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Regulators and Health Technology Assessment (HTA) bodies are increasingly familiar with, and publishing guidance on, external controls derived from real‐world data (RWD) to generate real‐world evidence (RWE). We recently conducted a systematic literature review (SLR) evaluating publicly available information on the use of RWD‐derived external controls to contextualize outcomes from uncontrolled trials submitted to the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and/or select HTA bodies. The review identified several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary. This paper builds on the SLR findings by delineating a set of key takeaways for the responsible generation of fit‐for‐purpose RWE. Practical methodological and operational guidelines for designing, conducting, and reporting RWD‐derived external control studies are explored and discussed. These considerations include: (i) early engagement with regulators and HTA bodies during the study planning phase; (ii) consideration of the appropriateness and comparability of external controls across multiple dimensions, including eligibility criteria, temporality, population representation, and clinical evaluation; (iii) ensuring adequate sample sizes, including hypothesis testing considerations; (iv) implementation of a clear and transparent strategy for assessing and addressing data quality, including data missingness across trials and RWD; (v) selection of comparable and meaningful endpoints that are operationalized and analyzed using appropriate analytic methods; and (vi) conduct of sensitivity analyses to assess the robustness of findings in the context of uncertainty and sources of potential bias. [ABSTRACT FROM AUTHOR]

Study sponsors and market authorization holders are required by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to enroll patients administered a gene therapy product, whether in a trial setting or post‐licensure, in a long term follow‐up safety study to continue the safety assessments of their product. These follow‐up studies range between 5 and 15 years after dosing. This unprecedented duration of engagement with patients and caregivers raises logistical challenges that will require innovation and collaboration across sponsors and regulators. In this paper we delineate some of the key considerations for designing long term follow‐up protocols in the gene therapy setting, with an eye toward platform and master protocol approaches, and offer guidance for innovative operational and statistical methods that can help assess the safety profile and durability of response for these novel therapeutics. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) guidances on small‐molecule drug–drug interactions (DDIs), with input from the International Transporter Consortium (ITC), recommend the evaluation of nine drug transporters. Although other clinically relevant drug uptake and efflux transporters have been discussed in ITC white papers, they have been excluded from further recommendation by the ITC and are not included in current regulatory guidances. These include the ubiquitously expressed equilibrative nucleoside transporters (ENT) 1 and ENT2, which have been recognized by the ITC for their potential role in clinically relevant nucleoside analog drug interactions for patients with cancer. Although there is comparatively limited clinical evidence supporting their role in DDI risk or other adverse drug reactions (ADRs) compared with the nine highlighted transporters, several in vitro and in vivo studies have identified ENT interactions with non‐nucleoside/non‐nucleotide drugs, in addition to nucleoside/nucleotide analogs. Some noteworthy examples of compounds that interact with ENTs include cannabidiol and selected protein kinase inhibitors, as well as the nucleoside analogs remdesivir, EIDD‐1931, gemcitabine, and fialuridine. Consequently, DDIs involving the ENTs may be responsible for therapeutic inefficacy or off‐target toxicity. Evidence suggests that ENT1 and ENT2 should be considered as transporters potentially involved in clinically relevant DDIs and ADRs, thereby warranting further investigation and regulatory consideration. [ABSTRACT FROM AUTHOR]

