain at the remit of each National Competent Authority. The Committee for Advanced Therapies is responsible for the scientific evaluation of the marketing authorisation applications and for generating a draft opinion that goes to the Committee for Human Medicinal Products for a final opinion. For every application, data and information relating to manufacturing processes and quality control of the active substance and final product have to be submitted for assessment together with data from non-clinical and clinical safety and efficacy studies. Technical requirements for ATMP are defined in the legislation, and guidance for different products is available through several EMA/CAT guidelines.Due to the diverse and complex nature of ATMP, a need for some regulatory flexibility was recognised. Thus, a risk-based approach was introduced in Regulation 1394/2007 allowing adapted regulatory requirements. This has led, for instance, to the development of good manufacturing practice (GMP) guidelines specific for ATMP. This, together with enhanced regulatory support, has allowed an increasing number of successful marketing authorisation applications resulting in 25 licensed ATMP in the EU, mainly gene therapy medicinal products. The promise of messenger RNA and genome editing technologies as therapeutic tools make the future for these innovative medicinal products look even brighter.This chapter reviews the regulatory landscape together with some of the support initiatives developed for ATMP in the EU.

European Conditional Marketing Authorization in a Rapidly Evolving Treatment Landscape: A Comprehensive Study of Anticancer Medicinal Products in 2006-2020.

Since 2006, the European conditional marketing authorization (CMA) aims to facilitate timely patient access to medicinal products for which there is an unmet medical need by accepting less comprehensive data than normally required. The granting of CMA requires a positive benefit-risk balance, unmet medical needs to be fulfilled, likely submission of comprehensive data postauthorization, and the benefit of immediate availability to outweigh the risks of data noncomprehensiveness. Since its first use, more than half of all CMAs represent (hemato-)oncology indications. Therefore, we aimed to investigate the conditions in which CMA has been applied for anticancer medicinal products and whether they have changed over time. We retrospectively assessed the European public assessment reports of the 30 anticancer medicinal products granted CMA in 2006-2020 (51% of all 59 CMAs). Comparison of 2006-2013 to 2014-2020 highlighted increased proportions of proactively requested CMAs (+40%), medicinal products that addressed unmet medical needs by providing a major therapeutic advantage over authorized treatments (+38%), and orphan designated indications (+32%). In contrast, it showed decreased proportions of medicinal products for which a scientific advisory group was consulted (-55%) and phase III randomized controlled trial data were available (-38%). This suggests that applicants and the European Medicines Agency have learned how to use the CMA as a regulatory tool, among others, through better planning and proactive interaction. However, the increasing number of granted CMAs complicates the establishment of unmet medical need and the benefit-risk balance, especially in crowded indications and when only phase II uncontrolled trials are available.

Options for imaging cellular therapeutics in vivo: a multi-stakeholder perspective.

Cell-based therapies have been making great advances toward clinical reality. Despite the increase in trial activity, few therapies have successfully navigated late-phase clinical trials and received market authorization. One possible explanation for this is that additional tools and technologies to enable their development have only recently become available. To support the safety evaluation of cell therapies, the Health and Environmental Sciences Institute Cell Therapy-Tracking, Circulation and Safety Committee, a multisector collaborative committee, polled the attendees of the 2017 International Society for Cell & Gene Therapy conference in London, UK, to understand the gaps and needs that cell therapy developers have encountered regarding safety evaluations in vivo. The goal of the survey was to collect information to inform stakeholders of areas of interest that can help ensure the safe use of cellular therapeutics in the clinic. This review is a response to the cellular imaging interests of those respondents. The authors offer a brief overview of available technologies and then highlight the areas of interest from the survey by describing how imaging technologies can meet those needs. The areas of interest include imaging of cells over time, sensitivity of imaging modalities, ability to quantify cells, imaging cellular survival and differentiation and safety concerns around adding imaging agents to cellular therapy protocols. The Health and Environmental Sciences Institute Cell Therapy-Tracking, Circulation and Safety Committee believes that the ability to understand therapeutic cell fate is vital for determining and understanding cell therapy efficacy and safety and offers this review to aid in those needs. An aim of this article is to share the available imaging technologies with the cell therapy community to demonstrate how these technologies can accomplish unmet needs throughout the translational process and strengthen the understanding of cellular therapeutics.

