Recent European Medicines Agency Research Articles

Gene therapy for neurotransmitter-related disorders.

Inborn errors of neurotransmitter (NT) metabolism are a group of rare, heterogenous diseases with predominant neurological features, such as movement disorders, autonomic dysfunction, and developmental delay. Clinical overlap with other disorders has led to delayed diagnosis and treatment, and some conditions are refractory to oral pharmacotherapies. Gene therapies have been developed and translated to clinics for paediatric inborn errors of metabolism, with 38 interventional clinical trials ongoing to date. Furthermore, efforts in restoring dopamine synthesis and neurotransmission through viral gene therapy have been developed for Parkinson's disease. Along with the recent European Medicines Agency (EMA)and Medicines and Healthcare Products Regulatory Agency (MHRA) approval of an AAV2 gene supplementation therapy for AADC deficiency, promising efficacy and safety profiles can be achieved in this group of diseases. In this review, we present preclinical and clinical advances to address NT-related diseases, and summarise potential challenges that require careful considerations for NT gene therapy studies.

Gene Therapy for Dopamine Dyshomeostasis: From Parkinson's to Primary Neurotransmitter Diseases.

Neurological disorders encompass a broad range of neurodegenerative and neurodevelopmental diseases that are complex and almost universally without disease modifying treatments. There is, therefore, significant unmet clinical need to develop novel therapeutic strategies for these patients. Viral gene therapies are a promising approach, where gene delivery is achieved through viral vectors such as adeno-associated virus and lentivirus. The clinical efficacy of such gene therapies has already been observed in two neurological disorders of pediatric onset; for spinal muscular atrophy and aromatic L-amino acid decarboxylase (AADC) deficiency, gene therapy has significantly modified the natural history of disease in these life-limiting neurological disorders. Here, we review recent advances in gene therapy, focused on the targeted delivery of dopaminergic genes for Parkinson's disease and the primary neurotransmitter disorders, AADC deficiency and dopamine transporter deficiency syndrome (DTDS). Although recent European Medicines Agency and Medicines and Healthcare products Regulatory Agency approval of Upstaza (eladocagene exuparvovec) signifies an important landmark, numerous challenges remain. Future research will need to focus on defining the optimal therapeutic window for clinical intervention, better understanding of the duration of therapeutic efficacy, and improved brain targeting. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Access to Non-Summary Clinical Trial Data for Research Purposes Under EU Law

As indicated by the title and further explained in the Preface, the thesis explores if and under what conditions access to clinical trial data is granted and should be granted as a matter of research and innovation policy. Access to non-summary clinical trial data has been discussed in recent years, primarily from the perspective of data protection law and research ethics. Daria Kim’s thesis strives to provide a complementary view which conceptualizes clinical trial data as output of and input for innovative processes in medical and pharmacological R&D. Access to clinical trial data in the EU is highly topical for several reasons. First, EU data policy has recently shifted from the concept of exclusively held, proprietary industry data to an access paradigm which seeks to boost the European digital economy by access rights. The proposal for a European Data Act and the Digital Markets Act are the most prominent instruments. The thesis contributes to this more general discussion with a sector-specific exploration. Second, the COVID-19 pandemic has led to an unprecedented public awareness of the mechanisms of innovative processes in the pharmaceutical industry and the role of clinical trials for the success or failure of treatments and vaccines. This raises the question of whether access to clinical trial data may facilitate such innovative processes. Third, EU Regulation 536/2014 on clinical trials on medicinal products for human use and the recent European Medicines Agency (EMA) transparency policies represent a departure from the confidential treatment of non-summary clinical trial data which is still pursued by the US authorities and other regulatory bodies. This European approach of greater transparency has not yet been analyzed from an innovation policy perspective. Daria Kim’s thesis is therefore very well positioned at the crossroads of different legal and policy discourses.

What is the weight of expectation bias in oncology trials?

What is the weight of expectation bias in oncology trials?

Highlights on Medical Treatment of Uterine Fibroids.

Uterine fibroids (leiomyomas or myomas) are the most frequent benign tumors in women. Heavy menstrual bleeding with resultant anemia, dysmenorrhea, chronic pelvic pain, infertility, urinary symptoms and constipation are generally associated with uterine fibroids (UFs). Although strategies mainly resort to surgical intervention, medical treatments are considered the first-line treatment to preserve fertility and avoid surgery. The aim of this review is to offer available and the newest medical treatment options for symptomatic UFs. Various medical therapies are now available for women with uterine fibroids, although each therapy has its own advantages and disadvantages. Our topic specifically explores gonadotropin-releasing hormone (GnRH) analogs and selective progesterone receptor modulators (SPRMs), but also provides the reader with useful advice on the therapies for fibroids available after the recent European Medicines Agency (EMA) warning (EMA/160220/2020). The treatment options depend on the personal treatment objectives of the patients, in addition to treatment effectiveness and necessity for recurrent interventions.