The new In Vitro Diagnostic Regulation (EU) 2017/746 (IVDR) introduces important changes in the EU legal framework for companion diagnostics (CDx), including a new risk‐based classification system for in vitro diagnostic tests (IVDs), a first legal definition for CDx and enhanced involvement of notified bodies in the conformity assessment and certification process of CDx. The IVDR also establishes an important link between the assessment of a CDx and the corresponding medicinal product by requiring the notified body to seek a scientific opinion from the medicines regulator on the suitability of the CDx for use with the concerned medicinal product(s) before issuing an IVD certificate. Whereas the IVDR aims at establishing a robust regulatory framework for IVDs, it is also associated with several challenges, such as insufficient capacity of notified bodies and readiness of manufacturers. To ensure timely access for patients to essential IVDs, a progressive roll‐out for this new legislation has been introduced. In addition, the new consultation process for CDx requires increased collaboration and alignment of assessments performed by the different stakeholders involved in this process. The European Medicines Agency (EMA) and notified bodies are currently building experience based on the first CDx consultation procedures that have been submitted from January 2022 onward. In the current article, we describe the new European regulatory framework for certification of CDx and highlight several challenges for medicine and CDx co‐development. In addition, we briefly touch upon the interplay between the Clinical Trial Regulation (EU) No. 536/2014 (CTR) and the IVDR. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID‐19) pandemic and the accompanying control measures have significantly affected clinical trial (CT) conduct, and sponsors have needed to make rapid changes to their CT operations. As a result, regulatory guidance was pivotal during the initial phases of the pandemic. This study aimed to evaluate the regulatory readiness and guidance related to COVID‐19 in the European Union (EU). The European Medicines Agency (EMA) and national competent authorities' (NCAs') websites were searched in September and October 2020 for guidances on the management of CTs during the pandemic published from January 2020 onward. "Regulatory readiness" was defined as the number of days from the first European COVID‐19 case (January 24, 2020) to the first published guidance by the respective NCA. "Regulatory guidance" was evaluated by coding the guidances for the following predefined operational trial activities important for ongoing CTs: obtaining informed consent, participant information, clinic visits, home health visits, telemedicine visits, self‐monitoring, investigational medicinal product (IMP) supply, IMP adherence monitoring, CT monitoring, documentation management, regulatory management, and safety management. Twenty‐four of the 27 EU NCAs published country‐specific guidance. The time from the first European COVID‐19 case to the first published EMA guidance was 56 days and ranged from 47 to 66 days for the first national guidances. Guidance was provided most frequently for regulatory management (24/24), safety management (23/24), documentation management (22/24), and CT monitoring (22/24). The regulatory guidance provided during the pandemic, ensuring participant safety and data integrity, may now be the starting point to innovate future CT conduct. [ABSTRACT FROM AUTHOR]

Whereas islet autoantibodies (AAs) are well‐established risk factors for developing type 1 diabetes (T1D), there is a lack of biomarkers endorsed by regulators to enrich clinical trial populations for those at risk of developing T1D. As such, the development of therapies that delay or prevent the onset of T1D remains challenging. To address this drug development need, the Critical Path Institute's T1D Consortium (T1DC) acquired patient‐level data from multiple observational studies and used a model‐based approach to evaluate the utility of islet AAs as enrichment biomarkers in clinical trials. An accelerated failure time model was developed, discussed in our previous publication, which provided the underlying evidence required to receive a qualification opinion for islet AAs as enrichment biomarkers from the European Medicines Agency (EMA) in March 2022. To further democratize the use of the model for scientists and clinicians, we developed a Clinical Trial Enrichment Graphical User Interface. The interactive tool allows users to specify trial participant characteristics, including the percentage of participants with a specific AA combination. Users can specify ranges for participant baseline age, sex, blood glucose measurement from the 120‐minute timepoints of an oral glucose tolerance test, and HbA1c. The tool then applies the model to predict the mean probability of a T1D diagnosis for that trial population and renders the results to the user. To ensure adequate data privacy and to make the tool open‐source, a deep learning‐based generative model was used to generate a cohort of synthetic subjects that underpins the tool. [ABSTRACT FROM AUTHOR]

Cell and gene therapy (CGT) describes a broad category of medicinal products with potential applications to prevent and treat human disease in multiple therapeutic areas. These therapies leverage the use of modified nucleic acids, altered cells or tissue, or both. The modality, mechanism, route of administration, and therapeutic indication for a CGT product will influence the challenges and opportunities for early clinical development, some of which may be highly specific to the product under consideration. Both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) encourage early interaction between sponsor and health authority to align on key elements of the CGT development program. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have robust collaboration and dialogue around the need for data and the inclusion of pregnant and lactating individuals in clinical trials. Despite this collaboration, the two agencies have their own standards for the format and content of labeling for these populations. To understand these differences, the pregnancy and lactation labeling sections for 31 approved drugs were compared, and trends were assessed for use of language concordance and discordance related to use during pregnancy and lactation between the 2 agencies. Further analysis evaluated the presence of human data included in the labeling. The EMA and the FDA had high discordance between pregnancy and lactation labeling language, in 68% and 71% of labeling, respectively, and only 10% of pregnancy labeling and 16% of lactation labeling include human data. Concordance in labeling language is not the norm but occurs when there is a sizeable body of human data, animal data suggesting a particular safety issue, drug mechanism of action information, or disease‐specific considerations. This study highlights the need for more human data to inform prescribing decisions in these populations. The results also suggest that there is an opportunity for alignment in labeling across regions. [ABSTRACT FROM AUTHOR]

