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.

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.

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.

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.

Oral medicines for children in the European paediatric investigation plans.

INTRODUCTION: Pharmaceutical industry is no longer allowed to develop new medicines for use in adults only, as the 2007 Paediatric Regulation requires children to be considered also. The plans for such paediatric development called Paediatric Investigation Plans (PIPs) are subject to agreement by the European Medicines Agency (EMA) and its Paediatric Committee (PDCO). The aim of this study was to evaluate the key characteristics of oral paediatric medicines in the PIPs and the changes implemented as a result of the EMA/PDCO review. METHODS: All PIPs agreed by 31 December 2011 were identified through a proprietary EMA-database. PIPs were included if they contained an agreed proposal to develop an oral medicine for children 0 to 11 years. Information on the therapeutic area (EMA classification system); target age range (as defined by industry) and pharmaceutical characteristics (active substance, dosage form(s) as listed in the PIP, strength of each dosage form, excipients in each strength of each dosage form) was extracted from the EMA website or the EMA/PDCO assessment reports. RESULTS: A hundred and fifty PIPs were included corresponding to 16 therapeutic areas and 220 oral dosage forms in 431 strengths/compositions. Eighty-two PIPs (37%) included tablets, 44 (20%) liquids and 35 (16%) dosage forms with a specific composition/strength that were stored as a solid but swallowed as a liquid e.g. dispersible tablets. The EMA/PDCO review resulted in an increase of 13 (207 to 220) oral paediatric dosage forms and 44 (387 to 431) dosage forms with a specific composition/strength. For many PIPs, the target age range was widened and the excipient composition and usability aspects modified. CONCLUSION: The EMA/PDCO review realized an increase in the number of requirements for the development of oral dosage forms and a larger increase in the number of dosage forms with a specific composition/strength, both targeting younger children. Changes to their pharmaceutical design were less profound.

Paediatric investigation plans for pain: painfully slow!

PURPOSE: To examine the early impact of the Paediatric Regulation, which entered into force in Europe on 27 January 2007, on the development of pharmaceutical drugs in the therapeutic field of pain submitted to the Paediatric Committee (PDCO) and to the European Medicines Agency (EMA). METHODS: Paediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis. RESULTS: Of the 17 Paediatric Investigation Plans submitted, 14 have resulted in an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full waiver from development, and 1 resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1,282 children to be recruited into studies across five different products. Neonates were included in four of the products. CONCLUSIONS: The small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Now is an opportune time for clinicians, academics, learned societies and industry to collaborate for the benefit of children in pain.

The European paediatric initiative: 1 year of experience.

The European Regulation on medicines for pediatric use entered into force on 26 January 2007. It changes dramatically the way medicines are developed for children. This regulation will increase availability of and information on pediatric medicines through high quality, ethical research.