Search

Bringing therapeutic innovation and the latest science to routine patient care, while safeguarding principles of affordability and equality, is a challenging mission in the current complex multi-stakeholder environment. Precision oncology and new approaches to clinical trials (methods and clinical setting) have dramatically changed clinical research and the clinical development of new treatments. Improved understanding of molecular biology and immunology paves the way for innovative pharmacological approaches. However, we argue that the evidence generated during the clinical development of these new products for the purpose of obtaining marketing authorisations often does not address fundamental questions concerning the impact of these new interventions on the most relevant clinical outcomes: namely, quality of life and patient survival. Similarly, patient populations (for example defined by biomarkers), treatment duration, and sequence and combination of treatments within current treatment pathways are often poorly defined by clinical developments for regulatory purposes. Finally, the lack of integrated translational research within the pathway of development is a major limiting factor to delivering cost-effective and affordable, evidence-based care to clinical practice. This leaves many gaps in the knowledge on the efficacy and therapeutic use of medicines, which can impose a significant financial burden on healthcare systems, possibly to the detriment of more cost-effective interventions. We argue that policy changes are required to integrate clinical research and healthcare to inform clinical practice. New routes toward optimising the integration of drug development and care are being proposed to achieve this ultimate goal.

Background: The lower bound of the 95% confidence interval of measures of disproportionality (Lower95CI) is widely used in signal detection. Masking is a statistical issue by which true signals of disproportionate reporting are hidden by the presence of other medicines. The primary objective of our study is to develop and validate a mathematical framework for assessing the masking effect of Lower95CI. Methods: We have developed our new algorithm based on the masking ratio (MR) developed for the measures of disproportionality. A MR for the Lower95CI (MRCI) is proposed. A simulation study to validate this algorithm was also conducted. Results: We have established the existence of a very close mathematical relation between MR and MRCI. For a given drug–event pair, the same product will be responsible for the highest masking effect with the measure of disproportionality and its Lower95CI. The extent of masking is likely to be very similar across the two methods. An important proportion of identical drug–event associations affected by the presence of an important masking effect is revealed by the unmasking exercise, whether the proportional reporting ratio (PRR) or its confidence interval are used. Conclusion: The detection of the masking effect of Lower95CI can be automated. The real benefits of this unmasking in terms of new true-positive signals (rate of true-positive/false-positive) or time gained by the revealing of signals using this method have not been fully assessed. These benefits should be demonstrated in the context of prospective studies.

Objectives The primary objective of this study was to compare the availability and access of orphan medicinal products (OMPs) in the devolved nations in the United Kingdom (UK), France, Germany, Italy and Spain. Availability is defined as the possibility to prescribe OMPs. Access refers to their full or partial reimbursement by the public health service. Methods Data were collated on: marketing authorisations, Health Technology Assessment (HTA) decisions, commissioning, and reimbursement decisions, and respective dates of these events for all the OMPs centrally authorised. Indicators of availability of and access to OMPs were calculated in each country and compared. Results We found that since the implementation of the OMPs Regulation in 2000 to end of May 2016, 143 OMPs obtained a marketing authorisation in the European Union. These OMPs are most widely accessible in Germany and France. In the other countries between 30 and 60% of OMPs are reimbursed. In particular in England, less than 50% of centrally authorised OMPs are routinely funded by the NHS, with one-third of these recommended by NICE. In Germany reimbursement is automatically granted to all medicines which receive a marketing authorisation, immediately after authorisation – but since 2011, there is an evaluation and potentially a pricing negotiation between companies and sickness funds (third party payers). In the other countries, the shortest time from authorisation to a reimbursement decision is observed in Italy and France where it takes 18.6 and 19.5 months respectively on average. Conclusions Marketing authorisation granted to OMPs is only the first step, as medicines reach patients when reimbursement decisions are implemented by national health systems (this applies to non-OMPs too). We found that more than a half of centrally authorised OMPs were available in the five selected countries, but that access to patients was further restricted by different national reimbursement policies, especially in the UK, Italy and Spain. Electronic supplementary material The online version of this article (10.1186/s13023-019-1078-5) contains supplementary material, which is available to authorized users.

