European medicines agency approval summary: zaltrap for the treatment of patients with oxaliplatin-resistant metastatic colorectal cancer

On 1 February 2013, a marketing authorisation valid throughout the European Union was issued for aflibercept (Zaltrap) in combination with irinotecan/5-fluorouracil/ folinic acid chemotherapy for the treatment of adults with metastatic colorectal cancer resistant to or progressive after an oxaliplatin-containing regimen. Aflibercept is a recombinant fusion protein which blocks the activation of vascular endothelial growth factor (VEGF) receptors and the proliferation of endothelial cells, acting as a soluble decoy receptor that binds to VEGF-A with higher affinity than its native receptors, as well as placental growth factor and VEGF-B. The use of aflibercept was studied in a randomised, double-blind, placebo-controlled phase III study, in patients with metastatic colorectal cancer (mCRC) who had previously been treated with an oxaliplatinbased treatment with or without prior bevacizumab. Aflibercept (n=612) was compared with placebo (n=614), both in combination with FOLFIRI (infusional fluorouracil, leucovorin and irinotecan). The primary endpoint of the study was overall survival (OS). The median OS in the intent-to-treat population was 13.5 months in subjects treated with aflibercept compared with 12.1 months for subjects in the control arm (stratified HR=0.817, 95% CI 0.714 to 0.935, stratified pvalue=0.0032). The frequency of adverse events was higher in the aflibercept arm compared with the placebo arm, reflecting the toxicity profile of anti-VEGF agents in combination with chemotherapy. This paper is based on the scientific review of the application leading to approval of aflibercept in the EU. The detailed scientific assessment report and product information for this product are available on the European Medicines Agency website

How can a joint European health technology assessment provide an 'additional benefit' over the current standard of national assessments? Insights generated from a multi-stakeholder survey in hematology/oncology

Objectives We conducted a multi-stakeholder survey to determine key areas where a joint European health technology assessment (HTA) could provide 'additional benefit' compared to the status quo of many parallel independent national and subnational assessments. Methods Leveraging three iterative Delphi cycles, a semiquantitative questionnaire was developed covering evidence challenges and heterogeneity of value drivers within HTAs across Europe with a focus on hematology/oncology. The questionnaire consisted of five sections: i) background information; ii) value drivers in HTA assessments today; iii) evolving evidence challenges; iv) heterogeneity of value drivers across Europe; v) impact of Europe's Beating Cancer Plan (EBCP). The questionnaire was circulated across n = 189 stakeholder institutions comprising HTA and regulatory bodies, clinical oncology associations, patient representatives, and industry associations. Results N = 30 responses were received (HTA bodies: 9; regulators: 10; patients' and physicians' associations: 3 each; industry: 5). Overall, 17 countries and EU level institutions were represented in the responses. Consistency across countries and stakeholder groups was high. Most relevant value drivers in HTAs today (scale 1, low to 5, high) were clinical trial design (mean 4.45), right endpoints (mean 4.40), and size of comparative effect (mean 4.33). Small patient numbers (mean 4.28) and innovative study designs (mean 4.1) were considered the most relevant evolving evidence challenges. Heterogeneity between regulatory and HTA evidence requirements and heterogeneity of the various national treatment standards and national HTA evidence requirements was high. All clinical and patient participants stated to have been with EBCP initiatives. Conclusions For a European HTA to provide an 'additional benefit' over the multitude of existing national assessments key methodological and process challenges need to be addressed. These include approaches to address uncertainty in clinical development; comparator choice; consistency in approaching patient-relevant endpoints; and a transparent and consistent management of both HTA and regulatory procedures as well as their interface, including all involved stakeholder groups

Overview of the European Medicines Agency's development of product-specific bioequivalence guidelines

The authors thank the observers of the PKWP who have supported the development of the PSBGL and also Efthymios Manolis, Quirine Fillekes, and Milton Bonelli for constructive comments. Pharmacokinetics Working Party: Ridha Belaiba (ANSM, France); Eva-Gil Berglund (MPA, Sweden); Susan Cole (MHRA, UK); Alfredo García-Arieta (AEMPS, Spain); Sotiris Michaleas (Ministry of Health Pharmaceutical Services, Cyprus); Janet Mifsud (Medicines Authority, Malta); Jan Neuhauser (AGES, Austria); Henrike Potthast (BfArM, Germany); Carolien Versantvoort (MEB, The Netherlands).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.peer-reviewe

