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The European Medicines Agency adopted their Geriatric Medicines Strategy more than a decade ago. The strategy aims at elucidating the evidence basis for marketing authorization of new medicines which will be used in the older population, and at ensuring the appropriate communication of findings to the patient and healthcare provider. During the past decade new tools and data sources have emerged to support the strategy goals, and their use should be considered. Possible concrete actions are presented to improve the design of clinical trials, the data collection both pre‐ and post‐approval, the assessment of the findings, and the communication to assist informed prescription and safe medicine taking. Implementation and prioritization of these actions should be done from the perspective of addressing the needs of patients while maximizing efficient use of resources, with the aim of integrating geriatric aspects into routine medicines development and assessment. [ABSTRACT FROM AUTHOR]

The article discusses the European Geriatric Medicine Society's (EuGMS) view on improving drug evaluation in older patients as of September 2024. Topics covered include guidance on evaluating patients' frailty and morbidity status, the challenge of older subjects' heterogeneity in determining medication, and concerns on the choice of outcomes for them. Also noted is the need to consider outcomes that matter most to older people.

The present study was aimed at preparing stable dry adsorbed nanoparticles (DANs) of olanzapine (OLZ) loaded solid lipid nanoparticles (SLNs) for sustained release. OLZ SLNs were prepared by hot melt emulsification and ultrasonication using Precirol ATO 5 (PRE) as a solid lipid, combination of Kolliphor ELP (KELP) and Tween 80 (T80) as surfactants, after optimising formulation and process variables. The SLN system was subjected to evaluation of particle size, zeta potential, entrapment efficiency (EE), in-vitro drug release and ex-vivo intestinal permeability studies using the chicken intestinal segments (jejunum). Further, these SLNs were converted into stable DANs by adsorbing onto a Neusilin US2 (NUS2) and Avicel CL 611 (ACL) carriers using the granulation-evaporative drying method. The DANs were characterised for redispersion properties, in-vitro drug release, thermal behaviour, crystallinity, and morphology. The SLN and DAN had a particle size of 238.0 nm [0.274 polydispersity index (PdI)] and 302.4 [0.494 PdI] respectively. The zeta potentials of SLN and DAN were found to be −29.3 mV and −26.3 mV, respectively. The SLN had 67% EE, and showed a sustained drug release in various media. The highest permeability of SLNs was observed in ex-vivo permeation model compared to the OLZ suspension, indicating that SLNs have the potential to bypass hepatic metabolism. The adsorption of SLNs onto carriers was confirmed by surface morphology. The DAN had good flow properties and sustained drug release similar to that of SLNs. The X-ray diffraction (XRD) patterns and endothermic peaks confirmed the complete encapsulation of actives in lipid matrices. The encapsulating of OLZ in SLNs and converting it into DAN showed a sustained release and adsorption technique that can be used for improving the stability of NLC dispersion. The DANs can be offered in dosage forms such as filling into sachets, capsules and compressed into tablets. [ABSTRACT FROM AUTHOR]

Digital health technology (DHT) is increasingly used to facilitate the conduct of clinical drug trials. The European regulatory environment would benefit from some adjustments to realize the full potential of DHTs. Considering current discussions such as the European Accelerating Clinical Trial Initiative (ACT EU), we propose four concrete adjustments to this regulatory landscape to introduce risk-based qualification approaches for DHTs. In our view, these changes would have the potential to facilitate the use of DHT in clinical research and thus provide access to innovative therapies in Europe. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), breast cancer (BC) and prostate cancer (PC) continue to be high in the research and innovation agenda of the European Commission (EC). This is due to their exceptionally large burden to the national health systems, the profound economic effects of opportunity costs attributable to decreased working ability, premature mortality and the ever-increasing demand for both hospital and home-based medical care. Over the last two decades, the EC has been steadily increasing both the number of proposals being funded and the amounts of financial resources being allocated to these fields of research. This trend has continued throughout four consecutive science funding cycles, namely framework programme (FP)5, FP6, FP7 and Horizon 2020 (H2020). We performed a retrospective assessment of the outputs and outcomes of EC funding in AD, BC and PC research over the 1999–2019 period by means of selected indicators. These indicators were assessed for their ability to screen the past, present and future for an array of causal relationships and long-term trends in clinical, epidemiological and public health sphere, while considering also the broader socioeconomic impact of funded research on the society at large. This analysis shows that public–private partnerships with large industry and university-based consortia have led to some of the most impactful proposals being funded over the analysed time period. New pharmaceuticals, small molecules and monoclonal antibodies alike, along with screening and prevention, have been the most prominent sources of innovation in BC and PC, extending patients' survival and enhancing their quality of life. Unlike oncology, dementia drug development has been way less successful, with only minor improvements related to the quality of supportive medical care for symptoms and more sensitive diagnostics, without any ground-breaking disease-modifying treatment(s). Significant progresses in imaging diagnostics and nanotechnology have been largely driven by the participation of medical device industry multinational companies. Clinical trials funded by the EC were conducted, leading to the development of brand-new drug molecules featuring novel mechanisms of action. Some prominent cases of breakthrough discoveries serve as evidence for the European capability to generate cutting-edge technological innovation in biomedicine. Less productive areas of research may be reconsidered as priorities when shaping the new agenda for forthcoming science funding programmes. [ABSTRACT FROM AUTHOR]