Sophie Cooper, Jacoline Bouvy and colleagues discuss the challenges that histology independent cancer drugs will pose for NICE and the NHS

Background Masking is a statistical issue by which signals are hidden by the presence of other medicines in the database. In the absence algorithm, the impact of the masking effect has not been fully investigated. Objective Our study is aimed at assessing the extent and the impact of the masking effect on two large spontaneous reporting databases. Study design Cross sectional study using a set of terms of importance for public health in two spontaneous reporting databases. Setting The analyses were performed on EudraVigilance (EV) and the Pfizer spontaneous reporting database (PfDB). Main outcome measure Using the masking ratio, we have identified and removed the products inducing the highest masking effect. Results Studying a total of almost 50 000 drug-event combinations masking had an impact on approximately 60% of drug-event combinations were masked by another product with a masking ratio >1 in EV and 84% in PfDB. The prevalence of important masking was quite rare (0.003% of the DECs) and mainly affected events rarely reported in EV. The products involved in the highest masking effects are products known to induce the reaction. The removal of the masking effect of the highest masking product has revealed 974 signals of disproportionate reporting in EV including true signals. The study shows that the original ranking provided by the quantitative methods included in our study is marginally affected by the removal of the masking product. Conclusion Our study suggests that significant masking is rare in large spontaneous databases and mostly affects events rarely reported in EV. Copyright © 2013 John Wiley & Sons, Ltd.

Background Masking is a statistical issue by which true signals of disproportionate reporting are hidden by the presence of other products in the database. Masking is currently not perfectly understood. There is no algorithm to identify the potential masking drugs to remove them for subsequent analyses of disproportionality. Objective The primary objective of our study is to develop a mathematical framework for assessing the extent and impact of the masking effect of measures of disproportionality. Method We have developed a masking ratio that quantifies the masking effect of a given product. We have conducted a simulation study to validate our algorithm. Results The masking ratio is a measure of the strength of the masking effect whether the analysis is performed at the report or event level, and the manner in which reports are allocated to cells in the contingency table significantly impact the masking mechanisms. The reports containing both the product of interest and the masking product need to be handled appropriately. The proposed algorithm can use simplified masking provided that underlying assumptions (in particular the size of the database) are verified. For any event, the strongest masking effect is associated with the drug with the highest number of records (reports excluding the product of interest). Conclusion Our study provides significant insights with practical implications for real-world pharmacovigilance that are supported by both real and simulated data. The public health impact of masking is still unknown. Copyright © 2013 John Wiley & Sons, Ltd.

The primary objective of the study was to analyse the proposed clinical development and economic evaluation plans for investigational medicinal products for which pharmaceutical companies have sought health technology assessment (HTA) scientific advice (SA).We have selected and analysed all the scientific advice procedures undertaken by National Institute for Health and Care Excellence (NICE) SA between 1 January 2009 and 3 December 2015 for investigational medicinal products. We have mapped the questions asked by the companies and the areas of advice highlighted in the advice reports to the sections of the NICE methods guide to the technology appraisals (2013).An overwhelming proportion of SA procedures have addressed questions related to the clinical development and specifically the main pivotal efficacy studies. Approximately a quarter of the questions relate to the approaches to economic evaluation. Questions raised in European Medicines Agency-HTA procedures generally focus on clinical efficacy issues whereas cost-effectiveness ones tend to dominate in NICE-only procedures. Our analysis shows that the issues mostly discussed in the HTA SA are the choice of comparator, the generalisability of the clinical trial evidence to the NHS practice and the impact of the clinical trial outcomes on quality of life and survival. Less disagreement with the developers' plans was seen in the choice of clinical endpoints, population definition, position of the technology in the treatment pathway and study design.Scientific advice is designed to improve the quality of evidence and approaches to evidence generation for future regulatory approval and HTA evaluation. Our experience to date suggests that payer requirements are inconsistently integrated in the clinical development programmes. More efforts should be dedicated to demonstrating the clinical value of new medicinal products to patients and key decision-makers.