Where is industry getting it wrong? : A review of quality concerns raised at Day 120 by the Committee for Medicinal Products for Human Use during European centralised marketing authorisation submissions for chemical entity medicinal products

Purpose The aim of this study was to identify common trends in the deficiencies identified in the quality part of the dossier during the evaluation of marketing authorisation applications for medicinal products for human use submitted through the EU’s centralised procedure. Methods We analysed all the adopted Day 120 list of questions on the quality module of 52 marketing authorisation applications for chemical entity medicinal products submitted to the European Medicines Agency and evaluated by the Committee for Medicinal Products for Human Use (CHMP), during 12 consecutive plenary meetings held in 2007 and 2008. Subsequently we calculated the frequency of common deficiencies identified across these applications. Results Frequencies and trends on quality deficiencies have been recorded and presented for 52 marketing authorisation applications. 32 “Major Objections” originated from 13 marketing authorisation applications. 13 concerned were raised regarding drug substances and 19 for drug products. Furthermore, 905 concerns on drug substance and 1,054 on drug product were also adopted. Conclusions The impact of the frequencies and trends in quality deficiencies that were identified are discussed from a regulatory point of view. It is expected that the results of this study will not only be of interest to pharmaceutical companies but will also aid regulators’ in obtaining consistent information on drug products based on transparent rules safeguarding the necessary pharmaceutical quality of medicinal products

Regulatory evaluation of Glybera in Europe-two committees, one mission

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Pragmatic clinical trials in the context of regulation of medicines

The pragmatic clinical trial addresses scientific questions in a setting close to routine clinical practice and sometimes using routinely collected data. From a regulatory perspective, when evaluating a new medicine before approving marketing authorization, there will never be enough patients studied in all subgroups that may potentially be at higher risk for adverse outcomes, or sufficient patients to detect rare adverse events, or sufficient follow-up time to detect late adverse events that require long exposure times to develop. It may therefore be relevant that post-marketing trials sometimes have more pragmatic characteristics, if there is a need for further efficacy and safety information. A pragmatic study design may reflect a situation close to clinical practice, but may also have greater potential methodological concerns, e.g. regarding the validity and completeness of data when using routinely collected information from registries and health records, the handling of intercurrent events, and misclassification of outcomes. In a regulatory evaluation it is important to be able to isolate the effect of a specific product or substance, and to have a defined population that the results can be referred to. A study feature such as having a wide and permissive inclusion of patients might therefore actually hamper the utility of the results for regulatory purposes. Randomization in a registry-based setting addresses confounding that could otherwise complicate a corresponding non-interventional design, but not any other methodological issues. Attention to methodological basics can help generate reliable study results, and is more important than labelling studies as 'pragmatic'

Non-vitamin-Koral anticoagulants and laboratory testing:Now and in the future: Views from a workshop at the European Medicines Agency (EMA)

In contrast to vitamin K antagonists, no routine coagulation monitoring is required in patients taking non-vitamin-K oral anticoagulants (NOACs). However, dosing must take into account factors such as patient age, renal function, and accompanying haemorrhagic risk. There has been considerable debate about when laboratory measurement might be appropriate and which tests should be used. A workshop at the European Medicines Agency recently discussed the evidence about laboratory measurement from formal studies, clinical experience, and the multiple perspectives on NOAC treatment, and considered how our knowledge might be further enhanced

A guide for reporting the results of population pharmacokinetic analyses: A Swedish perspective

Population pharmacokinetic analyses are frequently part of regulatory submissions and are mainly used to provide information on special populations (effects of age, renal impairment, etc) and drug-drug interactions. A varying standard of population analysis reports has been received at the Medical Products Agency in Sweden, some very good and some unassessable. In the latter case, it may be that it is a report of an inadequate analysis or may be a report of a perfectly acceptable analysis, but too little detail has been provided in the report for the conclusions reached to be properly assessed. A sufficient level of detail must be present in these reports in order for them to be assessable and to allow the conclusions reached to be incorporated into the summary of product characteristics. The report should specify the goal(s) of the analysis, describe in detail the origin and nature of the data, clearly describe the model-building process, include a range of goodness of fit (GOF) plots to support decisions made during the model-building process, and demonstrate that the final model is a good description of the data. The use of color in GOF plots is encouraged so that key features are easily visible. Covariate effects in the final model should be clearly presented and their clinical relevance discussed. In the case of many covariates in the final model, it may be useful to perform some simulations to illustrate the effect of various covariate combinations for a series of different “typical” subjects