Dutch Medicines Evaluation Board Research Articles

An innovative method to strengthen evidence for potential drug safety signals using Electronic Health Records

Reports from spontaneous reporting systems (SRS) are hypothesis generating. Additional evidence such as more reports is required to determine whether the generated drug-event associations are in fact safety signals. However, underreporting of adverse drug reactions (ADRs) delays signal detection. Through the use of natural language processing, different sources of real-world data can be used to proactively collect additional evidence for potential safety signals. This study aims to explore the feasibility of using Electronic Health Records (EHRs) to identify additional cases based on initial indications from spontaneous ADR reports, with the goal of strengthening the evidence base for potential safety signals. For two confirmed and two potential signals generated by the SRS of the Netherlands Pharmacovigilance Centre Lareb, targeted searches in the EHR of the Leiden University Medical Centre were performed using a text-mining based tool, CTcue. The search for additional cases was done by constructing and running queries in the structured and free-text fields of the EHRs. We identified at least five additional cases for the confirmed signals and one additional case for each potential safety signal. The majority of the identified cases for the confirmed signals were documented in the EHRs before signal detection by the Dutch Medicines Evaluation Board. The identified cases for the potential signals were reported to Lareb as further evidence for signal detection. Our findings highlight the feasibility of performing targeted searches in the EHR based on an underlying hypothesis to provide further evidence for signal generation.

The Evolution of Drug Regulatory Sciences in the Netherlands: More than a Country Report.

In the Netherlands, drug regulatory science is a vibrant national and internationally oriented community. In this review, we present the factors that have contributed to this successful collaboration between relevant stakeholders and that led to a surge of activities around how regulatory science became embedded in the ecosystem of medicines research, clinical pharmacology, policymaking and regulation. We distinguished three pivotal episodes: (i) TI Pharma Escher-project, (ii) Dutch Medicines Evaluation Board as catalyst of the big jump, and (iii) Regulatory Science Network Netherlands and multistakeholder engagement. The research agenda has been influenced by the dynamic evolution of legal frameworks in Europe, such as the EU orphan medicines legislation of 2001 and the EU pharmacovigilance legislation of 2012. All these developments have inspired and have raised pertinent regulatory sciences questions. Furthermore, clinical pharmacology as a discipline has been very influential in shaping regulatory science, contributing to discussions on the level of clinical evidence that is necessary to justify marketing approval of a new medicine. With a growing interest of multiple parties such as academics, European Medicines Agency, national agencies, patient organizations and EFPIA, connecting regulatory science activities is key.

Ethnic differences in response to atypical antipsychotics in patients with schizophrenia: individual patient data meta-analysis of randomised placebo-controlled registration trials submitted to the Dutch Medicines Evaluation Board.

Little is known about the effect of ethnicity on the response to antipsychotic medication in patients with schizophrenia. To determine whether ethnicity moderates the response to antipsychotic medication in patients with schizophrenia, and whether this moderation is independent of confounders. We analysed 18 short-term, placebo-controlled registration trials of atypical antipsychotic medications in patients with schizophrenia (N = 3880). A two-step, random-effects, individual patient data meta-analysis was applied to establish the moderating effect of ethnicity (White versus Black) on symptom improvement according to the Brief Psychiatric Rating Scale (BPRS) and on response, defined as >30% BPRS reduction. These analyses were corrected for baseline severity, baseline negative symptoms, age and gender. A conventional meta-analysis was performed to determine the effect size of antipsychotic treatment for each ethnic group separately. In the complete data-set, 61% of patients were White, 25.6% of patients were Black and 13.4% of patients were of other ethnicities. Ethnicity did not moderate the efficacy of antipsychotic treatment: pooled β-coefficient for the interaction between treatment and ethnic group was -0.582 (95% CI -2.567 to 1.412) for mean BPRS change, with an odds ratio of 0.875 (95% CI 0.510-1.499) for response. These results were not modified by confounders. Atypical antipsychotic medication is equally effective in both Black and White patients with schizophrenia. In registration trials, White and Black patients were overrepresented relative to other ethnic groups, limiting the generalisability of our findings.