Prior to deployment of coronavirus disease 2019 (COVID‐19) vaccines in the European Union in 2021, a high vaccine uptake leading to an unprecedented volume of safety data from spontaneous reports and real‐world evidence, was anticipated. The European Medicines Agency (EMA) implemented specific activities to ensure enhanced monitoring of emerging vaccine safety information, including intensive monitoring of reports of adverse events of special interest and the use of observed‐to‐expected analyses. The EMA also commissioned several independent observational studies using a large network of electronic healthcare databases and primary data collection via mobile and web‐based applications. This preparedness was key for two high‐profile safety signals: thrombosis with thrombocytopenia syndrome (TTS), a new clinical entity associated with adenovirus‐vectored vaccines, and myocarditis/pericarditis with messenger RNA vaccines. With no existing case definition nor background rates, the signal of TTS posed particular challenges. Nevertheless, it was rapidly identified, evaluated, contextualized and the risk minimized thanks to close surveillance and an efficient use of available evidence, clinical expertise and flexible regulatory tools. The two signals illustrated the complementarity between spontaneous and real‐world data, the former enabling rapid risk identification and communication, the latter enabling further characterization. The COVID‐19 pandemic has tremendously enhanced the development of tools and methods to harness the unprecedented volume of safety data generated for the vaccines. Areas for further improvement include the need for better and harmonized data collection across Member States (e.g., stratified vaccine exposure) to support signal evaluation in all population groups, risk contextualization, and safety communication. [ABSTRACT FROM AUTHOR]

Selective safety data collection may simplify late‐stage clinical trials and improve their feasibility. However, the impact on increasing overall drug safety knowledge is unknown. The aim of this study is to evaluate how much safety information is added to the drug label based on large trials after initial authorization. Changes made to the "undesirable effects" section of the drug label of cardiometabolic agents approved between 2000 and 2020 based on the results of large (> 1,000 patient) clinical trials submitted to the European Medicines Agency (EMA) were evaluated. The study focused on glucose lowering, antithrombotic, and lipid‐modifying agents. The primary outcome was the number of changes in adverse drug reactions in the drug label. The EMA reviewed 55 large trials concerning 25 cardiometabolic agents after the initial marketing authorization, which included 402,444 patients. Ultimately, 38 trials (69%) resulted in a safety section update, whereas 17 trials (31%) did not. Changes in listed adverse drug reactions were made following 19 trials (35%) for 12 agents: 77 adverse drug reactions were added, 11 were deleted, and the frequencies of 43 were changed. Most changes in adverse drug reactions arose from trials with antithrombotic agents (88%) and trials performed in a new population (92%). Large trials for cardiometabolic agents reported after authorization add limited new safety information on adverse drug reactions, especially when performed in the population studied prior to approval. This suggests that selective safety data collection does not reduce learnings from late stage cardiometabolic trials in populations comprehensively studied before. [ABSTRACT FROM AUTHOR]

The aging processes alter the body's response to a medicine's pharmacokinetics, pharmacodynamics, and susceptibility to adverse effects. In addition, older adults, especially the oldest age category (85+ years) or those with multiple chronic health conditions, polypharmacy, or frailty, are under‐represented in clinical trials of new medicines. Evidence‐based prescribing guidelines based on these trials might result in inappropriate prescription, increasing the risk of drug interactions and adverse drug reactions. Regulators face a conundrum between acquiring sufficient data and putting susceptible patients at risk in the early stages of a development program, when little is known about a medicine's effects. Healthcare professionals and patients deserve to have access to clear information on the knowledge and evidence gaps leading to the approval of a new medicinal product. This should also include proper consideration of the population of older patients. In the present article, we outline the approach taken by the European Medicines Agency (EMA) regulators in the assessment of a new medicine's dossier. [ABSTRACT FROM AUTHOR]