Mining scientific advice reports on cell-based products: Insight into the nonclinical development program.

AIMS: The field of cell-based therapies for human diseases is currently evolving from promising treatment options to established therapeutic concepts. The design of the nonclinical development program for cell-based products, intended to provide a rationale for treatment and to gain insight into the safety profile, is challenging because of limitations caused by species-specificity. The elements of the nonclinical package for cell-based products were evaluated using advice reports from the European Medicines Agency database from 2013 to 2018 to identify the approach followed for nonclinical development of these products. METHODS: The number and purpose of proposed and performed in vivo studies was recorded, as well as the type and design of in vitro and in vivo studies addressing biodistribution and tumorigenicity. Subsequently, the nonclinical development program was analysed for consistency across products. RESULTS: In vivo studies for cell-based therapies were primarily aimed at proof-of-concept (75/86), followed by addressing safety (64/86), biodistribution (49/86) and tumourigenicity (46/86). No animal studies were performed or proposed by sponsors or regulators for 6/86 products which contained cell types that have been studied in humans for a relatively long time. For one-third of the products in vivo biodistribution and/or tumourigenicity studies were not considered necessary. in vivo tumourigenicity studies were regarded as having limited value. CONCLUSIONS: Compared to more conventional medicinal products, the nonclinical development program for cell-based products was more tailored and focused on proof-of-concept. For tumourigenicity an in vitro approach may suffice. Total omission of in vivo studies appears to be possible for products with sufficient clinical experience.

Dawn of Monitoring Regulatory T Cells in (Pre-)clinical Studies: Their Relevance Is Slowly Recognised.

Regulatory T cells (Tregs) have a prominent role in the control of immune homeostasis. Pharmacological impact on their activity or balance with effector T cells could contribute to (impaired) clinical responses or adverse events. Monitoring treatment-related effects on T cell subsets may therefore be part of (pre-)clinical studies for medicinal products. However, the extent of immune monitoring performed in studies for marketing authorisation and the degree of correspondence with data available in the public domain is not known. We evaluated the presence of T cell immunomonitoring in 46 registration dossiers of monoclonal antibodies indicated for immune-related disorders and published scientific papers. We found that the depth of Treg analysis in registration dossiers was rather small. Nevertheless, data on treatment-related Treg effects are available in public academia-driven studies (post-registration) and suggest that Tregs may act as a biomarker for clinical responses. However, public data are fragmented and obtained with heterogeneity of experimental approaches from a diversity of species and tissues. To reveal the potential added value of T cell (and particular Treg) evaluation in (pre-)clinical studies, more cell-specific data should be acquired, at least for medicinal products with an immunomodulatory mechanism. Therefore, extensive analysis of T cell subset contribution to clinical responses and the relevance of treatment-induced changes in their levels is needed. Preferably, industry and academia should work together to obtain these data in a standardised manner and to enrich our knowledge about T cell activity in disease pathogenesis and therapies. This will ultimately elucidate the necessity of T cell subset monitoring in the therapeutic benefit-risk assessment.

EMA Recommendation for the Pediatric Indications of Plerixafor (Mozobil) to Enhance Mobilization of Hematopoietic Stem Cells for Collection and Subsequent Autologous Transplantation in Children with Lymphoma or Malignant Solid Tumors.