National survey on access to new oncology drugs pending health technology assessment and financial arrangements.

e13599 Background: In the Netherlands, the health insurance package usually covers cancer drugs after EMA approval and positive recommendation of the Dutch Society of Medical Oncology (NVMO). However, the government can temporarily exclude newly licensed indications with high budget impact from coverage until the national HTA-body advises on the clinical effectiveness and cost effectiveness. Based on the recommendations of the HTA-body, the government negotiates a financial arrangement with manufacturers. Because submitting value dossiers, assessments and negotiations takes time there have been concerns regarding patients’ access to these novel treatments, especially for life threatening conditions such as cancer. Due to a lack of transparency, it is not known to what extent patients are given access to ‘free of charge programmes’ (FCPs). Methods: A list of oncology drugs and indications which were temporarily excluded from reimbursement due to negotiations with the government (July 2015-Dec. 2020). We contacted all the pharmaceutical companies that were engaged in the process above, to inquire about access to their products during the HTA evaluation and negotiations. Results: In total 17 oncology drugs (46 EMA registered indications) of 11 companies were subjected to financial agreements by the government. In 41,3% (19/46) of cases, FCPs were available via individual prescriber requests in a selected number of hospitals. In all other cases such arrangements were not needed because alternative treatment options were available (15,2%; 7/46) or because treatment was not recommended by the NVMO (13,0%; 6/46). For one indication FCP was available but the treatment eventually received a negative recommendation. In 30,4% (14/46) of the cases there was immediate reimbursement in place following a positive NVMO recommendation through umbrella agreements. Such agreements cover existing indications but also all the indications that will be licensed in the future. Umbrella agreements were especially set up for immune checkpoint inhibitors that showed benefit across multiple indications. As anticipated, some patient-access programmes had already started prior to EMA approval. In 5 cases an official compassionate use programme was set up through the Dutch Medicines Evaluation Board prior to authorisation. Conclusions: Our survey indicates that all manufacturers are committed to enabling patients’ and clinicians’ early access to their products pending payers’ approval in a high income country such as the Netherlands. However, the lack of transparency regarding the hospitals offering these programmes may result in inequity in access. Besides, there is no structural data collection. Recently, the NVMO has established a platform (DRUG Access Protocol) to harmonise all compassionate use programmes and FCPs, generating real-world data and ensuring equal access for all patients.

Ethics and the marketing authorization of pharmaceuticals: what happens to ethical issues discovered post-trial and pre-marketing authorization?

BackgroundIn the EU, clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use are obliged to assess the ethical aspects of a clinical development program and include major ethical flaws in the marketing authorization deliberation processes. To this date, we know very little about the manner that these regulators put this obligation into action. In this paper, we intend to look into the manner and the extent that ethical issues discovered during inspection have reached the deliberation processes.MethodsTo gather data, we used the Dutch Medicines Evaluation Board database and first searched for the inspections, and their accompanying site inspection reports and integrated inspection reports, related to central marketing authorization applications (henceforth, application/s) of drugs submitted to the European Medicines Agency (EMA) from 2011 to 2015. We then extracted inspection findings that were purely of ethical nature, i.e., those that did not affect the benefit/risk balance of the study (issues related to informed consent, research ethics committees, and respect for persons). Only findings graded at least major by the inspectorate were included. Lastly, to identify how many of the ethically relevant findings (ERFs) reach the application deliberation processes, we extracted the relevant joint response assessment reports and reviewed the sections that discussed inspection findings.ResultsFrom 2011 to 2015, there were 390 processed applications, of which 65 had inspection reports and integrated inspection reports accessible via the database of the Dutch Medicines Evaluation Board. Of the 65, we found ERFs in 37 (56.9%). The majority of the ERFs were graded as major and half of the time it was informed-consent related. A third of these findings were related to research ethics committee processes and requirements. Of the 37 inspections with ERFs, 30 were endorsed in the integrated inspection reports as generally GCP compliant. Day 150 joint response assessment reports and Day 180 list of outstanding issues were reviewed for all 37 inspections, and none of the ERFs were carried over in any of the assessment reports or list of outstanding issues.ConclusionNone of the ethically relevant findings, all of which were graded as major or critical in integrated inspection reports, were explicitly carried over to the joint assessment reports. This calls for more transparency in EMA application deliberations on how ERFs are considered, if at all, in the decision-making processes.

