Marketing Authorization Holders Research Articles

The French reporting system for drug shortages: description and trends from 2012 to 2018: an observational retrospective study

ObjectivesThe aim was to provide figures for drug shortages in France and describe their characteristics, causes and trends between 2012 and 2018.MethodsData from the national reporting system from the Agency...

Pulmonary Administration: Strengthening the Value of Therapeutic Proximity.

In recent years inhaled systems have shown momentum as patient-personalized therapies emerge. A significant improvement in terms of therapeutic efficacy and/or reduction adverse systemic effects is anticipated from their use owing these systems regional accumulation. Nevertheless, whatever safety and efficacy evidence required for inhaled formulations regulatory approval, it still poses an additional hurdle to gaining market access. In contrast with the formal intravenous medicines approval, the narrower adoption of pulmonary administration might rely on discrepancies in pre-clinical and clinical data provided by the marketing authorization holder to the regulatory authorities. Evidences of a diverse and inconsistent regulatory framework led to concerns over toxicity issues and respiratory safety. However, an overall trend to support general concepts of good practices exists. Current regulatory guidelines1 that supports PK/PD (pharmacokinetics/pharmacodynamic) assessment seeks attention threatening those inhaled formulations set to be approved in the coming years. A more complex scenario arises from the attempt of implementing nanomedicines for pulmonary administration. Cutting-edge image techniques could play a key role in supporting diverse stages of clinical development facilitating this pharmaceutics take off and speed to patients. The ongoing challenge in adapting conventional regulatory frameworks has proven to be tremendously difficult in an environment where market entry relies on multiple collections of evidence. This paper intention is to remind us that an acceptable pre-clinical toxicological program could emerge from, but not only, an accurate and robust data imaging collection. It is our conviction that if implemented, inhaled nanomedicines might have impact in multiple severe conditions, such as lung cancer, by fulfilling the opportunity for developing tailored treatments while solving dose-related toxicity issues; the most limiting threat in conventional lung cancer clinical management.

Pregnancy outcomes in interferon-beta-exposed patients with multiple sclerosis: results from the European Interferon-beta Pregnancy Registry

BackgroundFamily planning is an important consideration for women with multiple sclerosis (MS), who are often diagnosed during their reproductive years. Currently, limited data are available on pregnancy outcomes in patients exposed to interferon-beta (IFN-beta) before or during pregnancy. Here, we present the cumulative pregnancy exposure data and prevalence of pregnancy and infant outcomes in IFN-beta-exposed pregnant women with MS from the European IFN-beta Pregnancy Registry.MethodsUsing spontaneous and solicited reports, the registry collected data from 26 countries of the European Economic Area, consisting of information on women with MS identifying themselves to one of the Marketing Authorisation Holders (Bayer, Biogen, Merck KGaA, and Novartis) or healthcare professionals as pregnant and exposed to IFN-beta during pregnancy or within 1 month before conception. The outcomes collected by the registry included ectopic pregnancies, spontaneous abortions, elective terminations, live, and stillbirths with or without congenital anomalies. The prevalence of pregnancy outcomes was put in context with those reported in the general population.ResultsBetween 2009 and 2017, the registry collected 948 pregnancy reports with a known pregnancy outcome. Overall, 82.0% (777/948) of pregnancies resulted in live birth without congenital anomaly. When comparing IFN-beta-exposed pregnancies with the general population, the prevalence of spontaneous abortions (10.7% vs. 10–21%) and congenital anomalies in live births (2.1% vs. 2.1–4.1%) were found to be within reported ranges.ConclusionsThe data gathered from these pregnancy cases suggest no evidence that IFN-beta exposure before conception and/or during pregnancy adversely increases the rate of congenital anomalies or spontaneous abortions.

Efficacy, safety and tolerability of progesterone vaginal pessaries versus progesterone vaginal gel for luteal phase support after in vitro fertilisation: a randomised controlled trial.

Efficacy, safety and tolerability of progesterone vaginal pessaries versus progesterone vaginal gel for luteal phase support after in vitro fertilisation: a randomised controlled trial.

The pre- and post-authorisation data published by the European medicines agency on the use of biologics during pregnancy and lactation.

