Global Cancer Drug Development-A Report From the 2022 Accelerating Anticancer Agent Development and Validation Meeting.

Rapidly expanding systemic treatment options, combined with improved screening, diagnostic, surgical, and radiotherapy techniques, have led to improved survival outcomes for many cancers over time. However, these overall survival gains have disproportionately benefited patients in high-income countries, whereas patients in low- and middle-income countries (LMICs) continue to experience challenges in accessing timely and guideline concordant care. In September 2022, the Accelerating Anticancer Agent Development and Validation workshop was held, focusing on global cancer drug development. Panelists discussed key barriers such as the lack of diagnostic services and human resources, drug accessibility and affordability, lack of research infrastructure, and regulatory and authorization challenges, with a particular focus on Africa and Latin America. Potential opportunities to improve access and affordability were reviewed, such as the importance of prioritizing investments in diagnostics, investing health infrastructure and work force planning, coordinated drug procurement efforts and streamlined regulatory processing, incentivized pricing through regulatory change, and the importance of developing and promoting clinical trials that can answer relevant clinical questions for patients in LMICs. As a cancer community, we must continue to advocate for and work toward equitable access to high-quality interventions for patients, regardless of their geographical location.

Reliance is key to effective access and oversight of medical products in case of public health emergencies.

INTRODUCTION: Responding to new threats and public health emergencies (PHE) creates serious challenges to regulators. The pandemic due to SARS-CoV-2 has been the catalyzer for change in global and local regulatory practices. Intensified collaboration, rapid and coordinated actions, and reliance mechanisms were key elements of the regulators' response to COVID-19 for all regulatory functions. AREAS COVERED: This article presents how collaboration and reliance among regulators were crucial tools for the regulatory responses to COVID-19, describes the reliance approaches for authorization of COVID-19 vaccines and other commodities, and the importance of reliance for other regulatory functions to avoid duplication and save resources where possible. This article also presents the results of a follow-up survey of reliance approaches in case of public health emergencies conducted between the International Pharmaceutical Regulators Programme (IPRP) members and discusses the forward-looking potential of reliance, analyzing the journey from theoretical concepts to real-life implementation. EXPERT OPINION: Regulatory reliance is an essential tool for regulators to act quickly and collectively in times of public health emergencies. Reliance approaches facilitate regulatory approvals and allow a more efficient use of resources, ultimately serving patients by facilitating earlier access to quality assured, safe and effective medicines.

WHO collaborative registration procedure using stringent regulatory authorities' medicine evaluation: reliance in action?

INTRODUCTION: The regulatory approval of medical products in countries with limited regulatory resources can be lengthy, which often compromises patients' timely access to much-needed medicines. To improve the efficiency of regulatory systems, reliance is being used. Reliance allows an authority to leverage the work performed by other authorities, such as scientific evaluations, to decide on medical products approval within their jurisdiction. This reduces duplication of regulatory efforts, resources and time, while maintaining national sovereignty. AREAS COVERED: This article analyzes the outcomes and stakeholders' experience of using medicines assessments performed by Stringent Regulatory Authorities (SRA) in the Collaborative Registration Procedures (CRP). Since its establishment in 2015, 59 approvals were granted to 16 medicines in 23 countries through SRA CRP. Results show that the procedure is delivering on the intended benefits of access and speed, with long-term positive impact for resource-limited countries. The article concludes with recommendations on the need for guidance on management of post-approval changes, wider promotion of the procedure, and increased collaboration between authorities. EXPERT OPINION: The SRA CRP provides a mechanism for the use of reliance by strengthening communication and promoting the exchange of information among regulators. This fosters faster regulatory approvals and, consequently, earlier access to medicines.

Assuring Access to Safe Medicines in Pregnancy and Breastfeeding.

Scientists and regulators in Europe and the United States continue to seek methods and strategies to improve knowledge on rational use of medicines for pregnant and breastfeeding populations, an important subset of women's health. Regulatory agencies have made strides toward improvement, but much more is needed. Recognizing the importance of international collaboration, we have begun to consider how to address these important public health issues more globally. The health of the child begins with the health of the mother.

Reliance: a smarter way of regulating medical products - The IPRP survey.