On March 28, 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion recommending the marketing authorization for the medicinal product plerixafor. The marketing authorization holder for this medicinal product is Genzyme Europe B.Th. The adoption was for an extension of the existing adult indication in combination with granulocyte colony-stimulating factor (G-CSF) to pediatric patients (aged 1 year to <18 years) to enhance mobilization of hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in children with lymphoma or solid malignant tumors. This treatment is indicated either preemptively, when circulating stem cell count on the predicted day of collection after adequate mobilization with G-CSF (with or without chemotherapy) is expected to be insufficient with regard to desired hematopoietic stem cells yield, or in children who previously failed to collect sufficient hematopoietic stem cells. The efficacy and safety of plerixafor were evaluated in an open label, multicenter, phase I/II, dose-ranging, and randomized controlled study (DFI12860) in pediatric patients with solid tumors, including neuroblastoma, sarcoma, Ewing sarcoma, or lymphoma, who were eligible for autologous hematopoietic stem cell transplantation. Forty-five patients (aged 1 year to <18 years) were randomized, 2:1, using 0.24 mg/kg of plerixafor plus standard mobilization (G-CSF with or without chemotherapy) versus control (standard mobilization alone). The primary analysis showed that 80% of patients in the plerixafor arm experienced at least a doubling of the peripheral blood (PB) CD34+ count, observed from the morning of the day preceding the first planned apheresis to the morning prior to apheresis, versus 28.6% of patients in the control arm (p = .0019). The median increase in PB CD34+ cell counts from baseline to the day of apheresis was 3.2-fold in the plerixafor arm versus by 1.4-fold in the control arm. The observed safety profile in the pediatric population was consistent with that in adults, with adverse events mainly related to injection site reactions, hypokalemia, and increased blood bicarbonate. Importantly, plerixafor exposure did not seem to negatively affect transplant efficiency. This article summarizes the scientific review of the application leading to regulatory approval in the European Union. IMPLICATIONS FOR PRACTICE: This review of the marketing authorization of plerixafor will raise awareness of pediatric indication granted for this medicinal product.

European Medicines Agency review of midostaurin (Rydapt) for the treatment of adult patients with acute myeloid leukaemia and systemic mastocytosis.

On 18 September 2017, a marketing authorisation valid through the European Union (EU) was issued for midostaurin in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy and for patients in complete response followed by midostaurin single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are Fms-like tyrosine kinase 3 mutation positive and as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN) or mast cell leukaemia (MCL). The recommended dose of midostaurin is 50 mg orally twice daily for AML and 100 mg orally twice daily for ASM, SM-AHN and MCL. Midostaurin was evaluated in two pivotal studies. Study A2301 (RATIFY) included 717 patients with AML. Overall survival (OS) was statistically significantly different between the two groups, and the median OS was 74.7 months in the midostaurin+daunorubicin+cytarabine group and 25.6 months in the placebo+daunorubicin+cytarabine group (HR 0.774; 95% CI 0.629 to 0.953; p=0.0078). Study D2201 included 116 patients with ASM, SM-AHN or MCL. An overall response rate, by IWG-MRT/ECNM (international working group - myelofibrosis research and treatment/European competence network on mastocytosis) criteria of 28.3% was observed in all patients and 60.0%, 20.8% and 33.3% in patients with ASM, SM-AHN and MCL respectively. The most common adverse drug reactions (ADRs) with midostaurin treatment in AML were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae and fever. In ASM, SM-AHN, MCL the most common ADRs were nausea, vomiting, diarrhoea, peripheral oedema and fatigue. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the EU.

Development of cell therapy medicinal products by academic institutes.

In the rapidly evolving fields of cellular immunotherapy, gene therapy and regenerative medicine, a wide range of promising cell therapy medicinal products are in clinical development. Most products originate from academic research and are explored in early exploratory clinical trials. However, the success rate toward approval for regular patient care is disappointingly low. In this paper, we define strengths and hurdles applying to the development of cell therapy medicinal products in academic institutes, and analyze why only a few promising cell therapies have reached late-stage clinical development. Subsequently, we provide recommendations to stakeholders involved in development of cell therapies to exploit their potential clinical benefit.

Risk factors in the development of stem cell therapy.