Aim: This Phase I study evaluated the safety and early efficacy of an aldosterone synthase inhibitor (BI 690517) in people with diabetes and albuminuric chronic kidney disease. Methods: Double‐blind, placebo‐controlled study (NCT03165240) at 40 sites across Europe. Eligible participants [estimated glomerular filtration rate ≥20 and <75 ml/min/1.73 m2; urine albumin/creatinine ratio (UACR) ≥200 and <3500 mg/g] were randomized 6:1 to receive once‐daily oral BI 690517 3, 10 or 40 mg, or eplerenone 25‐50 mg, or placebo, for 28 days. The primary endpoint was the proportion of participants with drug‐related adverse events (AEs). Secondary endpoints included changes from baseline in the UACR. Results: Fifty‐eight participants were randomized and treated from 27 November 2017 to 16 April 2020 (BI 690517: 3 mg, n = 18; 10 mg, n = 13; 40 mg, n = 14; eplerenone, n = 4; placebo, n = 9) for 28 days. Eight (13.8%) participants experienced drug‐related AEs [BI 690517: 3 mg (two of 18); 10 mg (four of 13); 40 mg (two of 14)], most frequently constipation [10 mg (one of 13); 40 mg (one of 14)] and hyperkalaemia [3 mg (one of 18); 10 mg (one of 13)]. Most AEs were mild to moderate; one participant experienced severe hyperkalaemia (serum potassium 6.9 mmol/L; BI 690517 10 mg). UACR responses [≥20% decrease from baseline (first morning void urine) after 28 days] were observed for 80.0% receiving BI 690517 40 mg (eight of 10) versus 37.5% receiving placebo (three of eight). Aldosterone levels were suppressed by BI 690517, but not eplerenone or placebo. Conclusions: BI 690517 was generally well tolerated, reduced plasma aldosterone and may decrease albuminuria in participants with diabetes and albuminuric chronic kidney disease. [ABSTRACT FROM AUTHOR]

Antifungal drug development is essential as invasive fungal disease is still associated with a very high mortality rate and the emergence of resistant species in the last decade. In Europe, the European Medical Agency (EMA) approves antifungals and publishes the European Public Assessment Report (EPAR) including the information leading up to the authorisation. We looked at EMA-approved antifungals and their reports within the last 23 years. We focused primarily on the role of pharmacokinetic/pharmacodynamic indices in antifungal development and the level of information depicted in their corresponding report. Furthermore, we investigated guidelines applicable to the development process at the time and compared the content with a focus on pharmacokinetic/pharmacodynamic studies and preclinical requirements. Since 2000, six new antifungal substances have been authorised. Most were authorised for treatment of Candida infections or Aspergillus infections but also included rarer pathogens. Pharmacokinetic/pharmacodynamic indices were scarcely investigated and/or mentioned in the report. Current antifungal EMA guidelines started emphasising investigating pharmacokinetic/pharmacodynamic indices in 2010 and then again in 2016. It remains to be seen how this translates into the authorisation process for new antifungals. [ABSTRACT FROM AUTHOR]

The pharmaceutical industry is highly capital and knowledge-intensive, spending approximately 15% of its total revenue on research and development (R&D). This study aims to find the relationship between pharmaceutical businesses' financial performance and investments made in drug research and development in Europe. The study employs regression analysis with a time-lag effect of R&D spending on operating earnings. It is hypothesised that the investment expenditure of the previous year's R&D investment will significantly and concurrently impact the economic-financial performance of the country and the findings show a strong and positive link between the previous year's R&D expenditure and the current year's operating profit in the European countries, providing convincing evidence that R&D investments will pay off financially in the years ahead for the development of pharmaceuticals. The study also conducted diagnosis tests for the validation of the estimated models. [ABSTRACT FROM AUTHOR]

With the development of novel treatment therapies as well as evolving and innovative approaches to conduct clinical trials, the landscape of pediatric oncology drug development has dramatically changed in recent years. Despite this change, approvals for new drugs and labeling updates to ensure availability of proper treatment for pediatric patients with cancer remain slow. The context of drug development in pediatric tumors has also changed with regulatory initiatives in the US and Europe, creating a great need for faster development of novel drugs. Today, conventional study designs have been replaced or complemented by novel clinical trial designs, such as master protocols and platform trials, to optimize cancer drug development and enable faster regulatory approval. The iMATRIX platform is a mechanism-of-action (MOA)–based phase 1/2 trial framework for concurrently studying multiple molecules across a range of relevant pediatric tumor types, taking into account the biology of each pediatric tumor type. Six studies have been conducted, ongoing, or planned on the iMATRIX platform – investigating atezolizumab, cobimetinib, entrectinib, idasanutlin, alectinib, and glofitamab. A brief overview of study designs and characteristics are shared in this article, along with learnings from them. [ABSTRACT FROM AUTHOR]

This study bridged pharmacokinetic, efficacy, and safety clinical trial data from Japan to a Western population using real‐world evidence (RWE) to investigate the antibody–drug conjugate trastuzumab deruxtecan (T‐DXd) in the treatment of human epidermal growth factor receptor 2 (HER2)‐positive advanced gastric cancer. Using population pharmacokinetic and exposure–response (efficacy/safety) models, exposure–efficacy data from 117 patients and exposure–safety data from 158 patients in Japan who received T‐DXd 6.4 mg/kg as second‐line or later treatment were bridged to RWE including covariate information from 25 Western patients with HER2‐positive gastric cancer who received second‐line or later T‐DXd treatment. Pharmacokinetic simulations indicated that intact T‐DXd and released drug (DXd) steady‐state exposures were comparable between Western patients and patients from Japan; the Western/Japan ratio of exposure medians ranged from 0.82 (T‐DXd steady‐state minimum concentration) to 1.18 (DXd steady‐state maximum concentration). Exposure–efficacy simulations estimated a confirmed objective response rate of 28.6% (90% confidence interval, 20.8‐38.4) in real‐world Western patients versus 40.1% (90% confidence interval, 33.5‐47.0) in patients from Japan, possibly because of checkpoint inhibitor use in 4% versus 30% of patients, respectively. Western patients had a higher estimated rate of serious adverse events than patients from Japan (42.2% vs 34.6%); however, the rate of interstitial lung disease was lower (less than 10%) in Western patients. Overall, T‐DXd was predicted to have meaningful clinical activity and a manageable safety profile in Western patients with HER2‐positive gastric cancer. Using RWE, bridging analysis supported US approval of T‐DXd 6.4 mg/kg in advanced gastric cancer before a clinical trial was completed in Western patients. [ABSTRACT FROM AUTHOR]