The contribution of direct patient reported ADRs to drug safety signals in the Netherlands from 2010 to 2015.

The purpose of this study was to investigate the contribution of patient reports to signals sent by the Netherlands Pharmacovigilance Centre Lareb to the Dutch Medicines Evaluation Board and to determine if there are certain types of signals where patient report add a distinct contribution. All signals from 2010 until 2015 were included. First, we investigated how many patient reports were present in the signals and the characteristics of these reports compared to the health care professional and marketing authorization holders' reports. In addition to source, the analysis included ATC code of the drug, MedDRA® system organ class and preferred term for the adverse drug reaction (ADR), seriousness of the ADR, and 7 other factors like reports on over-the-counter medication, and how often an ADR listed in the important medical event terms list was present. Secondly, we determined the proportion of reports submitted by the individual groups to signals, in a cross-sectional manner. A total of 150 signals were included, including 1691 ADR reports. Our results show that 26.3% of all ADR reports in Dutch drug safety signals were reported by patients, and 30.5% of the patient reports in the signals contained one or more terms listed as important medical events. The proportion of reports by patients which were included the signals was 2% and 3.9% for health care professional reports and 0.2% for marketing authorization holders reports. Patients had an important contribution to signals overall, but especially for ADRs related to generic drug substitution and psychiatric ADRs.

Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis

BackgroundInexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results.ResultsThe trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug.ConclusionsIn theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability.

Early Nonresponse in the Antipsychotic Treatment of Acute Mania: A Criterion for Reconsidering Treatment? Results From an Individual Patient Data Meta-Analysis.

To investigate whether early nonresponse to antipsychotic treatment of acute mania predicts treatment failure and, if so, to establish the best definition or criterion of an early nonresponse. Short-term efficacy studies assessing antipsychotics that were submitted to the Dutch Medicines Evaluation Board during an 11-year period as part of the marketing authorization application for the indication of acute manic episode of bipolar disorder. Pharmaceutical companies provided their raw patient data, which enabled us to perform an individual patient data meta-analysis. All double-blind, randomized, placebo-controlled trials assessing the efficacy of antipsychotics for acute manic episode of bipolar disorder were included (10 trials). All patients with data available for completer analysis (N = 1,243), symptom severity scores on the Young Mania Rating Scale (YMRS) at weeks 0, 1, and 2 and at study end point (week 3 or 4). The a priori chances of nonresponse and nonremission at study end point were 40.9% (95% CI, 38.2%-43.6%) and 65.3% (95% CI, 62.0%-68.6%), respectively. Early nonresponse in weeks 1 and 2, defined by cutoff scores ranging from a ≤ 10% to a ≤ 50% reduction in symptoms compared to baseline on the YMRS, significantly predicted nonresponse (≤ 0% symptom reduction) and nonremission (YMRS score higher than 8) in week 3. The predictive value of early nonresponse (PVnr_se) at week 1 for both nonresponse and nonremission at study end point declined linearly with increasing cutoff scores of early nonresponse; nonresponse: 76.0% (95% CI, 69.7%-82.3%) for a ≤ 10% response to 48.7% (95% CI, 45.5%-51.9%) for a ≤ 50% response; nonremission: 92.2% (95% CI, 88.3%-96.1%) for a ≤ 10% response to 76.8% (95% CI, 74.4%-79.5%) for a ≤ 50% response. A similar linear decline was observed for increasing cutoff scores of early nonresponse at week 2 for nonresponse, but not for nonremission at end point: nonresponse 90.3% (95% CI, 84.6%-96.0%) for a ≤ 10% response to 65.0% (95% CI, 61.4%-68.6%) for a ≤ 50% response; nonremission: 94.2% (95% CI, 89.7%-98.7%) for a ≤ 10% response and 93.2% (95% CI, 93.1%-95.1%) for a ≤ 50% response. Specific antipsychotic characteristics did not modify these findings at either time point (week 1: P = .127; week 2: P = .213). When patients fail to respond early (1-2 weeks) after the initiation of antipsychotic treatment for acute mania, clinicians should reconsider their treatment choice using a 2-stage strategy.