Biosimilar monoclonal antibodies (mAbs) have been approved in the European Union since 2013 and have been demonstrated to reduce healthcare costs and to expand patient access. Biosimilarity is mainly established on the basis of demonstrated similarity of relevant quality attributes (QAs), determined by comprehensive physiochemical and functional analyses, and demonstration of bioequivalence. In addition, comparative efficacy/safety studies have been requested for all approved biosimilar mAbs so far, although the European Medicines Agency (EMA) Guidelines state that such confirmatory clinical trials may not be necessary in specific circumstances. In order to evaluate the degree of analytical similarity, how residual uncertainty regarding biosimilarity was resolved, and the value of clinical data, we analyzed the quality and clinical data packages for authorized adalimumab (7 products) and bevacizumab (5 products) biosimilars. The percentage of biosimilar batches meeting the similarity range for QAs, as defined by the biosimilar manufacturer based on a comprehensive characterization of the EU reference product (RP), was determined and clinical data were reviewed. Our analyses show that QAs of approved adalimumab and bevacizumab biosimilars have varying concordance with the EU‐RP similarity range. In this study, we found that clinical efficacy data played a limited role in addressing quality concerns. Therefore, we encourage a regulatory review of the standards for clinical data requirements for mAb and fusion protein biosimilars. This study outlines a quality data driven approach for facilitating tailored clinical programs for biosimilars. [ABSTRACT FROM AUTHOR]

Real‐world data/evidence (RWD/RWE) may provide insightful information on medicines' clinical effects to guide regulatory decisions. While its contribution has been recognized for safety monitoring and disease epidemiology across medicines' life cycles, using RWD/RWE to demonstrate efficacy requires further evaluation. This study aimed to (i) characterize RWD/RWE presented by applicants to support claims on medicines' efficacy within initial marketing authorization applications (MAAs) and extension of indication applications (EoIs), and (ii) analyze the contribution of RWD/RWE to regulatory decisions on medicines' benefit–risk profile. RWD/RWE was included to support efficacy in 32 MAAs and 14 EoIs submitted 2018–2019. Of these, RWD/RWE was part of the preauthorization package of 16 MAAs and 10 EoIs, and was (i) considered supporting the regulatory decision in 10 applications (five MAAs, five EoIs), (ii) considered not supporting the regulatory decision in 11 (seven MAAs, four EoIs), and (iii) not addressed at all in the evaluation of 5 applications (four MAAs, one EoI). Common limitations of submitted RWD/RWE included missing data, lack of representativeness of populations, small sample size, absence of an adequate or prespecified analysis plan, and risk of several types of bias. The suitability of RWD/RWE in a given application still requires a case‐by‐case analysis considering its purpose of use, implying reflection on the data source, together with its assets and limitations, study objectives and designs, and the overall data package issued. Early interactions and continuous dialogues with regulators and relevant stakeholders is key to optimize fit‐for‐purpose RWE generation, enabling its broader use in medicines development. [ABSTRACT FROM AUTHOR]

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration‐time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax), to be included within the tighter acceptance range of 90.00–111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one‐size‐fits‐all" criterion is particularly questionable when the within‐subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within‐subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00–125.00% acceptance range for highly variable drugs. The 80.00–125.00% acceptance range is narrowed, only if the within‐subject variability is lower than 30%, down to the current NTI acceptance range of 90.00–111.11% when the within‐subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within‐subject variability is 20–30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within‐subject variability are frequently exposed to bioavailability differences larger than 10%. [ABSTRACT FROM AUTHOR]