We analyzed the European countries participation in clinical trials addressing to new drug development focused on rare diseases in women comparing to more prevalent diseases as breast cancer. Participation was not associated with type of healthcare system neither socio-economic features, but it was associated with population size. Protocol ratios focused on breast cancer vs. orphan drugs and rare diseases was 15:1 and 9:1, respectively, mainly focused on ovarian cancer. Protocol number was insufficient to evaluate the success of Regulation (EC) 141/2000, it is necessary to increase the scientific quality and the number of really new molecules. [ABSTRACT FROM AUTHOR]

Drug side effects (DSEs), or adverse drug reactions (ADRs), constitute an important health risk, given the approximately 197,000 annual DSE deaths in Europe alone. Therefore, during the drug development process, DSE detection is of utmost importance, and the occurrence of ADRs prevents many candidate molecules from going through clinical trials. Thus, early prediction of DSEs has the potential to massively reduce drug development times and costs. In this work, data are represented in a non-euclidean manner, in the form of a graph-of-graphs domain. In such a domain, structures of molecule are represented by molecular graphs, each of which becomes a node in the higher-level graph. In the latter, nodes stand for drugs and genes, and arcs represent their relationships. This relational nature represents an important novelty for the DSE prediction task, and it is directly used during the prediction. For this purpose, the MolecularGNN model is proposed. This new classifier is based on graph neural networks, a connectionist model capable of processing data in the form of graphs. The approach represents an improvement over a previous method, called DruGNN, as it is also capable of extracting information from the graph-based molecular structures, producing a task-based neural fingerprint (NF) of the molecule which is adapted to the specific task. The architecture has been compared with other GNN models in terms of performance, showing that the proposed approach is very promising. [ABSTRACT FROM AUTHOR]

Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs. Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development. An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings. • Regulatory decision-making in the context of product development life cycle. • PIP as a plan, allowing for evidence generation, able to be modified. • Fostering collaborative development environment, not competitive. • Need to identify priorities based on science. • Collaboration among all stakeholders key, as exemplified by ACCELERATE. [ABSTRACT FROM AUTHOR]

Paediatric drug development faces several barriers. These include fragmentation of stakeholders and inconsistent processes during the conduct of research. This review summarises recent efforts to overcome these barriers in Europe. Two exemplar initiatives are described. The European Paediatric Translational Research Infrastructure facilitates preclinical research and other work that underpins clinical trials. conect4children facilitates the design and implementation of clinical trials. Both these initiatives listen to the voices of children and their advocates. Coordination of research needs specific effort that supplements work on science, resources and the policy context. [ABSTRACT FROM AUTHOR]

The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities. • mTKIs are being evaluated in osteosarcoma and Ewing sarcoma. • Ongoing or planned randomised studies will inform further development. • Toxicity is tolerable when mTKIs are combined with chemotherapy. • Increased understanding of predictive biomarkers and tumour biology is crucial. • A joint academic-industry consortium should share and analyse biomarker samples. [ABSTRACT FROM AUTHOR]

Vutrisiran (AMVUTTRA™) is a subcutaneously administered transthyretin-directed small interfering ribonucleic acid (siRNA) therapeutic (also called RNA interference, or RNAi therapeutic) being developed by Alnylam Pharmaceuticals, Inc. for the treatment of amyloid transthyretin-mediated (ATTR) amyloidosis, including hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis. Vutrisiran was approved in June 2022 in the USA for the treatment of the polyneuropathy of hATTR amyloidosis in adults and received a positive opinion in the EU in July 2022 for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy. Vutrisiran is also under regulatory review for the treatment of the polyneuropathy of hATTR amyloidosis in adults in Japan and Brazil. This article summarizes the milestones in the development of vutrisiran leading to this first approval in hATTR amyloidosis. [ABSTRACT FROM AUTHOR]

The delicate balance of funding research and development of treatments for rare disease is only imperfectly achieved in Europe, and even the current provisional equilibrium is under a new threat from well-intentioned policy changes now in prospect that could—in addition to the intrinsic complexities of research—reduce the incentives on which commercial activity in this area is dependent. The European Union review of its pharmaceutical legislation, for which proposals are scheduled to appear before the end of 2022, envisages adjusting the decade-old incentives to meet objectives that are more precisely targeted. However, researchers, physicians, patients and industry have expressed concerns that ill-considered modifications could have unintended consequences in disrupting the current balance and could reduce rather than increase the flow of innovative treatments for rare diseases. [ABSTRACT FROM AUTHOR]

Although the "drug lag"—namely, the delay in drug approval time in Japan relative to the United States and/or European Union (US/EU)—has been shortened for drugs approved in Japan, there remain many new drugs that have been approved in the US/EU, but not in Japan. To assess the possibility of a future drug lag, this study has examined the current lag in drug development in Japan based on "ClinicalTrials.gov" data from multiregional clinical trials (MRCTs) conducted in the US/EU and East Asia. Among 828 MRCTs registered as of April 5th, 2021, the percentage of MRCTs in which Japan participated (jMRCTs) was 57.1%. jMRCTs were common for some diseases such as "nervous system" and "visual system" disorders, but less common for "neoplasm," infection," "mental," and "circulatory" disorders. Regarding the investigational drugs in non-jMRCTs (i.e., MRCTs without Japanese participation) in the latter four therapeutic areas (i.e., neoplasm, infection, mental and circulatory disorders), approximately 80% (313/399) of drugs were not being developed in Japan. Furthermore, many of these drugs were being developed by the top 50 pharmaceutical companies by sales, and the majority would be recognized as a new active ingredient with a new mode of action in Japan. This study has highlighted the possibility of a future drug lag in Japan, especially in the therapeutic areas of neoplasm, infection, mental, and circulatory disorders. Such a lag may arise not only between Japan and the US/EU, but also between Japan and other countries in the East Asian region. [ABSTRACT FROM AUTHOR]