IQN path ASBL report from the first European cfDNA consensus meeting: expert opinion on the minimal requirements for clinical ctDNA testing

Liquid biopsy testing is a new laboratory-based method that detects tumour mutations in circulating free DNA (cfDNA) derived from minimally invasive blood sampling techniques. Recognising the significance for clinical testing, in 2017, IQN Path provided external quality assessment for liquid biopsy testing. Representatives of those participating laboratories were invited to attend a workshop to discuss the findings and how to achieve quality implementation of cfDNA testing in the clinical setting, the discussion and outcomes of this consensus meeting are described below. Predictive molecular profiling using tumour tissue in order to select cancer patients eligible for targeted therapy is now routine in diagnostic pathology. If insufficient tumour tissue material is available, in some circumstances, recent European Medicines Agency (EMA) guidance recommends mutation testing with plasma cfDNA. Clinical applications of cfDNA include treatment selection based on clinically relevant mutations derived from pre-treatment samples and the detection of resistant mutations upon progression of the disease. In order to identify tumour-related mutations in amongst other nucleic acid material found in plasma samples, highly sensitive laboratory methods are needed. In the workshop, we discussed the variable approaches taken with regard to cfDNA extraction methods, the tests, and considered the impact of false-negative test results. We explored the lack of standardisation of complex testing procedures ranging from plasma collection, transport, processing and storage, cfDNA extraction, and mutation analysis, to interpretation and reporting of results. We will also address the current status of clinical validation and clinical utility, and its use in current diagnosis. This workshop revealed a need for guidelines on with standardised procedures for clinical cfDNA testing and reporting, and a requirement for cfDNA-based external quality assessment programs.

OP136 Provision Of A Chimeric Antigen Receptor T-Cell Program: A Rapid Review

IntroductionThe recent European Medicines Agency (EMA) approval of chimeric antigen receptor (CAR) T-cell therapies, axicabtagene ciloleucel and tisagenlecleucel, means the imminent arrival of health technology assessment (HTA) submissions to HTA agencies. HTA requires identification of all resources and organizational impacts pertaining to an intervention. Rapid review is a form of knowledge synthesis that abbreviates certain methodological aspects of systematic reviews to produce information in a timelier manner. Considering the time-sensitive nature of CAR T-cell HTAs, the aim of this research was to conduct a rapid review to identify the institutional requirements for the provision of a CAR T-cell program.MethodsA Rapid Review protocol was developed and registered in PROSPERO. Electronic databases, EMBASE and MEDLINE, and grey literature were searched. All study designs published in English after the year 2000 were included. Studies pertained to the use of CAR T-cells in adult and pediatric patients with solid and hematological malignancies. No restrictions were placed on the comparators or study setting. Primary outcomes were organized into two categories: (i) resource use, (ii) processes relating to implementation of CAR T-cell programs. Secondary outcomes included associated costs of implementation and barriers to successful implementation. Screening, review, and extraction of relevant data was conducted by a single reviewer. Extracted data included publication details, population and setting, study characteristics, outcomes and outcome measures, and strengths and limitations of research. Data was synthesized by means of thematic analysis.ResultsResults indicate that the provision of a CAR T-cell program in Ireland will require the establishment of bespoke infrastructural support. This includes additional outpatient facilities, ICU resources, and nursing capacity. Close relationships will need to be formed between hematology, ICU and neurology.ConclusionsThe findings of this Rapid Review will inform the assessment of organizational impacts associated with the introduction of a CAR T-cell program, ensuring a robust HTA assessment.

How much information about the benefits of medicines is included in patient leaflets in the European Union? - A survey.

Patient information leaflets (PILs) are required with all licensed medicines throughout the European Union (EU) and they must include information about all side effects and their likelihood. This has led to criticism of a lack of balance, with little information included about potential benefits. Recent European Medicines Agency guidance proposed the inclusion of benefit information, and this study examined the current prevalence and type of such information in PILs in the EU. A survey and content analysis of the English translation of PILs in the EUwas carried out. Random quota sampling was used on the most frequently dispensed (n = 50) and newly licensed medicines (n = 50) in 2011/2. Leaflets were searched for benefit information meeting predefined criteria, and data synthesised and categorised into 10 categories. Eighty-five (85%) leaflets described how the medicine works, with 45 providing information about the rationale for treatment (more commonly for newly licensed (32/50) than most commonly dispensed medicines (13/50; P < 0.001). Nearly half (47) did not describe whether the medicine was curative, symptomatic or preventative. The terms used to communicate uncertainty were imprecise (such as 'may help'). None communicated numerical benefit information. Current PILs do not appropriately communicate information about benefit. At the basic level, around a half did not include information about treatment rationale or whether the treatment was to treat symptoms, curative or preventative. However, for true informed decision making, patients need quantitative information about benefits and none of the leaflets provided this.