Information derived from routinely collected real‐world data has for a long time been used to support regulatory decision making on the safety of drugs and has more recently been used to support marketing authorization submissions to regulators. There is a lack of detailed information on the use and types of this real‐world evidence (RWE) as submitted to regulators. We used resources held by the European Medicines Agency (EMA) to describe the characteristics of RWE included in new marketing authorization applications (MAAs) and extensions of indication (EOIs) for already authorized products submitted to the EMA in 2018 and 2019. For MAAs, 63 of 158 products (39.9%) contained RWE with a total of 117 studies. For 31.7% of these products, the RWE submitted was derived from data collected before the planned authorization. The most common data sources were registries (60.3%) followed by hospital data (31.7%). RWE was mainly included to support safety (87.3%) and efficacy (49.2%) with cohort studies being the most frequently used study design (88.9%). For EOIs, 28 of 153 products (18.3%) contained RWE with a total of 36 studies. For 57.1% of these products, studies were conducted prior to the EOIs. RWE sources were mainly registries (35.6%) and hospital data (27.0%). RWE was typically used to support safety (82.1%) and efficacy (53.6%). Cohort studies were the most commonly used study design (87.6%). We conclude that there is widespread use of RWE to support evaluation of MAAs and EOIs submitted to the EMA and identify areas where further research is required. [ABSTRACT FROM AUTHOR]

Real‐world data/real‐world evidence (RWD/RWE) are considered to have a great potential to complement, in some cases, replace the evidence generated through randomized controlled trials. By tradition, use of RWD/RWE in the postauthorization phase is well‐known, whereas published evidence of use in the pre‐authorization phase of medicines development is lacking. The primary aim of this study was to identify and quantify the role of potential use of RWD/RWE (RWE signatures) during the pre‐authorization phase, as presented in the initial marketing authorization applications of new medicines centrally evaluated with a positive opinion in 2018–2019 (n = 111) by the European Medicines Agency (EMA). Data for the study was retrieved from the evaluation overviews of the European Public Assessment Reports (EPARs), which reflect the scientific conclusions of the assessment process and are accessible through the EMA website. RWE signatures were extracted into an RWE Data Matrix, including 11 categories divided over 5 stages of the drug development lifecycle. Nearly all EPARs included RWE signatures for the discovery (98.2%) and life‐cycle management (100.0%). Half of them included RWE signatures for the full development phase (48.6%) and for supporting regulatory decisions at the registration (46.8%), whereas over a third (35.1%) included RWE signatures for the early development. RWE signatures were more often seen for orphan and conditionally approved medicines. Oncology, hematology, and anti‐infectives stood out as therapeutic areas with most RWE signatures in their full development phase. The findings bring unprecedented insights about the vast use of RWD/RWE in drug development supporting the regulatory decision making. [ABSTRACT FROM AUTHOR]

Timely and successful drug development for rare cancer populations, such as pediatric oncology, requires consolidated efforts in the spirit of shared responsibility. In order to advance tailored development efforts, the concept of multistakeholder Strategy Forum involving industry, academia, patient organizations, and regulators has been developed. In this study, we review the first five pediatric oncology Strategy Forums co‐organized by the European Medicines Agency between 2017 and 2020, reflecting on the outcomes and the evolution of the concept over time and providing an outline of how a "safe space" for multistakeholder engagement facilitated by regulators could be of potential value beyond pediatric oncology drug development. [ABSTRACT FROM AUTHOR]

This study aimed to determine to which extent data on potential pharmacogenetic‐pharmacokinetic (PG‐PK) interactions are provided to, and assessed by, the European Medicines Agency (EMA) in novel drug marketing authorization applications (MAAs), and whether regulatory assessment of PG‐PK interactions is adequate or could be optimized. For this purpose, we retrospectively analyzed MAAs of small molecule drugs assessed by the EMA between January 2014 and December 2017. As per two key requirements in the EMA's guideline, we analyzed cases where (i) a single functionally polymorphic drug metabolizing enzyme (DME) metabolizes > 25% of the drug, or (ii) the drug's PK shows high interindividual variability not explained by other factors than PG. Results showed that, of 113 drugs analyzed, 53 (47%) had ≥ 1 functionally polymorphic DME accounting for > 25% of the drug's metabolism, yielding 55 gene‐drug pairs. For 36 of 53 (68%) of the products, CYP3A4 was the major DME. Compliance with European Union (EU) guidance on PG‐PK issues in drug development was notably different for CYP3A4 substrates vs. non‐CYP3A4 substrates. Adequate PG‐PK data were provided during registration in 89% (16/18) of cases concerning non‐CYP3A4 substrates, compared with 32% (12/37) of cases concerning CYP3A4 substrates. Concluding, PG‐PK interactions related to non‐CYP3A4 substrate drugs were, in general, addressed adequately in EU MAAs. PG‐PK information on CYP3A4 substrates was available less frequently, despite some available evidence on the functional relevance of CYP3A4 polymorphisms. A more harmonized approach toward assessment of PG‐PK issues in EU MAAs seems warranted, and a discussion on the relevance of CYP3A4 polymorphisms, such as CYP3A4*22, is recommended. [ABSTRACT FROM AUTHOR]