Background: Rare cancers occur with an incidence of no more than six cases per 100,000 people according to the definition used by the Surveillance of Rare Cancers in Europe project. For a variety of reasons (low prevalence, cytotoxicity), it is challenging to perform the necessary clinical studies to investigate the safety and efficacy of investigational medicines against such rare malignancies, reformulating even at the earliest stages of the drug development process. This article investigates the differences between phase I rare cancer trials performed in commercial (companies) and non-commercial settings (academic hospitals). Materials and Methods: The differences were explored through the conduct of semi-structured interviews with three different stakeholder groups: representatives from academia (n = 7), representatives from companies (n = 4) and representatives from patient organizations (n = 4). All the interviews were transcribed verbatim and analyzed in NVivo using the framework method. Results: According to the interviewees, the academic and commercial stakeholders collaborate in the majority of phase I rare cancer trials. In general, the commercial partner finances the trial, whereas academia is responsible for the execution of the study procedures. The average cost of undertaking these trials is difficult to estimate because it depends on what is specifically requested during the trial. The 3 + 3 study design remains the most widely used design and the use of expansion cohorts is controversial. With regard to the regulatory aspects of phase I rare cancer trials, it was expressed that a good regulatory framework facilitates the conduct of these studies, but that increased regulation and oversight also has drawbacks, e.g., differences in standards between different ethics committees, over interpretation of the rules, insufficient availability of qualified personnel and higher workloads. The patient organization representatives claimed that patients experience no differences in terms of accommodation, compensation and paperwork between the academic and commercial settings or the degree of follow-up. They also believed that the direct input of patients can bring added value to such studies not only with regard to the recruitment process and the feasibility of the study but also the legibility of the informed consent forms. Conclusion: The growing need for first-in-man trials in rare malignancies needs to be highlighted, as difficult as they are to undertake and to co-develop, not only because rare cancer patients deserve an appropriate treatment, but also because these medicines represent the future of cancer therapy in the precision medicine era. Cooperation of commercial and academic sites are needed. Patient organizations need to be educated to take part in this process. [ABSTRACT FROM AUTHOR]

The growth in drug development over the past years reflects significant advancements in basic sciences and a greater understanding of molecular pathways of disease. Benchmarking industry practices has been important to enable a critical reflection on the path to evolve pharmaceutical testing, and the outcome of past industry surveys has had some impact on best practices in testing. A survey was provided to members of SPS, ACT, and STP. The survey consisted of 37 questions and was provided to 2550 participants with a response rate of 24%. Most respondents (∼75%) came from the US and Europe. The survey encompassed multiple topics encountered in nonclinical testing of pharmaceuticals. The most frequent target indications were oncology (69%), inflammation (55%), neurology/psychiatry/pain (46%), cardiovascular (44%), and metabolic diseases (39%). The most frequent drug-induced toxicology issues confronted were hepatic, hematopoietic, and gastrointestinal. Toxicological effects that impacted the no observed adverse effect level (NOAEL) were most frequently based on histopathology findings. The survey comprised topics encountered in the use of biomarkers in nonclinical safety assessment, most commonly those used to assess inflammation, cardiac/vascular, renal, and hepatic toxicity as well as common practices related to the assessment of endocrine effects, carcinogenicity, genotoxicity, juvenile and male-mediated developmental and female reproductive toxicity. The survey explored the impact of regulatory meetings on program design, application of the 3 Rs, and reasons for program delays. Overall, the survey results provide a broad perspective of current practices based on the experience of the scientific community engaged in nonclinical safety assessment. [ABSTRACT FROM AUTHOR]

In 2023, seventy novel drugs received market authorization for the first time in either Europe (by the EMA and the MHRA) or in the United States (by the FDA). Confirming a steady recent trend, more than half of these drugs target rare diseases or intractable forms of cancer. Thirty drugs are categorized as "first-in-class" (FIC), illustrating the quality of research and innovation that drives new chemical entity discovery and development. We succinctly describe the mechanism of action of most of these FIC drugs and discuss the therapeutic areas covered, as well as the chemical category to which these drugs belong. The 2023 novel drug list also demonstrates an unabated emphasis on polypeptides (recombinant proteins and antibodies), Advanced Therapy Medicinal Products (gene and cell therapies) and RNA therapeutics, including the first-ever approval of a CRISPR-Cas9-based gene-editing cell therapy., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Abstract: Sickle cell disease (SCD) is a hereditary red cell disorder with a large disease burden at a global level. In the United States and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the United States and Europe over the last 2 decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 ODs for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021), development of 34 of 57 ODs was completed. Four ODs were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared with products targeting disease consequences. Large companies showed a fourfold higher success rate compared with small-medium enterprises. Failures in clinical development were mainly seen in phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study end point, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical end points., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Developing medicines for children is now established in legislation in both the United States and Europe; new drugs require pediatric study or investigation plans as part of their development. Particularly in early age groups, many developmental processes are not reflected by simple scalars such as body weight or body surface area, and even projecting doses based on simple allometric scaling can lead to significant overdoses in certain age groups. Modeling and simulation methodology, including physiologically based modeling, has evolved as part of the drug development toolkit and is being increasingly applied to various aspects of pediatric drug development. Pediatric physiologically based pharmacokinetic (PBPK) models account for the development of organs and the ontogeny of specific enzymes and transporters that determine the age‐related pharmacokinetic profiles. However, when should this approach be used, and when will simpler methods such as allometric scaling suffice in answering specific problems? The aim of this review article is to illustrate the application of allometric scaling and PBPK in pediatric drug development and explore the optimal application of the latter approach with reference to case examples. In reality, allometric scaling included as part of population pharmacokinetic and PBPK approaches are all part of a model‐informed drug development toolkit helping with decision making during the process of drug discovery and development; to that end, they should be viewed as complementary. [ABSTRACT FROM AUTHOR]