Benefit-risk reassessment of medicines: a retrospective analysis of all safety-related referral procedures in Europe during 2001-2012

The aim of this study was to determine the outcomes and timing within the product life cycle of all benefit-risk reassessment procedures for marketed products that were completed by the committee for medicinal product for human use during 2001-2012. A cohort of all referral procedures for benefit-risk reassessment (Article 20, Article 31, Article 36, Article 107 procedures) for which committee for medicinal product for human use issued an opinion between 1 January 2001 and 31 December 2012 was created. The European Medicines Agency website and the Dutch Medicines Evaluation Board website were used to collect all data. There were a total of 73 benefit-risk reassessments during the study period; 61 reassessments for a single product and 12 reassessments for multiple products or an entire product class. Nineteen reassessments resulted in the recommendation to remove the product from the market. On average, a benefit-risk reassessment was performed 18.7 years after the product was first marketed. Seventeen products were marketed 5 years or less when the reassessment procedure was completed; six of these products were subsequently removed from the market. The majority of all benefit-risk reassessments that were performed during the study period did not result in removing the product from the market, but rather, in confirming the positive benefit-risk of the product, conditional to changes to the product's marketing authorisation. About half of all products that were removed from the market during the 2000s had been marketed for more than 20 years. Copyright © 2016 John Wiley & Sons, Ltd.

Post-Approval Safety Issues with Innovative Drugs: A European Cohort Study

At time of approval, knowledge of the full benefit risk of any drug is limited, in particular with regards to safety. Post-approval surveillance of potential drug safety concerns is recognized as an important task of regulatory agencies. For innovative, often first-in-class drugs, safety knowledge at time of approval is often even less extensive and these may require tighter scrutiny post approval. We evaluated whether more post-approval serious safety issues were identified for drugs with a higher level of innovation. A cohort study was performed that included all new active substances approved under the European Centralized Procedure and for which serious safety issues were identified post-approval from 1 January 1999 to 1 January 2012. Serious safety issues were defined as issues requiring a Direct Healthcare Professional Communication to alert individual healthcare professionals of a new serious safety issue, or a safety-related drug withdrawal. Data were retrieved from publicly available websites of the Dutch Medicines Evaluation Board and the European Medicines Agency. The level of innovation was scored using a validated algorithm, grading drugs as important (A), moderate (B) or modest (C) innovations or as pharmacological or technological (pharm/tech) innovations. The data were analyzed using appropriate descriptive statistics and Kaplan-Meier analysis, with a Mantel-Cox log-rank test, and Cox-regression models correcting for follow-up duration, to identify a possible trend in serious safety issues with an increasing level of innovation. In Europe, 279 new drugs were approved between 1999 and 2011. Fifty-nine (21 %) were graded as important, 63 (23 %) moderate, or 34 (12 %) modest innovations and 123 (44 %) as non-innovative (pharm/tech), while 15 (25 %), 13 (21 %), 8 (24 %) and 17 (14 %) had post-approval safety issues, respectively (p = 0.06, linear-by-linear test). Five drugs were withdrawn from the market. The Kaplan-Meier-derived probability for having a first serious safety issue was statistically significant, log-rank (Mantel-Cox) p = 0.036. In the final adjusted Cox proportional hazard model there was no statistically significant difference in occurrence of a first serious safety issue for important, moderate and modest innovations versus non-innovative drugs; hazard ratios 1.76 (95 % CI 0.82-3.77), 1.61 (95 % CI 0.76-3.41)], and 1.25 (95 % CI 0.51-3.06), respectively. A higher level of innovation was not clearly related to an increased risk of serious safety issues identified after approval.