AimsThe effects of biologics on reproduction/lactation are mostly unknown although many patients that receive biologics are women of reproductive age. The first objective of this study was to investigate the publicly available data on pregnancy/lactation before and after marketing authorization in Europe of biologics for the indications of rheumatologic inflammatory autoimmune diseases and inflammatory bowel disease. Secondary objectives included the assessment of the clinical relevance of the provided data and comparison of initial and post‐authorization data.MethodsInitial and post‐authorization data were extracted from the European Public Assessment Reports and the latest versions of Summary of Product Characteristics using publicly available documents on the European Medicines Agency's website. Four sections were categorized regarding pregnancy outcomes: pre‐clinical/animal studies, human female fertility, pregnancy‐related outcomes and congenital malformations in the human fetus. Three sections were categorized regarding lactation outcomes: pre‐clinical/animal studies, excretion in human breast milk and absorption in children through breastfeeding. The clinical applicability of each category was scored by specified criteria, based on scientific literature, and further as defined by the authors.ResultsFor the 16 included biologics, post‐authorization data were delivered only for adalimumab, certolizumab pegol, etanercept and infliximab. For the 12 remaining biologics limited data on pregnancy and lactation during the post‐marketing period of 2–21 years were available.ConclusionsIn this article several suggestions are provided for improving a multidisciplinary approach to these issues. The initiation of suitable registries by marketing authorization holders and data transparency for clinicians and academics are highly endorsed.

Adverse drug reaction reporting practice and associated factors among medical doctors in government hospitals in Addis Ababa, Ethiopia.

IntroductionAdverse drug reactions (ADRs) are global public health problems. In its severe form it may cause hospital admission, morbidity and mortality. Early reporting of suspected ADRs to regulatory authorities is known to be appropriate measure toinsure health and safety of public form such adverse drug reaction of drugs. In Addis Ababa, there is limited information on ADR reporting practices among medical doctors. Hence, this study aimed to assess ADR reporting practices and associated factors among doctors in government hospitals in Addis Ababa.MethodsAn institution based cross-sectional mixed-methods study design was used. Data werecollected from 407 doctors using self-administered questionnaire and five key informants using semi-structured questionnaire from October 01 to December 31, 2017. Binary logistic regression and thematic analysis methods for quantitative and qualitative data analysis were used respectively.ResultsOnly 94(27.4%) of doctors had ever reported ADRs to national pharmacovigilance center. The study showed that sex (AOR = 3.51, 95% CI: 1.76–7.03), level ofeducation (AOR = 5.01, 95% CI: 2.23–11.28), work experience (AOR = 4.59, 95% CI: 1.21–17.40), existence of ADR reporting form (AOR = 3.96, 95% CI: 1.07–14.61) and reporting to respective marketing authorization holders (AOR = 21.41, 95% CI: 5.89–77.88) were significantly associated with ADR reporting practices. Poor awareness and training on risk of under-reporting, feeling that reporting is minor, absence of appropriate reporting tools, delay and/or absence of feedback on reported ADRs, overly burdened doctors, negligence, fear of legal liabilityand communication gap were cited by key informants as barriers for reporting practice.ConclusionsAdverse drug reaction reporting practice among doctors wasfound to be low. Sex, level of education, work experience, existence of reporting form and reporting to marketing authorization holderswere significantly associated with ADR reporting practice. In addition, there are gaps in availabilities of guidelines, reporting systems and structure, pre-service and in-service training, and awareness of doctors on impact of reporting. Hence, improving access to ADR reporting form, decentralize safety monitoring system, and conducting awareness training on ADR reporting are essential to improve the ADR reporting practice.

Preparation of Direct Healthcare Professional Communication: An Exploratory Study on the Experiences and Perceptions of European Pharmaceutical Companies and the EMA.