• Most patients with SMA in Europe do not have access to the approved treatment. • Stabilization following treatment is considered progress. • Traditional SMA type classifications often do not reflect disease severity. • Patients want access to alternative treatments and clinical trials. • The active SMA community should be included in all stages of drug development. Following the 2017 approval of a first spinal muscular atrophy (SMA) treatment by the European Medicines Agency, SMA Europe launched a Europe-wide survey with the goal of understanding patients' treatment expectations, realities of daily living and access to clinical trials and therapy, and how this varied according to parameters such as age and disease severity. A response rate of 31% yielded 1474 completed surveys from 26 European countries. In line with findings from a 2015 SMA Europe-led survey, participants considered stabilization of their condition to be progress. Notably, responses indicated that the current classification of SMA at diagnosis by 'type' often does not reflect current mobility level. Large gaps in treatment access were identified that varied in particular between age and disease severity groups, yet there was high interest in clinical trial participation. In addition, alternative treatment options, including combination therapies, are now expectations. These perspectives should be central considerations through the research and development processes of new SMA therapies, through data generation and discussions on access to therapies. Results from this survey indicate that collaboration between stakeholders is essential to the foundation upon which innovative approaches for SMA treatments and access can be explored. [ABSTRACT FROM AUTHOR]

The growing prevalence and burden of Alzheimer's disease has catalysed huge investments in research on its causes, diagnosis, treatment and care. After many high-profile failures, recent clinical trials of anti-amyloid drugs have marked a turning point for the field, leading to the approval of the first disease-modifying therapies for Alzheimer's disease by the FDA. It is now up to European regulators to determine whether there is sufficient evidence to approve these drugs for patients with mild cognitive impairment or mild dementia due to Alzheimer's disease. Here, we outline Alzheimer Europe's position on anti-amyloid therapies for Alzheimer's disease, which was adopted by the Board of Alzheimer Europe following consultations with our member associations and with the European Working Group of People with Dementia. Beyond questions of drug efficacy, safety and cost, we highlight important issues that must be addressed by industry, regulators, payers, healthcare systems and governments, to ensure that patients have timely, appropriate and equitable access to innovative treatments, regardless of their socio-economic background, insurance status, or place of residence. We also call for continued investment in research on treatments that might benefit people with more advanced Alzheimer's disease - as well as support and care services that can help people live well with dementia at all stages of the disease., Competing Interests: Angela Bradshaw and Jean Georges are employees of Alzheimer Europe, which has received grants from the European Union’s Health, Horizon Europe and Citizens, Equality, Rights and Values programme (CERV) programmes, the Innovative Health Initiative, the Joint Programme for Neurodegenerative Disease Research (JPND) and the Luxembourg Fonds National de la Recherche, as well as sponsorship and support from AbbVie, Biogen, Eisai, Essity, Fujirebio, GE Healthcare, Grifols, Janssen, Lilly, MSD, Novo Nordisk, Nutricia, Prothena, Roche and TauRx.

The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner. • Targeting epigenetic mechanisms is an important approach in paediatrics. • With the RACE Act, development of epigenetic modifiers should be considered early. • Preclinical studies are critically needed to support early clinical evaluation. • A combination approach is required for most epigenetic modifiers. • Menin inhibitors are high priority and their development should be accelerated. [ABSTRACT FROM AUTHOR]

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy. • The Neuroblastoma New Drug Development Strategy initiative aims to accelerate new drugs development. •Twenty two of 40 targets were identified as high priority for neuroblastoma. •Targeting telomere maintenance, ATRX , BRIP1 , RRM2 are high priority for drug discovery. •Drugs targeting CDK2/9, CDK7, ATR should enter paediatric clinical development rapidly. •Combining targeted therapies with immunological agents is crucial. [ABSTRACT FROM AUTHOR]

Background: In contrast to the European Union and the USA, no laws or regulations mandating pediatric drug development have been established in Japan. Based on the information on drugs approved for pediatric indications in Europe and Japan, we evaluated the recent status of pediatric drug approvals and their characteristics in Japan in comparison with those of Europe. Methods: Drugs approved for pediatric indications between 2007 and 2015 in both regions were included in the study. The proportion of drugs with pediatric indications was calculated by the Anatomical Therapeutic Chemical (ATC) classification, and the status of pediatric formulation development was examined. The time from adult to pediatric indication approval was determined. Results: A total of 135 drugs were approved for pediatric indications in Europe, with 208 approved in Japan. The proportion of drugs with pediatric indications in Japan among those approved for pediatric indications in Europe was lower among those with ATC classifications of N (Nervous system) and J (Antiinfectives for systemic use) and those with the development of pediatric formulations than among others. Excepting drugs for which adult and pediatric indications were simultaneously approved, the most commonly observed period from the adult indication approval to the pediatric indication approval was more than 12 years in Japan and 3–6 years in Europe. Conclusion: The present findings suggested that pediatric development is indeed being promoted in Japan. However, the period from adult to pediatric indication approval was longer in Japan than in Europe, and the development of pediatric drugs for certain diseases has been sluggish, indicating room for further improvement. [ABSTRACT FROM AUTHOR]

Background: Pediatric regulations enacted in both Europe and the USA have disrupted the pharmaceutical industry, challenging business and drug development processes, and organizational structures. Over the last decade, with science and innovation evolving, industry has moved from a reactive to a proactive mode, investing in building appropriate structures and capabilities as part of their business strategy to better tackle the challenges and opportunities of pediatric drug development. Methods: The EFGCP Children's Medicines Working Party and the IQ Pediatric working group have joined their efforts to survey their member company representatives to understand how pharmaceutical companies are organized to fulfill their regulatory obligations and optimize their pediatric drug development programs. Results: Key success factors and recommendations for a fit-for-purpose Pediatric Expert Group (PEG) were identified. Conclusion: Pediatric structures and expert groups were shown to be important to support optimization of the development of pediatric medicines. [ABSTRACT FROM AUTHOR]