Physiologically‐based pharmacokinetic (PBPK) modeling has been extensively used to quantitatively translate in vitro data and evaluate temporal effects from drug–drug interactions (DDIs), arising due to reversible enzyme and transporter inhibition, irreversible time‐dependent inhibition, enzyme induction, and/or suppression. PBPK modeling has now gained reasonable acceptance with the regulatory authorities for the cytochrome‐P450‐mediated DDIs and is routinely used. However, the application of PBPK for transporter‐mediated DDIs (tDDI) in drug development is relatively uncommon. Because the predictive performance of PBPK models for tDDI is not well established, here, we represent and discuss examples of PBPK analyses included in regulatory submission (the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA)) across various tDDIs. The goal of this collaborative effort (involving scientists representing 17 pharmaceutical companies in the Consortium and from academia) is to reflect on the use of current databases and models to address tDDIs. This challenges the common perceptions on applications of PBPK for tDDIs and further delves into the requirements to improve such PBPK predictions. This review provides a reflection on the current trends in PBPK modeling for tDDIs and provides a framework to promote continuous use, verification, and improvement in industrialization of the transporter PBPK modeling. [ABSTRACT FROM AUTHOR]

The increasing volume and complexity of data now being captured across multiple settings and devices offers the opportunity to deliver a better characterization of diseases, treatments, and the performance of medicinal products in individual healthcare systems. Such data sources, commonly labeled as big data, are generally large, accumulating rapidly, and incorporate multiple data types and forms. Determining the acceptability of these data to support regulatory decisions demands an understanding of data provenance and quality in addition to confirming the validity of new approaches and methods for processing and analyzing these data. The Heads of Agencies and the European Medicines Agency Joint Big Data Taskforce was established to consider these issues from the regulatory perspective. This review reflects the thinking from its first phase and describes the big data landscape from a regulatory perspective and the challenges to be addressed in order that regulators can know when and how to have confidence in the evidence generated from big datasets. [ABSTRACT FROM AUTHOR]

Biologicals are established treatment options that require pharmacovigilance adapted to their specific nature, including the need for products to be identifiable up to the specific manufacturer in reports of adverse drug reactions (ADRs). This study explored the identifiability of 10 classes of similar and related biologicals up to the level of the manufacturer in ADR reports received from European clinical practice between 2011 and June 2016. Adequate identifiers were reported for 96.7% of the suspected biologicals, ranging from 89.5% for filgrastim to 99.8% for interferon beta‐1a. The product identifiability remained consistently high over time for classes of biologicals for which biosimilars were introduced during follow‐up. The overall batch traceability was, however, only ensured for 20.5% of the suspected biologicals and needs further improvement. This study shows that the European system for identification of ADRs to the level of the manufacturer is robust, allowing for the timely detection of potential product‐specific safety signals for biologicals. [ABSTRACT FROM AUTHOR]

This commentary aims to demonstrate how frequent interactions between a medicines developer, regulators, Health Technology Assessment (HTA) bodies, and patients during the development can result in accelerated access by patients to an innovative product, in this case, a gene therapy medicinal product for beta-thalassemia. Patients with transfusion-dependent beta-thalassemia require lifelong blood transfusions, leading to iron overload that impacts the patients' quality of life. To comply with the requirements for long-term follow-up, a product registry has been set up for patients treated with Zynteglo and patients treated with transfusions or HLA-matched allogenic HSCT-treated patients. [Extracted from the article]