Introduction: A survey was conducted among national regulatory authorities' members of the International Pharmaceutical Regulators Programme (IPRP) to collect and share experiences of reliance approaches. Reliance allows formally, or informally, one regulatory authority to use assessments made by other regulatory authorities while remaining responsible for the final decision. Reliance is an essential concept to increase the efficiency of the global regulatory oversight of medical products by national regulatory authorities.Areas covered: This article describes the findings and recommendations from the IPRP survey. It shows that reliance in the area of medical product oversight is broadly accepted. The first part presents the acceptance and reasons for accepting reliance including the need for trust, then gives examples of the most common areas for reliance, and explains the difference between unilateral or reciprocal reliance. Finally, the article analyzes the lessons learned including challenges and opportunities for reliance on regulatory authorities to facilitate patient access in their jurisdictions.Expert opinion: Regulatory reliance facilitates regulatory approvals and allows to use resources in a more efficient way and ultimately serves patients by facilitating earlier access to quality-assured, safe, and effective medicines.

The European Medicines Agency facilitates access to medicines in low- and middle-income countries.

Introduction: As part of its contribution to promoting global health, the European Medicines Agency can assess medicines for use outside the European Union (EU) and issue scientific opinions in collaboration with the World Health Organization and non-EU national regulatory authorities. Ten positive scientific opinions have been adopted by the Committee for Medicinal Products for Human Use of the European Medicines Agency medicines (EU-M4all, or article 58). We have investigated for the first time their impact.Method: We included all positive scientific opinions (n = 10), contacted the sponsors (n = 8) and obtained and analyzed the lists of approval granted based on these opinions.Findings: 138 regulatory approvals have been granted in 90 countries, with 75 approvals in Africa, and the remainder in Latin and South America, Middle East and South-East Asia, and non-EU Europe and Central Asia.Discussion: These scientific opinions reflect the conditions of use and rely on high standards, but the final approval decision remains with these countries. Despite the small number of EU-M4all opinions, the many approvals have had an impact and contribute to access to innovation for patients with unmet needs in target countries.

Are the European Medicines Agency, US Food and Drug Administration, and Other International Regulators Talking to Each Other?

There is talk of regulatory collaboration worldwide to protect public health and allow patients timely access to medicines. Here, we present the reality of the collaboration between the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). This takes the form of near daily interactions, which may be less known outside of regulatory agencies. We present a review of what we call clusters, which involve the EMA, the FDA, and many other agencies under the umbrella of confidentiality arrangements. Through a survey of participants, we identified about 30 clusters of variable composition; these allow for the exchange of information and discussion among experts of applying regulatory science to common challenges in global drug development at every phase of its lifecycle and facilitate global medicines development.

Paediatric extrapolation: A necessary paradigm shift.

Legislative initiatives have been successful in increasing the availability of approved therapies for paediatric patients. However, additional measures to ensure the timely completion of paediatric studies are necessary to further increase the number of medicines available to children. Over the last 3 years, international experts convened to revise the ICH E11 guideline on clinical investigations of medicinal products in paediatric populations to harmonize approaches to paediatric extrapolation, striving to reduce substantial differences between regions in the acceptance of data for global paediatric medicine development programmes. Several areas of therapeutics development in children, such as human immunodeficiency virus and partial-onset seizures, have been streamlined and require fewer children enrolled in clinical trials because of the appropriate application of paediatric extrapolation. Based on this experience, it is clear that for paediatric extrapolation strategies to reach their full potential there is the need to understand the quality and quantity of data, often collected in adult patients, that will inform the appropriateness of the use of paediatric extrapolation, as well as to identify gaps in knowledge with respect to disease pathophysiology, organ maturation or drug target ontogeny. The generation of information that enhances our current understanding of these gaps in knowledge can further decrease the need for larger, paediatric clinical trials and can increase the efficiency of paediatric therapeutics development as well as protect children from participation in unnecessary studies. We hope that this publication will increase awareness, input and support from all the stakeholders involved in paediatric therapeutics development.

Adaptive designs in clinical trials: from scientific advice to marketing authorisation to the European Medicine Agency.