Drug repositioning is the scientific strategy of investigating existing drugs for additional clinical indications. The advantages of drug repositioning are that it benefits patients and that it adds new indications to existing drugs for lower costs compared to de novo drug development. Clinical research groups recognizing efficacy of these "old" drugs for a new indications often face an uphill struggle due to a lack of funding and support because of poor structural and regulatory support for clinical drug development. The current framework for drug repositioning allows "venture capital" companies to abuse loopholes in the legislation to gain long-term market authorization among with excessive high pricing. A new regulatory framework is needed to prevent abuse of the legislation and promote clinical investigator-driven drug repositioning. The COVID-19 pandemic has boosted funding and regulatory support for drug repositioning. The lessons learned from the COVID-19 pandemic should be implemented in a new clear blueprint for drug repositioning. This blueprint should guide clinicians through legislation for drug repositioning in the EU. This review summarizes the routes for registration and discusses the current state of drug repositioning in Europe. [ABSTRACT FROM AUTHOR]

Regulatory involvement in the generic drug development hastens the drug approval process which directly/indirectly accelerated the launching of drug into the market. The regulatory documents whether in-house of documents to be submitted to regulatory authorities should be carefully reviewed by the skilled personnel to minimize the queries raised by the regulatory agencies and speed up the approval process. These are few differences in the dossier submission requirements among the three regions, i.e., the USA, Europe, and India which has been clearly represented through succinct comparisons third part of this work. Generic manufacturers may file an abbreviated new drug application that incorporates the safety/effectiveness data submitted by original innovator drug manufacturer and adds only bioequivalence studies. Therefore, it is very difficult and challenging task to approve a drug by the manufacturing companies, simultaneously submitted in all the regulatory authorities. The literature work, the comparison parameters, and difference in generic drug approval requirements have been delineated in this work, which gives clear depict where India lies in its generic drug approval process and the challenges that Indian regulatory authority has to overcome in the near future. [ABSTRACT FROM AUTHOR]

Everolimus is currently approved in Europe as an adjunctive therapy for patients aged ≥ 2 years with tuberous sclerosis complex (TSC)–associated treatment‐refractory partial‐onset seizures, based on the EXIST‐3 study (NCT01713946) results. As TSC‐associated seizures can also affect children aged between 6 months and 2 years, a modeling and simulation (M&S) approach was undertaken to extrapolate exposure (trough plasma concentration (Cmin)) after a dose of 6 mg/m2 and reduction in seizure frequency (RSF). A physiologically based pharmacokinetic model using Simcyp was developed to predict Cmin in adult and pediatric patients, which was then used by a population pharmacodynamic model and a linear mixed effect model to predict short‐term and long‐term efficacy in adults (for validation) and in children, respectively. Based on the results of the M&S study, everolimus at the dose of 6 mg/m2 is anticipated to be an efficacious treatment in children 6 months to 2 years of age (up to 77.8% RSF) with concentrations within the recommended target range. [ABSTRACT FROM AUTHOR]

Background: In situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies.Methods and Findings: We used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as 'validated'. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being 'reasonably likely' (n = 30; 61%) or of having 'biological plausibility' (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway.Conclusions: The pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders. [ABSTRACT FROM AUTHOR]

Patient engagement in health care has been an emerging priority in the global effort and move toward the consideration of patients as experts of their own conditions. However, the input of pediatric patients and their families have not been consistently requested nor regarded as valuable when deriving protocols for, as well as assessing the outcomes of, pediatric clinical trials. Extending this mutual collaboration further upstream is important, especially in the area of pediatric drug development where the lack of formalized trials for children and adolescents result in the increased use of off-label prescribing and risk of adverse effects. While recent changes to European and North American legislation contributed to the inclusion of children and youth in pediatric drug development, the lack of systematic guidelines and methodologies in literature serve as barriers for practical application. When combined with the work of external pediatric advocacy and patient advisory groups, the hope is that pediatric patient voices can be brought forward for the future. This article brings together international experts to review current best practices, progress from regulatory agencies, as well as global advocacy efforts to involve patients and families in the pursuit of drug development processes that value the voice of children and youth. [ABSTRACT FROM AUTHOR]

The Innovative Medicines Initiative (IMI) WEB-RADR (Web-Recognising Adverse Drug Reactions) project looked at opportunities and challenges in using social media in pharmacovigilance as a rapidly evolving source of large, real-time data, which could provide new information on the actual use of medicines and potential safety issues. Two of the objectives were to develop principles for continuous monitoring of the safety of medicines without overburdening established pharmacovigilance systems and to propose a regulatory framework on the use of social media in pharmacovigilance. As a starting point, a review of existing legal requirements and regulatory guidance on social media use in pharmacovigilance was performed based on a survey conducted in 2014-2015. Furthermore, input from two large stakeholder workshops and evidence gathered from the research performed by WEB-RADR on the analysis of social media data were taken into consideration. Whilst analytical results of WEB-RADR indicated limited value of social media in detecting or confirming signals for a majority of the drugs studied, it is important to establish a regulatory framework for the use of social media in pharmacovigilance. Thus, the screening and reporting of suspected adverse reactions remains an important pillar in monitoring the safety and efficacy of medicines and the identification of new safety issues. Principles as to how social media can be used in pharmacovigilance are absolutely needed to provide clarity to patients, healthcare professionals, medicines regulators and the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

• Stakeholders must work collaboratively. • Efforts to address off label use of drugs through the drug approval regulatory pathway should be the goal. • Children should not be exposed to unnecessary clinical trials. The article, "Questionable Industry-Sponsored Studies in Children and Adolescents in Slovenia" provides an opportunity to discuss evolving US and EU legislative measures to improve the available clinical trial-derived pediatric data and provide coherent labeling for pediatric providers in dosing of drugs for children. [ABSTRACT FROM AUTHOR]