Despite the regulatory requirement for cooperation between marketing authorization holders (MAHs) and European Medicines Agency (EMA) in the direct healthcare professional communication (DHPC) preparation, no literature has explored DHPCs from an industry-regulator perspective. This constitutes a significant knowledge gap as any possibility of improving current DHPC effectiveness depends on decisions in the cooperative preparation phase. Thus, this EU-centered study explores differences in perceptions and experiences of DHPCs of European MAHs and EMA. European MAHs ([Formula: see text]) and EMA representatives ([Formula: see text]) were interviewed. The verbatim transcripts were coded into themes using NVivo software. Interview analysis was performed following a phenomenological approach of meaning condensation. The DHPC process was perceived as burdensome by the industry. One company stated the process was time-consuming either due to EMA's internal lengthy approval process or the translation activities with local company affiliates and national competent authorities. Three companies stated that DHPCs were not effective. One company stated that DHPCs are sent out due to legal Obligations and not because of their use as a risk minimization measure (RMM). Newly emerged safety concerns were found difficult to phrase. Optimization proposals included improved timelines, scrutinization of healthcare professionals and better communication tools in clinical practice. DHPCs were not perceived as optimal, although the most effective intervention as it targets healthcare professionals directly. Continuous evaluation by EMA of DHPCs and evaluation on how to reach healthcare professionals are necessary. It is believed that industry perceptions from this study can support EMA with improved regulatory decision making to benefit public health.

Status Analysis on the Marketing Authorization Holder of China's Drugs

We analyze the basic situation of Marketing Authorization Holder (MAH) of drugs in China. Mathematical analysis was carried out on the approval time, product category, dosage form, listing permit holder and production unit of 3239 MAH of drugs in China as of July 31, 2019. We found the following results. The approval time for MAH of drugs was concentrated in 2015, mainly based on chemicals, and the dosage forms were mostly tablets and injections. Furthermore, the number of MAH of drugs varies greatly among different provinces, and the number of Hebei, Guangdong, and Jiangsu ranks in the top three. Thirdly, there are time differences, variety types and geographical differences in the MAH of drugs. This is the application for examination and approval after the full implementation of the MAH of drugs system, and the patent and intellectual property protection in the process of entrusted production technology transfer. The research provides reference for enterprise declaration and regulatory approval management after the full implementation of the MAH system in China.

Формат электронного общего технического документа как основа единого фармацевтического рынка Евразийского экономического союза

Background. Due to ratification of the Decision of the EAC Commission on the circulation of medicinal products, a common EAEU pharmaceutical market will be formed, and registration dossiers will be accepted in electronic form of eCTD in XML format starting from January 1, 2021. It is related to the fact that the EAEU member states will exchange information on medicinal products and their results within the framework of an information integrated system. An application for marketing authorization is now submitted in electronic form in PDF format in accordance with the legislation of the Russian Federation. The XML format has been used in the EU since 2003, but not in the Russian Federation. To continue circulation of authorized medicinal products on the territory of the EAEU, it is necessary to bring the registration dossier in accordance with the requirements of the EAEU by December 31, 2025. Beginning on January 01, 2021, applications for marketing authorization of medicinal products will be only accepted under the legislation of the EAEU. In this regard, Russian enterprises - marketing authorization holders have been tasked with converting all registration dossiers to XTML files. The study is aimed to analyse the market for proposals for installation of software to convert documents to the required format and development recommendations for enterprises - marketing authorization (MA) holders - for making the necessary decisions. Commercial proposals of three software companies were studied and recommendations were developed for enterprises - MA holders within the framework of a situation analysis.Purpose of the study. To analyse the market for proposals for installation of software to convert documents to the required format and development recommendations for enterprises - marketing authorization (MA) holders for making the necessary decisions.Conclusion. The study identified factors that have an impact on the decision-making of the heads of pharmaceutical organizations regarding the choice of proposals for installation of software to convert registration dossier documents to the required format according to the rules of the EAEU. It investigated the consequences of various decisions. Recommendations have been developed for companies - MA holders for submitting an electronic DMF in accordance with the EAEU rules.

Évaluation et impact des pictogrammes « grossesse » apposés sur les conditionnements extérieurs des médicaments : enquête auprès de 281 femmes

In France, since 2017new pharmaceutical pictograms appeared on drugs with a potentieal risk during pregnancy. This apposition, left to the discretion of marketing authorization holders, has uncertain consequences for women's reactions to them. The present survey is the first one interested in the opinion of the women concerned (pregnant or of childbearing age) as well as on the interpretation that they make of it. The survey answers enhanced that the pregnancy pictogram is an initiative welcomed by women who estimate that it secures drug intake. However, we demonstrate a poor understanding of the message conveyed by these pictograms (more than 50% think they concern breastfeeding and more than 10% fertility) and inappropriate behavior towards them (more than 80 of women pregnant stopped or decreased their medication immediately, without medical advice). The survey also highlights the need for information of women concerned by these pictograms and the limited information given by health professionals on this subject. It seems urgent to revise the law, to limite the use of these pictograms that appear to be too broad, incoherent and sometimes unjustified. In addition, public information seems an essential issue when focusing on these new pharmaceutical pictograms.

