Future of the drug label: Perspectives from a multistakeholder dialogue.

Regulating drugs does not end when market access has been granted. Monitoring drugs over the life cycle has become state of the art, inherent to evolving legislation and societal need. Here, we explore how the drug label could move along in a changing playing-field and become a sustainable label for the future. A dialogue between academia, government, the pharmaceutical industry and patient/societal organizations was organized by the Regulatory Science Network Netherlands. This is their view.

Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications.

BACKGROUND: Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy's clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. MATERIALS AND METHODS: We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). RESULTS: Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). CONCLUSION: Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. IMPLICATIONS FOR PRACTICE: Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies.

Synthetic polypeptides using a biologic as a reference medicinal product - the European landscape of regulatory approvals.

Recent advances in synthetic drug manufacturing have introduced a new dynamic to the European regulatory system, with chemically synthesized polypeptide products using biological originator products as their reference medicine. Whereas biosimilars are subject to a dedicated regulatory framework in the EU, synthetically produced follow-on products are not eligible for assessment through this pathway, requiring approval via the traditional generic pathway under Article 10 (1), or via the hybrid pathway under Article 10 (3). This review presents an overview of recent developments in the field of synthetic peptides referencing biological originators in the EU. The use of different regulatory procedures can have potential implications for regulatory assessments, clinical practice and pharmacovigilance. As more complex synthetic products referencing recombinant originator products are expected in the coming years, this study promotes more transparency as well as global alignment about regulatory procedures for chemically synthesised products referencing biological originator products to ensure approval of safe and high-quality generics.

The Global Landscape of Manufacturers of Follow-on Biologics: An Overview of Five Major Biosimilar Markets and 15 Countries.

BACKGROUND: Current knowledge is limited about which manufacturers are active in the global field of biopharmaceutical product development and how many unique follow-on biologics are approved in global markets. OBJECTIVE: This study aimed to provide a cross-sectional overview of manufacturers of follow-on biologics approved in 15 large countries from different regions of the world, as well as in five major biosimilar markets with long established biosimilar frameworks. METHODS: We screened national drug databases to identify follow-on biologics and their manufacturers approved in 15 countries in Asia, Africa, Latin America and the rest of the world, as well as five major biosimilar markets: the European Union (including the UK), USA, Canada, Australia and Japan. RESULTS: This study identified a total of 304 follow-on biologics from different manufacturers for 18 active substance classes included in the analysis. Of these, 67 products are approved as biosimilars in at least one of the five major biosimilar markets. A total of 140 (46%) follow-on biologics are manufactured in India or China, of which only eight (seven from India and one from China) are approved as biosimilars in any of the five major biosimilar markets. This study found that the majority of follow-on biologics are only approved in the respective country of manufacturing. A small number of manufacturers, primarily from India and Argentina, supply their products to other regions in the world. As some countries have less stringent regulatory approaches for biosimilars, or have only recently implemented biosimilar guidance in line with World Health Organization standards, follow-on biologics could have been approved that would not be considered biosimilars according to the World Health Organization standards. CONCLUSIONS: With this study, we try to contribute to discussions on creating more transparency about global approvals of follow-on biologics and promoting access to high-quality biosimilars in countries around the world.

Regulatory Flexibilities and Guidances for Addressing the Challenges of COVID-19 in the EU: What Can We Learn from Company Experiences?

The COVID-19 pandemic required urgency in the development and delivery of effective vaccines and therapeutics; meanwhile, ongoing clinical research, regulation and supply for other much-needed therapeutics and vaccines needed to be sustained. In Europe, the European Commission, the European Medicines Agency (EMA) and the national regulatory agencies (NRAs) responded by issuing guidance outlining regulatory flexibilities mainly directed at COVID-19 vaccines and, belatedly, therapeutics. Using a survey methodology, this study gathered the views of the R&D based pharmaceutical industry in May-June 2021 on the value of these flexibilities for continued use in the post-pandemic era as well as for future use in health emergency situations. Findings indicate that many flexibilities were foreseen to have value beyond the pandemic, particularly where EU and Member States aligned closely to provide a singular, streamlined regulatory environment. Digitalization was a notable driver of these flexibilities, but innovations in regulatory process (e.g. rolling reviews, flexible Scientific Advice) improved the process and outcomes measurably. Finally, the rapid reaction of the EU regulatory system and extensive efforts by all involved in providing innovative therapeutics and vaccines to patients in need provides learnings for the upcoming overhaul of the pharmaceutical acquis.

Four scenarios for the future of medicines and social policy in 2030.