Stem cell therapy holds the promise to treat degenerative diseases, cancer and repair of damaged tissues for which there are currently no or limited therapeutic options. The potential of stem cell therapies has long been recognised and the creation of induced pluripotent stem cells (iPSC) has boosted the stem cell field leading to increasing development and scientific knowledge. Despite the clinical potential of stem cell based medicinal products there are also potential and unanticipated risks. These risks deserve a thorough discussion within the perspective of current scientific knowledge and experience. Evaluation of potential risks should be a prerequisite step before clinical use of stem cell based medicinal products.The risk profile of stem cell based medicinal products depends on many risk factors, which include the type of stem cells, their differentiation status and proliferation capacity, the route of administration, the intended location, in vitro culture and/or other manipulation steps, irreversibility of treatment, need/possibility for concurrent tissue regeneration in case of irreversible tissue loss, and long-term survival of engrafted cells. Together these factors determine the risk profile associated with a stem cell based medicinal product. The identified risks (i.e. risks identified in clinical experience) or potential/theoretical risks (i.e. risks observed in animal studies) include tumour formation, unwanted immune responses and the transmission of adventitious agents.Currently, there is no clinical experience with pluripotent stem cells (i.e. embryonal stem cells and iPSC). Based on their characteristics of unlimited self-renewal and high proliferation rate the risks associated with a product containing these cells (e.g. risk on tumour formation) are considered high, if not perceived to be unacceptable. In contrast, the vast majority of small-sized clinical trials conducted with mesenchymal stem/stromal cells (MSC) in regenerative medicine applications has not reported major health concerns, suggesting that MSC therapies could be relatively safe. However, in some clinical trials serious adverse events have been reported, which emphasizes the need for additional knowledge, particularly with regard to biological mechanisms and long term safety.

New adjuvanted vaccines in pregnancy: what is known about their safety?

The recent introduction of oil-in-water emulsions as adjuvants in several pandemic vaccines, such as the H1N1 vaccine, has challenged regulatory authorities to establish their safety in the general population, as well as in specific populations. Pregnant women were advised to be a target group for H1N1 vaccination owing to the risk of this group developing serious complications with this infection. However, the addition of adjuvants to the H1N1 vaccine has initiated a discussion on the safety of adjuvanted vaccines in this special population. Changes in the maternal immune system are essential for acceptance of the fetus and for development of the placenta. The potential effects on pregnancy of interfering with this uniquely adapted immune balance through the induction of proinflammatory reactions such as those induced by adjuvanted vaccines have only been studied rarely. Here, we review the available information and discuss how vaccination may interfere with pregnancy, fetal development and pregnancy outcomes.

Animal models in influenza vaccine testing.

The threat of a pandemic outbreak of influenza A H5N1 and H2N2 has brought attention to the development of new vaccines. Regulatory authorities require companies to provide data proving the effectiveness of vaccines, which cannot, however, be based on real efficacy data in humans. A weight-of-evidence approach may be used, based on evidence of protection in an appropriate animal model and the satisfaction of the surrogate end points in the clinical situation. In this review, we will discuss various animal species that can be infected with influenza. The main animals used for testing vaccines destined for human use are laboratory mice and ferrets and, to a lesser extent, macaques. We will focus particularly on these species.

Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy.

Radiotherapy is one of the most successful cancer therapies. Here the effect of irradiation on antigen presentation by MHC class I molecules was studied. Cell surface expression of MHC class I molecules was increased for many days in a radiation dose-dependent manner as a consequence of three responses. Initially, enhanced degradation of existing proteins occurred which resulted in an increased intracellular peptide pool. Subsequently, enhanced translation due to activation of the mammalian target of rapamycin pathway resulted in increased peptide production, antigen presentation, as well as cytotoxic T lymphocyte recognition of irradiated cells. In addition, novel proteins were made in response to gamma-irradiation, resulting in new peptides presented by MHC class I molecules, which were recognized by cytotoxic T cells. We show that immunotherapy is successful in eradicating a murine colon adenocarcinoma only when preceded by radiotherapy of the tumor tissue. Our findings indicate that directed radiotherapy can improve the efficacy of tumor immunotherapy.

Cutting edge: HLA-B27 acquires many N-terminal dibasic peptides: coupling cytosolic peptide stability to antigen presentation.