Implementation of adverse event reporting for medical devices, India.

ProblemRapid growth in the use of medical devices has drawn attention to gaps in the systematic monitoring of medical device-associated adverse events in India.ApproachImplementation of national regulations on medical devices started in January 2018. Supported by a nationwide network of monitoring centres, the Indian Pharmacopoeia Commission coordinates adverse event reports from manufacturers, legal representatives and patients or users. The commission follows-up and reviews reports with subject expert groups and sends recommendations on necessary action to the national regulatory authority.Local settingBefore 2015, no systematic structure was in place to collate adverse events associated with medical devices. Several reports of deaths and hospitalization due to faulty hip implants, cardiac stents and poor-quality devices prompted the health ministry to launch the materiovigilance programme.Relevant changesFrom July 2015 to October 2019, the commission received 1931 adverse event reports, mostly from marketing authorization holders; 1277 were serious events. Reporting increased markedly after 2017. Cardiac stents were the most reported device (926 events; 47.95%). To encourage a culture of reporting, the commission has raised awareness about the programme among stakeholders, developed user-friendly reporting tools and guidelines, and conducted training for hospital personnel on medical device adverse event reporting.Lessons learntRegular training to stakeholders develops a sense of responsibility towards reporting medical device adverse events and ensures quality data reporting. Reporters must be assured that reporting adverse events does not have any legal implications for them and given acknowledgement of their role in high-quality device associated adverse event reporting.

Blinatumomab for Acute Lymphoblastic Leukemia: The First Bispecific T-Cell Engager Antibody to Be Approved by the EMA for Minimal Residual Disease.

On November 15, 2018, the Committee for Medicinal Products for Human Use (CHMP) recommended the extension of indication for blinatumomab to include the treatment of adults with minimal residual disease (MRD) positive B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab was authorized to treat relapsed or refractory B-precursor ALL, and the change concerned an extension of use. On March 29, 2018, the U.S. Food and Drug Administration (FDA) granted accelerated approval to blinatumomab to treat both adults and children with B-cell precursor ALL who are in remission but still have MRD. On July 26, 2018, the CHMP had originally adopted a negative opinion on the extension. The reason for the initial refusal was that although blinatumomab helped to reduce the amount of residual cancer cells in many patients, there was no strong evidence that it led to improved survival. During the re-examination, the CHMP consulted the scientific advisory group. The CHMP agreed with the expert group's conclusion that, although there was no strong evidence of patients living longer, the available data from the main study (MT103-203) indicated a good durable response to blinatumomab, with an overall complete response rate for the primary endpoint full analysis set (defined as all subjects with an Ig or T-cell receptor polymerase chain reaction MRD assay with the minimum required sensitivity of 1 × 10-4 at central lab established at baseline [n = 113]) as 79.6% (90/113; 95% confidence interval, 71.0-86.6), with a median time to complete MRD response of 29.0 days (range, 5-71). Therefore, the CHMP concluded that the benefits of blinatumomab outweigh its risks and recommended granting the change to the marketing authorization. The Committee for Orphan Medicinal Products, following reassessment, considered that significant benefit continued to be met and recommended maintaining the orphan designation and thus 10 years market exclusivity (the Orphan Designation is a legal procedure that allows for the designation of a medicinal substance with therapeutic potential for a rare disease, before its first administration in humans or during its clinical development). The marketing authorization holder for this medicinal product is Amgen Europe B.V. IMPLICATIONS FOR PRACTICE: Immunotherapy with blinatumomab has excellent and sustainable results, offering new hope for patients with minimal residual disease-positive acute lymphoblastic leukemia, a disease with poor prognosis. New recommendations and change of practice for treatment of this patient group are detailed.