The future of medicines is likely determined by an array of scientific, socioeconomic, policy, medical need, and geopolitical factors, with many uncertainties ahead. Here, we report from a scenario project, analyzing various trends, crucial and complex developments in the medicines' space. From a range of 'critical uncertainties' we derived two scenario drivers: global convergence, ranging from very high (trust and solidarity), to very low (fragmented ecosystems); and disease orientation, ranging from public health first to interceptive medicine. This resulted in four contrasting portraits of the future of medicines and social policy: deprioritizing the high-end; sustainable flow; transformative healing; and global divide. All those involved in drug discovery and development can use these for strengthening preparedness for the crucial challenges ahead.

The performance of wearable sensors in the detection of SARS-CoV-2 infection: a systematic review.

Containing the COVID-19 pandemic requires rapidly identifying infected individuals. Subtle changes in physiological parameters (such as heart rate, respiratory rate, and skin temperature), discernible by wearable devices, could act as early digital biomarkers of infections. Our primary objective was to assess the performance of statistical and algorithmic models using data from wearable devices to detect deviations compatible with a SARS-CoV-2 infection. We searched MEDLINE, Embase, Web of Science, the Cochrane Central Register of Controlled Trials (known as CENTRAL), International Clinical Trials Registry Platform, and ClinicalTrials.gov on July 27, 2021 for publications, preprints, and study protocols describing the use of wearable devices to identify a SARS-CoV-2 infection. Of 3196 records identified and screened, 12 articles and 12 study protocols were analysed. Most included articles had a moderate risk of bias, as per the National Institute of Health Quality Assessment Tool for Observational and Cross-Sectional Studies. The accuracy of algorithmic models to detect SARS-CoV-2 infection varied greatly (area under the curve 0·52-0·92). An algorithm's ability to detect presymptomatic infection varied greatly (from 20% to 88% of cases), from 14 days to 1 day before symptom onset. Increased heart rate was most frequently associated with SARS-CoV-2 infection, along with increased skin temperature and respiratory rate. All 12 protocols described prospective studies that had yet to be completed or to publish their results, including two randomised controlled trials. The evidence surrounding wearable devices in the early detection of SARS-CoV-2 infection is still in an early stage, with a limited overall number of studies identified. However, these studies show promise for the early detection of SARS-CoV-2 infection. Large prospective, and preferably controlled, studies recruiting and retaining larger and more diverse populations are needed to provide further evidence.

Regulatory density as a means to refine current regulatory approaches for increasingly complex medicines.

The continuous scientific, societal, and technological advancements have shifted drug development toward increasingly complex and ever more targeted treatments. This creates new and unprecedented challenges for global regulatory systems. To address the increased risks and uncertainties of increasingly complex medicine, we advocate for a more tailored and flexible regulatory approach, which is explained here with the concept of 'regulatory density'. In the context of this paper, 'regulatory density' describes the relative amount of obligatory standards, measures and procedures applied to certain medicinal products or product classes and the resources required to meet these requirements. Given that risk and uncertainty are dynamic variables that can change over time, with this paper, we want to stimulate (re)thinking of regulatory approaches for managing the challenges of future complex medicines.

The Use of Remote Monitoring Technologies: A Review of Recent Regulatory Scientific Advices, Qualification Opinions, and Qualification Advices Issued by the European Medicines Agency.

Aims: Recently, the use of novel remote monitoring technologies (RMTs) in trials has gained much interest. To facilitate regulatory learning, we evaluated qualification opinions (QOs) and advices (QAs) and scientific advices (SAs) of the Committee for Medicinal Products for Human Use (CHMP) to gain insight in the types of devices that are intended to be used in clinical trials for supporting/submitting application for obtaining marketing authorization (registration trials) and the main recommendations of the CHMP. Methods: QOs, QAs, and SAs of the CHMP that assessed RMTs between 2013 and 2019 were eligible for our study. The following information was extracted from the documents: year of advice/opinion, device and endpoints used, type of endpoint (primary, secondary, exploratory, or safety), and main recommendations of the CHMP. Results: In total two QOs, four QAs, and 59 SAs were included in our study (total of SAs between 2013 and 2019 = 4,054). In the SAs, accelerometers to measure activity and/or sleep parameters (n = 31) were the most frequently used devices, followed by mobile applications (n = 6) and glucose monitoring devices (n = 6). Usually, these measures were proposed as secondary or exploratory endpoints (n = 32). The main recommendations of the CHMP were related to relevance of the (novel) outcome measure; validation; precision, accuracy, sensitivity, and specificity; compliance; sampling interval; and data handling and privacy. Conclusions: Although there was a trend toward an increased use over time, the use of RMTs in registration trials is still relatively rare. In the absence of formal European regulatory guidance on mHealth technologies, insight in the main recommendations of the CHMP may stimulate the use of novel RMTs in a regulatory context.