Contribution of metabolites to P450 inhibition-based drug-drug interactions: scholarship from the drug metabolism leadership group of the innovation and quality consortium metabolite group.

Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ≥ 25% of the parent and ≥ 10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is low. Only metabolites from 5 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R(met) strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic.

Time to Second Objective Disease Progression (PFS2): An Emerging Clinical Trial Endpoint with Regulatory and Reimbursement Implications

Introduction: Overall survival (OS) continues to be the preferred endpoint for measuring sustained clinical benefits in oncology trials. In some cases, measuring OS can be problematical due to trial design, multiple lines of treatment (Tx), long survival times, and other factors. In this context, there is growing interest in the time to second objective disease progression (PFS2) for Txs with good toxicity profiles.The European Medicines Agency (EMA) recommends the use of PFS2 to help understand the relevance of meaningful improvements in PFS when OS cannot be measured (e.g. maintenance Tx, increased number of “induction” cycles) (EMA, 2012). PFS2 is defined as “time from randomisation to objective tumour progression on next-line treatment or death from any cause. In some cases, time on next-line therapy may be used as proxy for PFS.”PFS2 is likely to become an important endpoint for regulatory and reimbursement evaluations in Europe and elsewhere as a result of the recent EMA guidance. Therefore there is a need to optimally understand the role PFS2 is likely to play in clinical trial results and their application.Methods: We undertook a search on clinicaltrials.gov for cancer trials that include PFS2 as an endpoint (search terms: cancer AND PFS; cancer AND PFS2). Through mapping of drugs vs. other endpoints, stage of development, likely or current indications, and other factors, we considered whether PFS2 would have a role in a potentially new or changed indication and therefore in regulatory and health technology assessment (HTA) submissions. Based on this, we have identified critical areas where understanding and use of PFS2 data may pose challenges in the submission processes, from the perspectives of the clinical trial sponsor and regulatory agency.Results: As of July 2014, a total of 7,957 cancer trials list PFS as an endpoint; 14 of these include PFS2. In all cases, PFS2 is listed as a secondary endpoint. PFS is the primary endpoint in 13/14, with time to failure as the primary endpoint in 1 trial. OS is not a primary endpoint in any trial that lists PFS2, but is a secondary endpoint in 13 of the 14 trials. It is being studied in the context of either maintenance (10/14 trials) or sequential Tx (3/14) and has the potential for inclusion in regulatory and HTA submissions in all cases.The types of oncology trials in which PFS2 is being assessed included multiple myeloma (n = 3), prostate cancer (n = 2), breast cancer (n = 2), head and neck cancer (n = 1), colorectal cancer (n = 4), non-small cell lung cancer (n = 1), and pancreatic cancer (n = 1). There are 6 phase 2 and 8 phase 3 trials that are listed as either not yet recruiting (n = 4), ongoing (n = 4), or recruiting (n = 6).We identified a number of issues for key groups that may arise from the inclusion of PFS2 in clinical trials. For healthcare professionals there is a need to understand the clinical relevance of a new endpoint that may provide additional and complementary information on Tx of progressive disease from both medical and patient (pt) perspectives. For trial sponsors, clear and clinically relevant communication of PFS2 results is needed and data must be included in medical and economic models. Agencies evaluating regulatory or HTA submissions must understand the benefits shown by an improved PFS2, whether or not there is an improvement in OS, and methodologies for evaluating the medical and economic value of PFS2 are required.Restricting our search to clinicaltrials.gov was associated with some limitations. For example, some trials in which PFS2 has been measured could have been missed due to ongoing updates to publically available information. Also, in some cases, post-hoc analyses may have evaluated PFS2 without a change to website details. Trials in which PFS2 has been measured and data published were not part of the search strategy.Conclusions: PFS2 is emerging as a secondary endpoint in a growing number of clinical oncology trials assessing the benefits of maintenance or sequential Tx. Although data are currently limited, the results of trials currently listed on clinicaltrials.gov will help to determine how PFS2 provides additional and complementary information about Tx of progressive disease from both medical and pt perspectives. DisclosuresMbanya:PHMR Associates: Consultancy. Chadda:PHMR Associates: Consultancy.

Summary report of PQRI Workshop on Nanomaterial in Drug Products: current experience and management of potential risks.