Industry Assessment of the Contribution of Patient Support Programs, Market Research Programs, and Social Media to Patient Safety

BackgroundOver the past decade, the volume of adverse events (AEs) reported to marketing authorization holders and regulators has been rapidly increasing each year, which has led to significant challenges in patient safety assessment. Three data sources that have largely contributed to the expansion in adverse event reports are patient support programs (PSPs), market research programs (MRPs), and social media. In this study, we sought to further understand the contribution of these safety data sources to the characterization of a product’s safety profile.MethodsThree separate approaches were taken that, when combined, can be used to evaluate each data source. The first identified any core company data sheet changes or drug safety label changes. The second evaluated the similarity of information through proportions of AEs between each solicited data source and spontaneous sources. Lastly, the completeness of information reported was evaluated through vigiGrade and compared across each data source.ResultsOne drug safety label change was identified from a patient support program, which involved regular contact with health care providers. No label changes were identified from market research programs or social media. Patient support programs, market research programs, and social media report similar proportions for HLGT as spontaneous sources. Market research programs and social media display very low vigiGrade scores. When broken down by subtype, traditional PSPs display high vigiGrade scores, while patient assistance programs display lower vigiGrade scores that were program dependent.ConclusionsThis study did not demonstrate that certain data sources such as market research programs, social media, and patient assistance programs meaningfully contributed to the further understanding of the characterization of a product’s safety profile.

584P - Noninferiority on overall survival of every-2-weeks vs weekly schedule of cetuximab for first-line treatment of RAS wild-type metastatic colorectal cancer

584P - Noninferiority on overall survival of every-2-weeks vs weekly schedule of cetuximab for first-line treatment of RAS wild-type metastatic colorectal cancer

The accessibility of data on environmental risk assessment of pharmaceuticals: Is the marketing authorisation procedure in conflict with the international right of access to environmental information?

BackgroundFor a large part of the active pharmaceutical ingredients (APIs) available on the market, there is no or no comprehensive environmental risk assessment (ERA) existent/available. Existing ERAs are, moreover, treated as commercially/industrial confidential information (CCI) and the information content on the ERAs contained in the Public Assessment Reports is very limited. Thus, neither the public can inform itself sufficient nor environmental authorities can use the ERAs to compile environmental quality standards. Environmental information law, on the other hand, requires the general accessibility of environmental information. Against this background, this investigation examines the following questions in conformity with the environmental information law: Which environmental information on pharmaceuticals is generated in the marketing authorisation? Which of the environmental information generated in the marketing authorisation is available to the public? Does the environmental information on pharmaceuticals concern CCI?ResultsAccording to international and European environmental information law, there is in principal a right of access to the ERAs of pharmaceuticals (environmental information according to Art. 2(3)(b) Aarhus Convention), which is ineffective due to product-based data and allegedly conflicting CCI. The practised blanket classification of CCI by the marketing authorisation holders is in conflict with the principle of transparency of environmental information law. In any case, the outcomes of the ERA (in particular the ecotoxicity endpoints) may not be classified as CCI. Furthermore, the publicly accessible information in the format of the Public Assessment Report does not sufficiently reflect the information from ERAs and thus does not fulfil the mandate of active access to information (Art. 5 Aarhus Convention). The conflict between the actual accessibility of environmental information on pharmaceuticals and the requirements of environmental information law could be resolved through an API-based publicly accessible database with the outcomes of the ERAs (including all underlying ecotoxicity endpoints). To fulfil the right of access to environmental information effectively, the database also needs to be extended to “old” APIs for which environmental risk assessments have not yet been carried out. This would be the basis for prioritisation of API and establishing a monograph system.ConclusionThe environmental information law requires an improved accessibility of ERAs that could be achieved through an API-based publicly accessible database.

Extrapolating Antibiotic Sales to Number of Treated Animals: Treatments in Pigs and Calves in Switzerland, 2011-2015.