The pharmaceutical sciences in 2020: report of a conference organized by the board of pharmaceutical sciences of the International Pharmaceutical Federation (FIP).

The Board of Pharmaceutical Sciences (BPS) of the International Pharmaceutical Federation (FIP) has developed a view on the future of pharmaceutical sciences in 2020. This followed an international conference with invited participants from various fields (academicians, scientists, regulators, industrialists, venture capitalists) who shared their views on the forces that might determine how the pharmaceutical sciences will look in 2020. The commentary here provides a summary of major research activities that will drive drug discovery and development, enabling technologies for pharmaceutical sciences, paradigm shifts in drug discovery, development and regulations, and changes in education to meet the demands of academia, industry and regulatory institutions for pharmaceutical sciences in 2020.

The UK BIO-TRAC Study: A Cross-Sectional Study of Product and Batch Traceability for Biologics in Clinical Practice and Electronic Adverse Drug Reaction Reporting in the UK.

INTRODUCTION: Due to the complexity of biologics and the inherent challenges for manufacturing, it is important to know the specific brand name and batch number of suspected biologics in adverse drug reaction (ADR) reports. OBJECTIVE: The aim of this study was to assess the extent to which biologics are traceable by brand name and batch number in UK hospital practice and in ADRs reported by patients and healthcare professionals. METHODS: We performed an online hospital pharmacist survey to capture information on how specific product details are recorded during the processes of prescribing, dispensing and administration of biologics in routine UK hospital practice. We also assessed the proportion of ADR reports specifying brand name and batch number from electronic ADR reports submitted to the UK national spontaneous reporting database, the Yellow Card Scheme, between 1 January 2009 and 30 September 2017. RESULTS: Brand name recording in routine hospital processes ranged from 79 to 91%, whereas batch numbers were less routinely recorded, ranging from 38 to 58%. Paper-based recording of product details was more commonly used for recording information. A total of 6108 electronic ADR reports were submitted to the Yellow Card Scheme for recombinant biologics, of which 38% and 15%, respectively, had an identifiable brand name and batch numbers. Whereas batch number traceability in electronic ADR reports improved slightly after the implementation of the European Union pharmacovigilance legislation in 2012, no improvement of brand name traceability was observed. CONCLUSION: Brand name and batch number traceability for biologics in UK ADR reports are generally low. Shortcomings in the systematic recording of product details in UK clinical practice may contribute to the limited traceability.

A Proposed Framework for a Globally Applicable Pragmatic Approach to Using Facilitated Regulatory Pathways.

BACKGROUND: As regulatory agencies come under increased pressure to review medicines of critical importance through efficient regulatory systems to provide equitable access, the benefits of using expedited review pathways are being explored. These facilitated regulatory pathways (FRPs) provide a variety of review strategies that can also expedite assessments. Stringent regulatory authorities (SRAs) use primary FRPs to accelerate development or to shorten review time. Some emerging national regulatory authorities can implement primary FRPs but are more likely to use secondary FRPs that rely on or recognize an SRA or reference agency decision, the World Health Organization Collaborative Prequalification of Medicines Programme, "altruistic" reviews, or collaborative work sharing. Despite their availability, there are no formal guidelines or consensus for the definition, basic elements, or best practices for FRPs. METHODS: Herein, we present a 4-step pragmatic approach to a framework designed to help agencies determine how best to use FRPs. Each step is based on characteristics identified through research, surveys, literature assessments, regulatory capacity categorization analyses, and practical experience. RESULTS: Step 1 assesses 4 domains of the environment preparedness, step 2 offers process criteria that should be in place to effectively use an FRP, step 3 tiers agencies through a self-assessment of readiness and capacity, and step 4 provides a pathway for agencies to determine the most relevant FRP for their use. Target timelines are proposed for FRPs. CONCLUSIONS: This framework represents the first endeavor to holistically address the multifaceted aspects that should be considered for the effective use of an FRP.

The use of driving impairing medicines: a European survey.