The European Medicines Agency's (EMA) product‐specific bioequivalence guidelines outline harmonized regulatory requirements for studies to demonstrate bioequivalence for products that may have particular needs due to their pharmacokinetics, in addition to those outlined in general guidance. As such they are potentially very useful to the pharmaceutical industry in the development of generic medicinal products and to regulatory authorities for harmonized decision‐making. Since their introduction in 2013, EMA product‐specific bioequivalence guidelines continue to increase in number, and as of June 2017, encompass a number of different pharmacotherapeutic groups and pharmaceutical forms. This article further elucidates the processes involved for stakeholders and reviews the Agency's experience with the development of these guidelines, including the scientific issues witnessed with their advancement. A comparison with the United States Food and Drug Administration approach to similar guidelines is also provided. [ABSTRACT FROM AUTHOR]

Extrapolation can be used to address challenges in pediatric drug development. This review describes how these challenges could be addressed by further evolution of quantitative frameworks (i.e., model‐based/informed drug discovery and development) and regulatory science in support of pediatric drug development. Included are examples of diseases/indications where extrapolation has been used in different ways as a basis for identifying gaps in the framework and opportunities for continued advancement of pediatric drug development. [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic (PBPK) modeling is a valuable tool in drug development and regulatory assessment, as it offers the opportunity to simulate the pharmacokinetics of a compound, with a mechanistic understanding, in a variety of populations and situations. This work reviews the use and impact of such modeling in selected regulatory procedures submitted to the European Medicines Agency (EMA) before the end of 2015, together with its subsequent reflection in public documents relating to the assessment of these procedures. It is apparent that the reference to PBPK modeling in regulatory public documents underrepresents its use. A positive trend over time of the number of PBPK models submitted is shown, and in a number of cases the results of these may impact the decision-making process or lead to recommendations in the product labeling. These results confirm the need for regulatory guidance in this field, which is currently under development by the EMA. [ABSTRACT FROM AUTHOR]

Adaptive pathways for medicines have gained momentum and, in Europe, adaptive pathways have recently been introduced into the European Medicines Agency (EMA) processes after a successful 2-year pilot. Although the concept, as initially proposed, contained several elements that would have required regulatory reforms, the adaptive pathways program has developed a more pragmatic scope (Box 1). In this article, we explore the main challenges and opportunities adaptive pathways pose from a European health technology assessment (HTA) perspective. [ABSTRACT FROM AUTHOR]

Risk Management Plans (RMPs) have become a cornerstone in the pharmacovigilance of new drugs in Europe. The RMP was introduced in 2005 to support a proactive approach in gaining knowledge on safety concerns through early planning of pharmacovigilance activities. However, the rate at which uncertainties in the safety profile are resolved through this proactive approach is unknown. We therefore examined the evolution of safety concerns in the RMP after initial approval for a selected cohort of 48 drugs, to provide insight into the knowledge gain over time. We found that 20.7% of the uncertainties existing at approval had been resolved 5 years after approval. Because new uncertainties were included in the RMP at a similar rate, the overall number of uncertainties remained approximately equal. The relatively modest accrual of knowledge, as demonstrated in this study through resolution of uncertainties, suggests that opportunities for optimization exist while ensuring feasible and risk-proportionate pharmacovigilance planning. [ABSTRACT FROM AUTHOR]

Aiming to emulate the successful accelerated development of HIV/AIDS drugs, the Critical Path Institute (C-Path), in collaboration with the Engelberg Center for Health Care Reform at the Brookings Institution, has formed the Coalition Against Major Diseases (CAMD). Members include 6 nonprofit groups representing patients’ interests, 15 leading pharmaceutical companies, the US Food and Drug Administration (FDA), the European Medicines Agency (EMEA), 2 institutes of the National Institutes of Health (NIH)—the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS)—and representatives from academia. The coalition’s purpose is to transform the drug development paradigm for neurodegenerative diseases and serve as a model for other major diseases. [ABSTRACT FROM AUTHOR]

The Food and Drug Administration (FDA) Critical Path Initiative1 as well as the European Medicines Agency Road Map to 2010 (ref. 2) call for opportunities for more efficient drug development. One of the initiatives that has emerged in this context is the elaboration through guidance of exploratory investigational new drugs (INDs)/clinical trial applications (CTAs). This article reviews the history of these emerging guidances as well as the experience to date in their use by the industry.Clinical Pharmacology & Therapeutics (2008) doi:10.1038/sj.clpt.6100461 [ABSTRACT FROM AUTHOR]