At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations. Areas where additional regulatory guidance and material characterization standards would help in the development and approval of nanomedicines were explored. Representatives from the US Food and Drug Administration (USFDA), Health Canada, and European Medicines Agency (EMA) presented information about the diversity of nanomaterials in approved and newly developed drug products. USFDA, Health Canada, and EMA regulators discussed the applicability of current regulatory policies in presentations and open discussion. Information contained in several of the recent EMA reflection papers was discussed in detail, along with their scope and intent to enhance scientific understanding about disposition, efficacy, and safety of nanomaterials introduced in vivo and regulatory requirements for testing and market authorization. Opportunities for interaction with regulatory agencies during the lifecycle of nanomedicines were also addressed at the meeting. This is a summary of the workshop presentations and discussions, including considerations for future regulatory guidance on drug products containing nanomaterials.

European Medicines Agency initiatives and perspectives on pharmacogenomics

Pharmacogenomics, the study of variations of DNA and RNA characteristics as related to drug response, has become an integral part of drug development and pharmacovigilance, as reflected by the incorporation of pharmacogenomic data in EU product information. In this short review article, we describe recent European Medicines Agency initiatives intended to support further the implementation of pharmacogenomics in drug development and surveillance so that patients and the public can benefit from advances in genomic science and technology.

Iron sucrose nanoparticles: Effects on tissue iron levels and hepatic gene expression in the rat

www.citoxlab.com IntroductIon In the present study we have examined iron biodistribution and hepatic gene expression following administration of two iron sucrose preparations to rats; Iron Sucrose Azad (ISA), a generic iron sucrose product and Venofer®, a reference iron sucrose product. The biodistribution study was undertaken to address the requirement of the recent European Medicines Agency (EMA) Reflection Paper (1) that comparative data from non clinical studies on the kinetics of iron biodistribution in major target organs should be presented in support of claims of essential similarity for injectable iron sucrose preparations. We have also evaluated the potential hepatic toxicity of these preparations using a gene expression approach.

Next-Generation Nanomedicines and Nanosimilars: EU Regulators’ Initiatives Relating to The Development and Evaluation of Nanomedicines

Over the last three decades many first-generation nanomedicines have successfully entered routine clinical use and it is now important for medicines regulatory agencies to consider the mechanisms needed to ensure safe introduction of 'follow-on' nanomedicine products, 'nanosimilars'. Moreover, drug regulators need to ensure that 'next'-generation nanomedicines enter clinical development and consequently the market in a safe and timely way for the benefit of public health. Here we review recent European Medicines Agency activities that relate to the effective development and evaluation of nanomedicine products while keeping patient and consumer safety at the forefront.

Modafinil for excessive daytime sleepiness in myotonic dystrophy type 1 – The patients’ perspective

Excessive daytime sleepiness (EDS), of very similar pattern to that seen in narcolepsy syndrome, is extremely common in myotonic dystrophy type 1 (DM1). In a significant minority it has a profound disabling effect on employment, social functioning and activities of daily living. Limited published studies have shown inconsistent results from use of the psychostimulant drug modafinil. A recent European Medicines Agency (EMA) review concluded that on current evidence regarding safety and efficacy, modafinil’s use should be restricted to the treatment of narcolepsy. In other conditions (although DM1 was not specifically considered) it was concluded that there was insufficient evidence of benefit to outweigh potentially serious side-effects, including severe skin reactions and cardiac arrhythmia. Clinicians with extensive experience in the management of DM1 have found modafinil to be extremely effective in appropriately selected patients with a very low incidence of serious side-effects. Given the recent EMA review, patients have expressed concern about the potential restriction of the use of modafinil in DM1. This brief review is an audit of the experience of a large group of patients and their clinicians concerning EDS and DM1 and concludes that despite the limited literature there is strong evidence to support the use of modafinil in carefully selected patients.

The ‘stage-by-stage’ deposition of drugs from commercial single-active and combination dry powder inhaler formulations

Inhalation of salmeterol xinafoate (SX) and fluticasone propionate (FP) from a combination product is reported to produce superior clinical outcomes in comparison to the concurrent administration of ‘similar’ doses via separate single-active inhalers. For bioequivalence determination across different products, emphasis is currently placed on the assessment of drug deposition within inertial impactors on a ‘stage-by-stage’ basis as stipulated in a recent European Medicines Agency guidance. The aim of this study was to compare the stage-by-stage deposition of drugs aerosolised from the single-active Accuhaler® products Serevent® (SX) and Flixotide® (FP) with the SX–FP combination product Seretide® Accuhaler® in vitro. Drug deposition on a stage-by-stage basis was assessed using the next generation impactor (NGI). Significant differences in drug deposition profiles were obtained following aerosolisation from the single-active versus combination products. The concurrent administration of the two single-active products: Serevent® and Flixotide® Accuhaler® may not be bioequivalent to inhalation of the combination product Seretide® Accuhaler®. The observed differences may have resulted from different characteristics of the active pharmaceutical ingredient (APIs) and the carrier alpha-lactose monohydrate between the single-active and combination inhalers and/or a change in the drug-carrier inter-particulate interaction as a consequence of the presence of a second active.