AIM: To analyse the consumption of a number of medicines with a known potential for increasing the risk of road traffic accidents in the general population of Europe. METHODS: Questionnaires were distributed through the European Drug Utilization Research Group (EuroDURG) and Post-Innovation Learning through Life-events of drugs (PILLS) networks. A total of 30 countries (the current EU Member States, Iceland, Norway and Switzerland) were asked to supply data on the use of driving impairing medicines for the period 2000-2005, aggregated at the level of the active substance and presented in Defined Daily Doses (DDDs) per 1000 inhabitants per day. RESULTS: National utilization data were provided by 12 of the 30 countries. Based on these data, a considerable increase in consumption was only seen for the antidepressants and the selective serotonin reuptake inhibitors. A slight increase, decrease or no increase was seen for the rest of the drugs studied (i.e. opioids, antipsychotics, anxiolytics, hypnotics and sedatives, drugs that are used in addictive disorders and antihistamines). Limitations were encountered when data on driving impairing medicines were compared between countries (e.g. variation in the data sources and providers, population coverage, inclusion of hospital data, use of divergent ATC/DDD versions) and, therefore, a cross-national comparison could not be performed. CONCLUSIONS: During the study period, trends within countries showed slight to no increase in the consumption of selected medicinal drug groups, with the exception of the antidepressants and the selective serotonin reuptake inhibitors: they showed a remarkable increased use during the study time-frame. Our results illustrate that it is still difficult to perform a valid and comprehensive collection of drug utilization data on driving impairing medicines. Therefore, efforts to harmonize data collection techniques are required and recommended.

Gap in publication of comparative information on new medicines.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Randomized active control trials are used by health care professionals and reimbursement authorities for the assessment of the added value of a new medicine. Failing to publish the results of clinical trials limits making an evidence based assessment and conducting systematic reviews. WHAT THIS STUDY ADDS: About one-third of the comparative trials used in the authorization process are published at the moment of market authorization and about four out of five within 2 or 3 years. Most of the rest remain unpublished. Unpublished trials contain information regarding a different therapeutic use or a different comparator of the same medicine and, in some cases, have influenced the risk : benefit assessment of the registration authorities. A standardized public registration of results of the main premarketing trials is advocated to fill the publication gap. AIMS: To determine the time-lag between the EU authorization of new medicines and the publications of the main randomized active control trials (RaCTs) used in the authorization process and to compare unpublished with published RaCTs of the same medicine. METHODS: All RaCTs for new medicines with a new active substance, authorized between 1999 and 2003, were extracted from the European Public Assessment Reports (EPAR). Information about the publication status of RaCTs was obtained from the MEDLINE and EMBASE databases. RESULTS: We identified 116 RaCTs for 42 new medicines; 28% of the RaCTs had been published at the moment of market authorization, 59% after 1 year, 78% after 2 and 83% after 3 years. Most of the rest of the studies remained unpublished after 3 years of follow-up. Unpublished RaCTs differed from published trials of the same medicine especially regarding therapeutic use and/or comparator. In some cases unpublished trials have influenced the risk : benefit asssessment of the registration authorities. CONCLUSIONS: Most of the main RaCTs, relevant for assessing the added value of a new medicine, are published subsequent to market entry; some of these trials remain unpublished. We argue for a standardized public registration of the results of the main premarketing clinical trials as a condition for market authorization.

Variable access to clopidogrel in a harmonized EU market.

OBJECTIVES: This study focuses on the different national coverage and reimbursement strategies and their consequences for access to clopidogrel, a drug with a central European Union (EU) registration. Our objectives are 1) to assess whether changes in reimbursement policies in EU member states influenced clopidogrel prescribing; and 2) to determine whether clopidogrel-specific policy characteristics, general characteristics of the health system, or indicators for the amount of cardiovascular care delivered were associated with the level of clopidogrel prescribing. METHODS: Data were collected in Austria, Belgium, Denmark, Germany, Hungary, Portugal, Slovenia, The Netherlands, and the United Kingdom (England). Utilization rates were expressed as defined daily doses (DDDs)/1000 persons/day. To determine whether changes in reimbursement policies influenced clopidogrel utilization, a segmented linear regression approach was used. RESULTS: Clopidogrel prescribing varied widely in the studied countries, from 2.76 (The Netherlands) to 6.83 (Belgium) DDDs/1000 persons/day (March 2005). Six countries had therapeutic indication restrictions to clopidogrel use. Health system characteristics did not explain variation in clopidogrel prescribing. CONCLUSION: A disconnect will be indicated in this study between the concept of a harmonized EU pharmaceuticals market and the reality in an individual member state. Although clopidogrel was centrally registered in the EU, policy measures at the national level result in different roles in clinical practice for this drug.