INTRODUCTION:Under the Orphan Regulation, the European Medicines Agency (EMA) intended to incentivize the research and development of new treatments for rare and life-threatening conditions. Marketing authorisation of orphan medicinal products (OMPs) by the EMA is only the first step, as medicines are made available to patients when reimbursement or Health Technology Assessment (HTA) decisions are implemented by national health systems. We analyzed the availability and access to OMPs in the United Kingdom (UK), France, Germany, Italy and Spain. We compared the availability, which is the possibility to prescribe a given OMP, to the access, which refers to the full or partial reimbursement by the public health service.METHODS:We collected data on launches, HTA decisions, any centralized commissioning and/or reimbursement decision for all the OMPs authorised since 2000 in the UK countries (England, Scotland and Wales), France, Germany, Italy and Spain.RESULTS:Since the Orphan Regulation inception, the EMA granted marketing authorization to 143 OMPs. These OMPs are most widely accessible in Germany and France. Reimbursement in Germany is immediate after authorization. France and Italy present a delay of 19 months from authorization to reimbursement, which is shorter than in other countries. In England, less than 50 percent of centrally authorised OMPs are routinely funded by the National Health Service (NHS), including one-third of these recommended by the National Institute for Health and Care Excellence (NICE), and those reimbursed via commissioning policies and the Cancer Drugs Fund.CONCLUSIONS:The assessment of degree of access to OMPs across Europe is limited by differences in the national HTA and reimbursement systems and the heterogeneous information made publicly available on their decisions. Nonetheless, our study suggests that the primary purpose to grant equal availability to OMPs to the patients in the Eropean Union via the implementation of the orphan regulation was partially achieved with important variations of access observed across the countries included in our study.

Background: Screening large databases of spontaneous case reports of possible adverse drug reactions (ADRs) is an established method of identifying hitherto unknown adverse effects of medicinal products; however, there is a lack of consensus concerning the value of formal statistical screening procedures in guiding such a process. This study was performed to clarify the nature of any added benefits and additional effort required when established pharmacovigilance techniques are supplemented with statistical screening. Objective: To evaluate whether statistical signal detection in spontaneous reporting data can lead to earlier detection of drug safety problems and to assess the additional regulatory work entailed. Methods: Using the EudraVigilance post-authorization module (EVPM), a screening procedure based on the proportional reporting ratio (PRR) was applied retrospectively to examine if regulatory investigations concerning ADRs in a predefined set of products could have been initiated earlier than occurred in practice. During the same time period, between September 2003 and March 2007, the number of PRR-based signals of disproportionate reporting (SDR) that arose in the same set of products was calculated and evaluated to determine the number requiring investigation. The outcome is expressed as the ratio of the number of SDRs requiring investigation compared with the number of signals pre-empted by the statistical screening approach. In those cases where the signal was discovered earlier, the delay was calculated between identification by the PRR method and by the method that originally identified the signal. Results: In 191 chemically different products, 532 adverse reactions were added to the summary of product characteristics during the study period. Of these, 405 were designated as important medical events (IMEs) based on a comprehensive predefined list. Of the IMEs, 217 (53.6%) were identified earlier by the statistical screening technique, 79 (19.6%) were detected after the date at which they were raised by standard pharmacovigilance methods and 109 (26.9%) were not signalled during the study period. 1561 SDRs requiring further evaluation were detected during the study period, giving a ratio of 7.2 assessments for each signal pre-empted. The mean delay between the discovery of signals using the statistical methods in the EVPM and established methods in the 217 cases detected earlier was 2.45 years. A review resulted in clear explanation for why the statistical method had not preempted detection in all but 77 of 188 cases. Conclusions: The form of statistical signal detection tested in this study can provide significant early warning in a large proportion of drug safety problems; however, it cannot detect all safety issues more quickly than other pharmacovigilance processes and hence it should be used in addition to, rather than as an alternative to, established methods.