BACKGROUND: In recent years, experience on the application of adaptive designs in confirmatory clinical trials has accumulated. Although planning such trials comes at the cost of additional operational complexity, adaptive designs offer the benefit of flexibility to update trial design and objectives as data accrue. In 2007, the European Medicines Agency (EMA) provided guidance on confirmatory clinical trials with adaptive (or flexible) designs. In order to better understand how adaptive trials are implemented in practice and how they may impact medicine approval within the EMA centralised procedure, we followed on 59 medicines for which an adaptive clinical trial had been submitted to the EMA Scientific Advice (SA) and analysed previously in a dedicated EMA survey of scientific advice letters. We scrutinized in particular the submission of the corresponding medicines for a marketing authorisation application (MAA). We also discuss the current regulatory perspective as regards the implementation of adaptive designs in confirmatory clinical trials. METHODS: Using the internal EMA MAA database, the AdisInsight database and related trial registries, we analysed how many of these 59 trials actually started, the completion status, results, the time to trial start, the adaptive elements finally implemented after SA, their possible influence on the success of the trial and corresponding product approval. RESULTS: Overall 31 trials out of 59 (53%) were retrieved. Thirty of them (97%) have been started and 23 (74%) concluded. Nine of these trials (39% out of 23) demonstrated a significant treatment effect on their primary endpoint and 4 (17% out of 23) supported a marketing authorisation (MA). An additional two trials were stopped using pre-defined criteria for futility, efficiently identifying trials on which further resources should not be spent. Median time to trial start after SA letter was given by EMA was 5 months. In the investigated trial registries, at least 18 trial (58% of 31 retrieved trials) designs were implemented with adaptive elements, which were predominantly dose selection, sample size reassessment (SSR) and stopping for futility (SFF). Among the 11 completed trials including adaptive elements, 6 demonstrated a significant treatment effect on their primary endpoint (55%). CONCLUSIONS: Adaptive designs are now well established in the drug development landscape. If properly pre-planned, adaptations can play a key role in the success of some of these trials, for example to help successfully select the most promising dose regimens for phase II/III trials. Interim analyses can also enable stopping of trials for futility when they do not hold their promises. Type I error rate control, trial integrity and results consistency between the different stages of the analyses are fundamental aspects to be discussed thoroughly. Engaging early dialogue with regulators and implementing the scientific advice received is strongly recommended, since much experience in discussing adaptive designs and assessing their results has been accumulated.

What to Know About Medicines With New Active Ingredients Approved in FY 2016 / 2016 in Japan and EU: A Brief Comparison of New Medicines Approved in Japan and the EU in 2016.

The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan and the European Medicines Agency (EMA) have a long-standing experience of reviews of new medicines, and they meet their target pre-market review periods. In FY 2016 / 2016, 112 and 83 new medicines were approved in Japan and EU, respectively. Out of these medicines, 41 and 27 medicines containing new active ingredients were approved with total pre-market review periods of 209 days and 428 days in Japan and EU, respectively. Approximately one-third of these medicines were reviewed by the Agencies in close timing, within 1 year between pre-market review applications in Japan and in EU. Taking into account the increasing number of global clinical trials and constant number of consultations or scientific advice related to global clinical trials in Japan, it is clear that the importance of the continuous, collaborative relationship between EMA and PMDA is more and more crucial, as it does facilitate close and timely exchange of information and opinions on products and technologies under development. There already are effective collaborative frameworks between PMDA and EMA in addition to daily communication, and our findings support the development and best use of regulatory tools such as consultation services and scientific advice/protocol assistance for the benefit of the pharmaceutical industry but mostly of patients.

Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including focusing on a limited number of prioritized formulations and strengthening existing partnerships to ensure that pediatric investigation plans are developed early in the drug development process. Simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more sustainable. Lessons learned from HIV should be shared to support progress in developing pediatric formulations for other diseases, including tuberculosis and viral hepatitis.

Enabling Development of Paediatric Medicines in Europe: 10 Years of the EU Paediatric Regulation.

The year 2017 marks the tenth anniversary of entry into force of the Paediatric Regulation in the European Union (EU). This law aimed to stimulate the development of paediatric medicines and provide more information on their use, as a response to the lack of evidence and approval of medicines for children. The European Medicines Agency (EMA) has had a central role in the implementation of the Regulation. Pharmaceutical companies need to submit a paediatric investigation plan (PIP) to the EMA's Paediatric Committee (PDCO) for every new medicine, unless an exemption (waiver) is granted. The plans, which describe the development of drugs for children, must be agreed well in advance of the request for marketing authorization of the medicine. Deferrals of studies can be granted to allow approval in adults before the completion of paediatric studies. Between January 2007 and December 2016, a total of 273 new medicines and 43 additional pharmaceutical forms appropriate for use in children were authorized in the EU, and 950 PIPs were agreed by the EMA. In addition, 486 waivers of the development of a medicine in one or more medical conditions were agreed. The Paediatric Regulation has had a very positive impact on paediatric drug development, as exemplified by a comparison of two periods of 3 years before and after entry into force of the Regulation. We conclude that the Regulation has resulted in more medicines for children and more information on the pediatric use of medicines in the EU being available to clinicians.

Fostering responsible research with genome editing technologies: a European perspective.

In this consensus paper resulting from a meeting that involved representatives from more than 20 European partners, we recommend the foundation of an expert group (European Steering Committee) to assess the potential benefits and draw-backs of genome editing (off-targets, mosaicisms, etc.), and to design risk matrices and scenarios for a responsible use of this promising technology. In addition, this European steering committee will contribute in promoting an open debate on societal aspects prior to a translation into national and international legislation.