Ag presentation by MHC class I is a highly inefficient process because cytosolic peptidases destroy most peptides after proteasomal generation. Various mechanisms shape the MHC class I peptidome. We define a new one: intracellular peptide stability. Peptides with two N-terminal basic amino acids are more stable than other peptides. Such peptides should be overrepresented in the peptidome of MHC class I-associated peptides. HLA-B27 binding peptides use anchor residue R at P2 and, although most amino acids are allowed, particular amino acids are overrepresented at P1, including R and K. We show that such N-terminal dibasic peptides are indeed more efficiently presented by HLA-B27. This suggests that HLA-B27 can present peptides from Ags present in fewer copies than required for successful peptide generation for other MHC class I molecules.

MHC class I alleles and their exploration of the antigen-processing machinery.

At the cell surface, major histocompatibility complex (MHC) class I molecules present fragments of intracellular antigens to the immune system. This is the end result of a cascade of events initiated by multiple steps of proteolysis. Only a small part of the fragments escapes degradation by interacting with the peptide transporter associated with antigen presentation and is translocated into the endoplasmic reticulum lumen for binding to MHC class I molecules. Subsequently, these newly formed complexes can be transported to the plasma membrane for presentation. Every step in this process confers specificity and determines the ultimate result: presentation of only few fragments from a given antigen. Here, we introduce the players in the antigen processing and presentation cascade and describe their specificity and allelic variation. We highlight MHC class I alleles, which are not only different in sequence but also use different aspects of the antigen presentation pathway to their advantage: peptide acquaintance.

Cross-presentation by intercellular peptide transfer through gap junctions.

Major histocompatibility complex (MHC) class I molecules present peptides that are derived from endogenous proteins. These antigens can also be transferred to professional antigen-presenting cells in a process called cross-presentation, which precedes initiation of a proper T-cell response; but exactly how they do this is unclear. We tested whether peptides can be transferred directly from the cytoplasm of one cell into the cytoplasm of its neighbour through gap junctions. Here we show that peptides with a relative molecular mass of up to approximately 1,800 diffuse intercellularly through gap junctions unless a three-dimensional structure is imposed. This intercellular peptide transfer causes cytotoxic T-cell recognition of adjacent, innocent bystander cells as well as activated monocytes. Gap-junction-mediated peptide transfer is restricted to a few coupling cells owing to the high cytosolic peptidase activity. We present a mechanism of antigen acquisition for cross-presentation that couples the antigen presentation system of two adjacent cells and is lost in most tumours: gap-junction-mediated intercellular peptide coupling for presentation by bystander MHC class I molecules and transfer to professional antigen presenting cells for cross-priming.

A major role for TPPII in trimming proteasomal degradation products for MHC class I antigen presentation.

Intracellular proteins are degraded by the proteasome, and resulting peptides surviving cytoplasmic peptidase activity can be presented by MHC class I molecules. Here, we show that intracellular aminopeptidases degrade peptides within seconds, almost irrespectively of amino acid sequence. N- but not C-terminal extension increases the half-life of peptides until they are 15 amino acids long. Beyond 15 amino acids, peptides are exclusively trimmed by the peptidase TPPII, which displays both exo- and endopeptidase activity. Surprisingly, most proteasomal degradation products are handled by TPPII before presentation by MHC class I molecules. We define three distinct proteolytic activities during antigen processing in vivo. Proteasome-generated peptides relevant for antigen presentation are mostly 15 amino acids or longer. These require TPPII activity for further trimming before becoming substrates for other peptidases and MHC class I. The heterogeneous pool of aminopeptidases will process TPPII products into MHC class I peptides and beyond.

Vigorous but short-term gamma interferon T-cell responses against a dominant HLA-A*02-restricted measles virus epitope in patients with measles.

The absolute and relative abundance of major histocompatibility complex class I-presented viral epitopes is important in the induction and maintenance of antiviral cytotoxic-T-lymphocyte (CTL) responses. We demonstrate that the supra-abundant HLA-A*0201-restricted peptide KLWESPQEI of the measles virus nonstructural C protein induces strong gamma interferon CD8(+)-T-cell responses in children with acute measles. However, longitudinal analysis indicates that these responses are only short-lived. Thus, some viral epitopes that can be immunodominant during primary infection may fail to establish memory CTL responses.