It has been postulated that the time to onset of adverse drug reactions is connected to the underlying pharmacological (or toxic) mechanism of adverse drug reactions whether the reaction is time dependent or not.We have conducted a preliminary study using the parametric modelling of the time to onset of adverse reactions as an approach to signal detection on spontaneous reporting system databases.We performed a parametric modelling of the reported time to onset of adverse drug reactions for which the underlying toxic mechanism is characterized. For the purpose of our study, we have used the reported liver injuries associated with bosentan, and the infections associated with the use of the tumour necrosis factor (TNF) inhibitors, adalimumab, etanercept and infliximab, which are used in Crohn's disease and rheumatoid arthritis, reported to EudraVigilance between December 2001 and September 2006.The main results reflect the fact that the reported time to onset is a surrogate of the true time to onset of the reaction and combines three hazards (occurrence, diagnosis and reporting) that cannot be disentangled. Consequently, the modelling of the time to onset of reactions reported with TNF inhibitors showed differences that could reflect different pharmacological activities, indications, monitoring of the patients or different reporting patterns. These variations could also limit the interpretation of the parametric modelling.Some consistency that was found between the occurrences of the infections with the TNF inhibitors suggests a causal association. There are statistical issues that are important to keep in mind when interpreting the results (the impact of the data quality on the fit of the distributions and the absence of a test of hypothesis linked to the absence of a relevant comparator). The study suggests that the modelling of the reported time to onset of adverse reactions could be a useful adjunct to other signal detection methods.

Data mining algorithms are increasingly being used to support the process of signal detection and evaluation in pharmacovigilance. Published data mining exercises formulated within a screening paradigm typically calculate classical performance indicators such as sensitivity, specificity, predictive value and receiver operator characteristic curves. Extrapolating signal detection performance from these isolated data mining exercises to performance in real-world pharmacovigilance scenarios is complicated by numerous factors and some published exercises may promote an inappropriate and exclusive focus on only one aspect of performance. In this article, we discuss a variation on positive predictive value that we call the ‘number needed to detect’ that provides a simple and intuitive screening metric that might usefully supplement the usual presentations of data mining performance. We use a series of figures to demonstrate the nature and application of this metric, and selected adaptive variations. Even with simple and intuitive metrics, precisely quantifying the performance of contemporary data mining algorithms in pharmacovigilance is complicated by the complexity of the phenomena under surveillance and the manner in which the data are recorded in spontaneous reporting systems.

Regulatory watch: Outcomes of early health technology assessment dialogues in medicinal product development

Wound healing is the main cause of the failure of filtering surgery in glaucoma. We developed a liposomal delivery system of mitoxantrone (MITX), an anthracyclin derivative, to allow a single adjuvant administration and to lessen ocular side-effects of the drug. In order to evaluate the antiproliferative activity of liposomal MITX, an ex vivo model consisting in the culture of subconjunctival tissue explants from rabbits pretreated with subconjunctival injections of free or liposomal MITX was used. We found that both forms of MITX decreased the growth rate as well as the explant proliferation surfaces 15 days or 1 month after a single administration of the drug in vivo. A morphometric analysis of the cells showed that the surface of the fibroblasts exposed to both forms of MITX was from 10 to 12 times as important as that of the control cells exposed to the empty liposomes and to the control buffer. A radioautographic study showed that more than 95% of the fibroblasts exposed to both forms of MITX were in the G1 phase of the cell cycle, while the control cell population was equally distributed among the different phases of the cell cycle.

Pharmacological blockade of fibroblastic proliferation after glaucoma filtration surgery by using antimitotic agents in different formulations (liposomes, nanospheres) is of great clinical interest. However, only limited comparative data are available on the effect of encapsulated drugs on intraocular pressure (IOP) after filtering surgery. Therefore we have studied the effect on IOP of liposomes, nanospheres and a solution of mitoxantrone (MTO), a well-known antimitotic, in rabbits before and after sclerectomy. MTO in solution form, as well as in a liposome formulation, improved the outcome of the surgery by reducing IOP when administered subconjunctivally just following surgery. This effect was similar to mitomycin-C application. In contrast, neither prior administration nor subconjunctival nanosphere injections induced a reduction in IOP. Liposome administration demonstrated no delayed action or promoting effect but reduced the occurrence of corneal opacity observed in groups treated with MTO in solution.