Background: The lack of appropriate pediatric formulations is a global issue and information on acceptability is urgently needed to develop standard pediatric formulations. This study aimed to assess perceptions of acceptability of several oral dosage forms among pediatric patients at a community and a pediatric hospital in Japan and collected information about age-appropriate pediatric formulations, aiming to contribute to drug development promotion worldwide. Methods: A cross-sectional observational study was performed. A convenience sample of caregivers was recruited from available chain-owned retail pharmacies and inpatient pediatric units. The questionnaire was composed of 3 parts: (1) acceptability of the 5 dosage forms (tablets, capsules, powders, liquids, and orally disintegrating tablet) by age; (2) acceptability of dosage size, amount, and volume by age; and (3) the actual method of administration. Face-to-face interviews were conducted at 3 independent community pharmacies (324 parents) and tertiary care pediatric hospital wards (112 nursing staff). Acceptability scores and acceptable dosages were then determined. The survey was conducted from October 1 to December 1, 2017, for the hospital setting and November 1 to 30, 2017, for the outpatient setting. Results: The acceptability of oral dosage forms was roughly similar to the matrix drafted by the European Medical Agency. Differences in perception of the powder forms between communities and hospitals were also observed, with the nursing staff perceiving powder as being acceptable from the neonatal period. Conclusions: The difference in caregivers' perception of the acceptability of oral formulations between Japan and Europe was small. The powder form was found to be more acceptable in Japan. Further intervention studies are needed to assess the preferred pediatric formulation worldwide. [ABSTRACT FROM AUTHOR]

Abstract Paediatric Strategy Forums have been created by the multistakeholder organisation, ACCELERATE, and the European Medicines Agency to facilitate dialogue between all relevant stakeholders and suggest strategies in critical areas of paediatric oncology drug development. As there are many medicines being developed for B-cell malignancies in adults but comparatively few in children with these malignancies, a Paediatric Strategy Forum was held to discuss the best approach to develop these products for children. It was concluded that as current frontline therapy is highly successful, despite associated acute toxicity, de-escalation of this or substitution of presently used drugs with new medicines can only be undertaken when there is an effective salvage regimen, which is currently not available. Therefore priority should be given to developing treatment for patients with relapsed and refractory mature B-cell lymphomas. The consensus of the clinicians attending the meeting was that CAR T-cells, T-cell engagers and antibody drug conjugates (excluding those with a vinca alkaloid–like drug) presently have the greatest probability of providing benefit in relapse in view of their mechanism of action. However, as producing autologous CAR T-cells currently takes at least 4 weeks, they are not products which could be quickly employed initially at relapse in rapidly progressing mature B-cell malignancies but only for the consolidation phase of the treatment. Global, industry-supported, academic-sponsored studies testing compounds from different pharmaceutical companies simultaneously should be considered in rare populations, and it was proposed that an international working group be formed to develop an overarching clinical trials strategy for these disease groups. Future Forums are planned for other relevant paediatric oncologic diseases with a high unmet medical need and relevant molecular targets. Highlights • Paediatric Strategy Forums involve all stakeholders in paediatric oncology drug development. • There are many medicines being developed for B-cell malignancies in adults. • However there are comparatively few in children with these malignancies. • The priority is to develop therapy for relapsed/refractory mature B-cell lymphomas. • CAR T-cells, T-cell engagers and antibody drug conjugates are the most promising agents. [ABSTRACT FROM AUTHOR]

Good practices around model‐informed drug discovery and development (MID3) aim to improve the implementation, standardization, and acceptance of these approaches within drug development and regulatory review. A survey targeted to clinical pharmacology and pharmacometric colleagues across industry, the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) was conducted to understand current and future roles of MID3. The documented standards were generally affirmed as a "good match" to current industry practice and regulatory expectations, with some identified gaps that are discussed. All have seen at least a "modest" step forward in MID3 implementation associated with greater organizational awareness and share the expectation for a future wider use and impact. The priority within organizations was identified as a limitation with respect to the future of MID3. Finally, potential solutions, including a global overarching MID3 regulatory guideline, to facilitate greater acceptance by industry and regulatory decision makers are discussed. [ABSTRACT FROM AUTHOR]

Galcanezumab-gnlm (Emgality™; Eli Lilly and Company), hereafter galcanezumab, is a humanized monoclonal antibody against the calcitonin gene-related peptide (CGRP) ligand. A potent vasodilator, CGRP is implicated in nociceptive transmission and migraine pathogenesis. In September 2018, the US FDA approved galcanezumab as a once-monthly subcutaneous injection for the preventive treatment of migraine in adults. In the same month, the EMA issued a positive opinion for galcanezumab for the prophylaxis of migraine in adults who have at least 4 migraine days per month. Galcanezumab is also undergoing phase III evaluation for the preventive treatment of cluster headache in North America and Europe. This article summarizes the milestones in the development of galcanezumab leading to its first approval for the preventive treatment of migraine in adults. [ABSTRACT FROM AUTHOR]