Important issues in the justification of a control treatment in paediatric drug trials.

OBJECTIVE: The value of comparative effectiveness trials in informing clinical and policy decisions depends heavily on the choice of control arm (comparator). Our objective is to identify challenges in comparator reasoning and to determine justification criteria for selecting a control arm in paediatric clinical trials. DESIGN: A literature search was completed to identify existing sources of guidance on comparator selection. Subsequently, we reviewed a randomly selected sample of comparators selected for paediatric investigation plans (PIPs) adopted by the Paediatric Committee of the European Medicines Agency in 2013. We gathered descriptive information and evaluated their review process to identify challenges and compromises between regulators and sponsors with regard to the selection of the comparator. A tool to help investigators justify the selection of active controls and placebo arms was developed using the existing literature and empirical data. RESULTS: Justifying comparator selection was a challenge in 28% of PIPs. The following challenging paediatric issues in the decision-making process were identified: use of off-label medications as comparators, ethical and safe use of placebo, duration of placebo use, an undefined optimal dosing strategy, lack of age-appropriate safety and efficacy data, and drug dosing not supported by extrapolation of safety/efficacy evidence from other populations. CONCLUSIONS: In order to generate trials that will inform clinical decision-making and support marketing authorisations, researchers must systemically and transparently justify their selection of the comparator arm for their study. This report highlights key areas for justification in the choice of comparator in paediatric clinical trials.

Enhanced Paediatric Pharmacovigilance at the European Medicines Agency: A Novel Query Applied to Adverse Drug Reaction Reports.

BACKGROUND: Databases of suspected adverse drug reactions (ADRs) are a cornerstone of pharmacovigilance. With increasing numbers of reports, additional statistical approaches are needed to better use the data. AIM: The present study was aimed at elucidating the European Medicines Agency's (EMA) use of a novel 'paediatric' query to analyse the data in its ADR database 'EudraVigilance'. METHODS: The proportional reporting ratio (PRR) is a measure of disproportionality for which the underlying principle is that a drug-event pair of interest is reported more often than expected relative to an independence model. The EMA's paediatric query, based on PRRs, was applied to the data in EudraVigilance to investigate the extent to which the known association between enalapril and renal toxicity was reflected in reported ADRs comparing children with adults and with adjustment for the effect of multiplicity. RESULTS: The comparison of PRRs for children (14.91, 95% confidence interval [CI] 13.05-17.04) versus adults (2.66, 95% CI 2.52-2.82) confirmed a higher risk of renal ADRs with enalapril when used in children compared with all other medicines and compared with adults. CONCLUSIONS: The EMA's paediatric query can be used to highlight an imbalance for a drug-event pair among ADRs for a medicine when used in children and as compared with adults. Applying the query in practice can help the EMA to decide on whether stand-alone paediatric medicine development is warranted, and which, if any, further studies are necessary. Ongoing evaluation of the query is contributing to the development of new methods and guidance.

Usage of unpublished paediatric data.

The European Paediatric Regulation (EC No 1901/2006) has three main objectives: increasing the number of appropriate medicines for children, increasing information on these medicines and stimulating high-quality ethical research with children. To contribute to the information, pharmaceutical companies were required under article 45 of the Regulation to submit existing paediatric studies to regulatory authorities for review and update of the product information. Nearly, 19 000 study reports have been identified for a thousand active substances. The data are being assessed by member states' competent authorities in collaboration with European Medicines Agency (EMA). After 7 years, 262 active substances have been assessed, all of the 62 centrally approved and nearly 200 nationally approved medicines. The review so far has led to 16 new paediatric indications, of importance in addressing previously unmet needs, in particular, in younger age groups. The information is being made publicly available in an EMA database accessible directly or through the public face of the European Clinical Trials Register. This will increase awareness of existing data that are useful to researchers and other healthcare professionals, and contribute to avoiding unnecessary duplication of paediatric trials.

White spots in pharmaceutical pipelines-EMA identifies potential areas of unmet medical needs.

Unmet medical needs are a priority for organizations such as the WHO and major public-private initiatives, such as Innovative Medicines Initiative, were established to speed up the development of better and safer medicines for patients. To assist such projects, the EMA in its 'Road Map to 2015' considered the mapping of unmet medical needs as a priority. This study has identified medical conditions for which the EMA could not identify developments in the pharmaceutical pipelines, that is, 'white spots'. Our analysis was made using external data sources as well as mining data of the EMA. The main areas for white spots were oncology, infectious diseases and certain psychiatric conditions. According to our data and a review of literature, in a number of these white spots, diagnostic tools may even be missing. The identification of those conditions will benefit stakeholders, including regulators, research funding bodies and patients' organizations.