To evaluate the contribution of antimicrobial use in human and veterinary medicine to the emergence and spread of resistant bacteria, the use of these substances has to be accurately monitored in each setting. Currently, various initiatives collect sales data of veterinary antimicrobials, thereby providing an overview of quantities on the market. However, sales data collected at the level of wholesalers or marketing authorization holders are of limited use to associate with the prevalence of bacterial resistances at species level. We converted sales data to the number of potential treatments of calves and pigs in Switzerland for the years 2011 to 2015 using animal course doses (ACD). For each authorized product, the number of potential therapies was derived from the sales at wholesaler's level and the ACD in mg per kg. For products registered for use in multiple species, a percentage of the sales was attributed to each authorized species according to their biomass distribution. We estimated a total of 5,914,349 therapies for pigs and 1,407,450 for calves in 2015. Using the number of slaughtered animals for that year as denominator, we calculated a treatment intensity of 2.15 therapies per pig and 5.96 per calf. Between 2011 and 2015, sales of veterinary antimicrobials decreased by 30%. The calculated number of potential therapies decreased by 30% for pigs and 15% for calves. An analysis of treatment intensity at antimicrobial class level showed a decrease of 64% for colistin used in pigs, and of 7% for macrolides used in both pigs and calves. Whereas the use of 3rd and 4th generation cephalosporins in calves decreased by 15.8%, usage of fluoroquinolones increased by 10.8% in the same period. Corresponding values for pigs were −16.4 and +0.7%. This is the first extrapolation of antimicrobial usage at product level for pigs and calves in Switzerland. It shows that calves were more frequently treated than pigs with a decreasing trend for both number of therapies and use of colistin, macrolides and cephalosporins 3rd and 4th generations. Nonetheless, we calculated an increase in the usage of fluoroquinolones. Altogether, this study's outcomes allow for trend analysis and can be used to assess the relationship between antimicrobial use and resistance at the national level.

Безпека використання протимікробних ветеринарних лікарських засобів в контексті ветеринарного фармаконагляду

У статті представлена модель дослідження безпеки при післяреєстраційному використанні протимікробних ветеринарних лікарських засобів в контексті вимог ветеринарного фармаконагляду. Найбільш поширеними заходами, які сприяють дослідженню безпеки застосованих протимікробних ветеринарних лікарських засобів є моніторинг і налагоджена система звітності за їх використанням в створеній виробником/власником реєстраційного посвідчення корпоративній системі ветеринарного фармаконагляду, яка підтверджена інформативною базою даних.

Preparation of Direct Healthcare Professional Communication: An Exploratory Study on the Experiences and Perceptions of European Pharmaceutical Companies and the EMA.

Despite the regulatory requirement for cooperation between marketing authorization holders (MAHs) and European Medicines Agency (EMA) in the direct healthcare professional communication (DHPC) preparation, no literature has explored DHPCs from an industry-regulator perspective. This constitutes a significant knowledge gap as any possibility of improving current DHPC effectiveness depends on decisions in the cooperative preparation phase. Thus, this EU-centered study explores differences in perceptions and experiences of DHPCs of European MAHs and EMA. European MAHs (n = 6) and EMA representatives (n = 2) were interviewed. The verbatim transcripts were coded into themes using NVivo software. Interview analysis was performed following a phenomenological approach of meaning condensation. The DHPC process was perceived as burdensome by the industry. One company stated the process was time-consuming either due to EMA's internal lengthy approval process or the translation activities with local company affiliates and national competent authorities. Three companies stated that DHPCs were not effective. One company stated that DHPCs are sent out due to legal obligations and not because of their use as a risk minimization measure (RMM). Newly emerged safety concerns were found difficult to phrase. Optimization proposals included improved timelines, scrutinization of healthcare professionals and better communication tools in clinical practice. DHPCs were not perceived as optimal, although the most effective intervention as it targets healthcare professionals directly. Continuous evaluation by EMA of DHPCs and evaluation on how to reach healthcare professionals are necessary. It is believed that industry perceptions from this study can support EMA with improved regulatory decision making to benefit public health.

The use of validated and nonvalidated surrogate endpoints in two European Medicines Agency expedited approval pathways: A cross-sectional study of products authorised 2011-2018.

BackgroundIn situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies.Methods and findingsWe used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as ‘validated’. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being ‘reasonably likely’ (n = 30; 61%) or of having ‘biological plausibility’ (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway.ConclusionsThe pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders.

Passive enhanced safety surveillance of GSK’s quadrivalent seasonal influenza vaccine in Belgium, Germany and Spain, an observational study: protocol for the 2018/2019 influenza season

IntroductionThe European Medicines Agency requires Marketing Authorisation Holders providing seasonal influenza vaccines in Europe to conduct enhanced safety surveillance accounting for the different age groups based on the vaccine indication,...