The Innovative Medicines Initiative is a public-private partnership between the European Union and the pharmaceuticals industry that was established in 2008, with an overall budget of €5.3 billion from 2008 until 2024. The objective of the initiative is to boost pharmaceutical innovation in Europe and speed up the development of innovative medicines, vaccines and medical technologies, in particular in areas with high unmet needs. This article discusses the objectives of the initiative, its governance and main results and impact. The initiative has proved to be a unique platform for multi-stakeholder collaborations across Europe. It has contributed to the acceleration of the development process for medicines, from drug discovery to clinical development. The initiative has made important steps towards accessing and using real-world evidence for pharmaceutical research and development, and for healthcare decision-making. Several projects have contributed to a better understanding of the causes of diseases, and some are already delivering results, such as a vaccine against Ebola virus. The initiative has also significantly contributed to building capacity and resources for open use by the broader research and innovation community. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the current practice of companies and agencies to assess the changes made in aligning regulatory and health technology assessment (HTA) stakeholders; to identify areas of commonality of evidentiary requirements that could occur; and to identify strategic issues and trends of regulatory and HTA synergy.Methods: Two separate questionnaires were developed to assess stakeholders' perceptions on regulatory and HTA alignment, one for pharmaceutical companies and the other for regulatory and HTA agencies. The responses were analyzed using descriptive statistics.Results: Seven regulatory and 8 HTA agencies from Australia, Canada, and Europe and 19 international companies developing innovative medicine responded to the survey. This study provided a snapshot of the current regulatory and HTA landscape. Changes made over the past 5 years were reflected in three main areas: there is an increasing interaction between regulatory and HTA agencies; current conditional regulatory approvals are not always linked with flexible HTA approaches; and companies are more supportive of joint scientific advice. Four types of evidentiary requirements were identified as building blocks for better alignment: acceptable primary end points, inclusion of an active comparator, use of patient-reported outcomes, and choice and use of surrogate end point.Conclusions: The study showed that the gap between regulatory and HTA requirements has narrowed over the past 5 years. All respondents supported synergy between regulatory and HTA stakeholders, and the study provided several recommendations on how to further improve evidentiary alignment including the provision of joint scientific advice, which was rated as a key strategy by both agencies and companies. [ABSTRACT FROM AUTHOR]

Background Multicenter neonatal clinical trials aim to provide evidence-based drug evaluation, but recruiting neonates requires collaboration, standard procedures, and trained neonatologists. Methods A questionnaire based on a previous Delphi study was sent to European neonatal intensive care units (NICUs) to collect their research experience and identify areas for improvement. Results Of 247 NICUs,79 (32%) responded: 69 were level III units and 10 were level II units. In level III centers, 62% had medical staff dedicated to research and 65% conducted regular in-house audits. Similarities were observed in the median number of trials peryear(level II: 2; level III: 5), Good Clinical Practice training (level II: 78%; level III: 66%), and standard operating procedures (level II: 63%; level III: 71%). Most NICUs had access to scientific advice for trial design, conduct, data management, and regulatory aspects. Involvement of patient advocacy groups was more common in level II units (level II: 75%; level III: 59%). A "quality" score of 34 "quality" research items was calculated for all centers (mean: 23.2 ± 6.2; range: 6-34). Conclusion Research experience and processes vary across Europe. Harmonizing research practices and setting standards will allow building a European neonatal network for effective, safe, and quality neonatal drug development. [ABSTRACT FROM AUTHOR]

Background: Although regulatory guidance defines which preclinical data are required in general before proceeding to first-inhuman clinical trials, a certain level of flexibility exists in the actual planning, timing, and design of a drug development program. Developing an ophthalmic medicinal product adds additional challenges, since the eye is a complex organ with unique features and specialized ophthalmic guidance documents are sparse. Methods: We analyzed the preclinical guidelines with a focus on European Union legislation and guidance documents provided by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). We elaborated the particularities specific to ophthalmic drug developments and deduced the preclinical knowledge needed to safely enter a first-in-human trial program. Two hypothetical medicinal products for ophthalmic indications were chosen and specificities for ophthalmic preclinical tests were elaborated. Results and conclusion: We conclude that the preclinical program of ophthalmic medicines is flexible and differs, based on the intended use and the nature of the active substance. [ABSTRACT FROM AUTHOR]

As per the EMA definition, adaptive pathways is a scientific concept for the development of medicines which seeks to facilitate patient access to promising medicines addressing high unmet need through a prospectively planned approach in a sustainable way. This review reports the findings of activities undertaken by the ADAPT-SMART consortium to identify enablers and explore the suitability of managed entry agreements for adaptive pathways products in Europe. We found that during 2006-2016 outcomes-based managed entry agreements were not commonly used for products with a conditional marketing authorization or authorized under exceptional circumstances. The barriers and enablers to develop workable managed entry agreements models for adaptive pathways products were discussed through interviews and a multi-stakeholder workshop with a number of recommendations made in this paper. [ABSTRACT FROM AUTHOR]

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A clear vision for vaccines research and development (R&D) is needed if Europe is to continue to lead the discovery of next generation vaccines. Innovation Partnership for a Roadmap on Vaccines in Europe (IPROVE) is a collaboration between leading vaccine experts to develop a roadmap setting out how Europe can best invest in the science and technology essential for vaccines innovation. This FP7 project, started in December 2013, brought together more than 130 key public and private stakeholders from academia, public health institutes, regulators, industry and small and medium-sized enterprises to determine and prioritise the gaps and challenges to be addressed to bolster innovation in vaccines and vaccination in Europe. The IPROVE consultation process was structured around seven themes: vaccine R&D, manufacturing and quality control, infrastructure, therapeutic vaccines, needs of small and medium-sized enterprises, vaccines acceptance and training needs. More than 80 recommendations were made by the consultation groups, mainly focused on the need for a multidisciplinary research approach to stimulate innovation, accelerated translation of scientific knowledge into technological innovation, and fostering of real collaboration within the European vaccine ecosystem. The consultation also reinforced the fact that vaccines are only as good as their vaccine implementation programmes, and that more must be done to understand and address vaccination hesitancy of both the general public and healthcare professionals. Bringing together a wide range of stakeholders to work on the IPROVE roadmap has increased mutual understanding of their different perspectives, needs and priorities. IPROVE is a first attempt to develop such a comprehensive view of the vaccine sector. This prioritisation effort, aims to help policy-makers and funders identify those vaccine-related areas and technologies where key investment is needed for short and medium-long term success. [ABSTRACT FROM AUTHOR]