Impact analysis of the discontinuation of reimbursement: the case of oral contraceptives.

BACKGROUND: We studied the impact of suspending oral contraceptive (OC) reimbursement in the Netherlands for women >21 years starting 1 January 2004. Discontinuation and switching patterns and the time course of the policy intervention's effects were determined. STUDY DESIGN: The intervention cohort contained OC users on 1 January 2004; the control cohort users on 1 January 2003. Follow-up duration was 1 year. Discontinuation and switching patterns were assessed using relative risks (RR). Weekly refill fractions were calculated to determine the time course of the policy effects. RESULTS: Our intervention cohort contained 434,917 OC users; the control cohort 489,904 users. When we excluded patients not affected by the policy intervention (i.e., all patients younger than 20 years), discontinuation rates were 15.3% (intervention cohort) and 12.3% (control cohort) (RR=1.24; 95% CI=1.23-1.26) and increased with age. Switching to cheaper OCs was greatest in the intervention cohort, particularly in the 40- to 44-year age group. Differences in cumulative refill fractions showed large variation over time. CONCLUSION: The OC reimbursement intervention led to an increase in the discontinuation rate of 24%. The effect increased with older age groups. Considering the time course of effects of policy interventions is of critical importance.

Challenges and Opportunities for the Traceability of (Biological) Medicinal Products.

This article provides an overview of the current situation regarding the traceability of medicinal products, with a focus on drug safety and biologics. Limited traceability of biologics, in particular with regard to the batch number, is associated with incomplete recording of exposure information in clinical practice. The current pharmaceutical barcode standards in the EU do not support the automatic recording of dynamic product information, such as batch numbers and expiry dates, by means of electronic barcode scanning in clinical practice. New barcode requirements, such as the 2D DataMatrix with encoded batch numbers and expiry dates, provided on both the primary and the secondary package, can facilitate routine barcode scanning at all points in the supply chain in different healthcare settings. To build a full track-and-trace system for medicines with electronic capture of relevant exposure information, alignment with other topics, such as the Falsified Medicines Directive and initiatives to reduce medication errors, is needed to increase the buy-in from all stakeholders and to solve multiple issues with a joint effort.

The future of drug development: the paradigm shift towards systems therapeutics.

Progress in cell biology, genetics, molecular, and systems pharmacology is the driving force behind a current paradigm shift in drug research. This paradigm shift shapes new avenues for advanced treatments that are commonly referred to as 'systems therapeutics'. Systems therapeutics differ in many ways from current drugs because they target biological networks rather than single transduction pathways, and affect disease processes rather than physiological processes. Here, we examine how the paradigm shift towards systems therapeutics will change current scientific concepts of the interactions between drugs and diseases, the organization of research and development, as well as the clinical use and therapeutic evaluations of therapeutic interventions.

When More Is Less: An Exploratory Study of the Precautionary Reporting Bias and Its Impact on Safety Signal Detection.

Concerns have been expressed that large numbers of nonvalue-added reports have been accumulating in adverse drug reaction (ADR) databases, for example, via patient support programs. We performed an assessment of the impact of such reports, which we refer to as "precautionary reports," on safety signal detection in the Netherlands. The case narratives of ADR reports of three case products were screened with text-mining algorithms to identify those reports that lack a causal relationship with the suspected medicinal product. We demonstrate that precautionary reports impede the optimal use of the pharmacovigilance system by, on the one hand, masking safety signals and, on the other hand, creating spurious signals. The precautionary reporting bias and its suppressing effect on statistical signal detection results in an altered adverse event safety profile. The findings from this study highlight the need for a better alignment between regulatory authorities and marketing authorization holders regarding pharmacovigilance guidelines.

Factors related to drug approvals: predictors of outcome?

There is growing interest in characterising factors associated with positive regulatory outcomes for drug marketing authorisations. We assessed empirical studies published over the past 15 years seeking to identify predictive factors. Factors were classified to one of four 'factor clusters': evidentiary support; product or indication characteristics; company experience or strategy; social and regulatory factors. We observed a heterogeneous mix of technical factors (e.g., study designs, clinical evidence of efficacy) and less studied social factors (e.g., company-regulator interactions). We confirmed factors known to be of relevance to drug approval decisions (imperative) and a cohort of less understood (compensatory) social factors. Having robust supportive clinical evidence, addressing rare or serious illness, following scientific advice and prior company experience were associated with positive outcomes, which illustrated the multifactorial nature of regulatory decision making and factors need to be considered holistically while having varying, context-dependent importance.