The Additional Value of an E-Mail to Inform Healthcare Professionals of a Drug Safety Issue: A Randomized Controlled Trial in the Netherlands

The usefulness and the impact of Direct Healthcare Professional Communications (DHPCs, or 'Dear Doctor letters') in changing the clinical behaviour of physicians have been debated. Changes in the current risk communication methods should preferably be based on the preferences of the healthcare professionals, to optimize the uptake of the message. The aim of this study was to assess whether safety issues are communicated more effectively with an additional e-mail sent by the Dutch Medicines Evaluation Board (MEB) than with the DHPC only. A randomized controlled trial was conducted amongst ophthalmologists and hospital pharmacists in the Netherlands, who were the target group of a DHPC that was issued for pegaptanib, a drug that is administered intra-ocularly in patients with macular degeneration. The intervention group (N = 110) received the pegaptanib DHPC, as well as the MEB e-mail. The control group (N = 105) received the traditional paper-based DHPC only. Two weeks later, the study population received an invitation to fill out an online questionnaire. Questions were asked about the respondents' knowledge and attitude regarding the pegaptanib issue, and any action they had consequently taken. Additional questions were asked about their satisfaction with the DHPC and the e-mail, and their preferred source of such information. Forty respondents (18.6%) completed the questionnaire. Eighty-one percent of the respondents in the intervention group (N = 21) and 47% of the control group (N = 19) correctly indicated that a serious increase in intra-ocular pressure could be caused by pegaptanib injections (Fishers' exact test, p = 0.046). Nine respondents in the intervention group versus none of the control group respondents indicated that they had taken action in response to the pegaptanib safety issue (Fishers' exact test, p = 0.01). The majority of both the intervention group and the control group confirmed that they would like to receive an MEB e-mail with safety information about drugs in the future (90 and 95 %, respectively). The results of this study indicate that an additional e-mail might strengthen the uptake of the safety information provided to healthcare professionals, who prefer to receive an e-mail from the MEB as a source of such information, as well as the DHPC. This study may serve as a starting point for new strategies to improve risk communication regarding safety issues associated with drugs and its impact on prescribing.

Neuropsychiatric Adverse Events of Varenicline

Over the past years, the impact of varenicline in patients with mental illness has been debated as serious neuropsychiatric adverse events (AEs) have been reported with varenicline use. To identify and summarize published case reports of neuropsychiatric AEs ascribed to varenicline and to determine potential risk factors for these AEs. A literature search of MEDLINE, the Cochrane Library, EMBASE, and PsychInfo database was conducted for case reports concerning the neuropsychiatric AEs of varenicline published in English from 2006 (approval year by the US Food and Drug Administration and the Dutch Medicines Evaluation Board) to January 1, 2012. We identified 25 published cases. In most reports, patients had been admitted to psychiatric hospitals with serious neuropsychiatric AEs due to varenicline. The average patient age was 46.4 years, and 56% were men; 68% of patients had a psychiatric history. The onset of symptoms started 2 days to 3 months after the initiation of varenicline. One report described completed suicide in a man with no psychiatric history. In most cases (84%), the neuropsychiatric symptoms resolved after the discontinuation of varenicline. Analysis of all reports using the Naranjo causality scale, a method for estimating the probability of adverse drug reactions, indicated probable causality in 76% of the cases and definite causality in 12% of cases. Varenicline is associated with an increased risk of serious neuropsychiatric AEs, especially in patients with a psychiatric illness. It is strongly recommended that varenicline be administered only to mentally stable patients and under close monitoring.

Correction: Epilepsy Is a Risk Factor for Sudden Cardiac Arrest in the General Population

There were errors in the Funding section. The correct funding information is as follows: HLT was supported by the Netherlands Organization for Scientific Research (NWO, grant ZonMW Vici 918.86.616), and the Dutch Medicines Evaluation Board (MEB/CBG). HLT, RDT, and JWS are supported by the National Epilepsy Foundation Netherlands (project number 10-07). The Arrest data collection was supported by an unconditional grant from Physio Control and a grant from the Netherlands Heart Foundation (grant 2006B179). Dr. Bardai was supported by the Netherlands Organization for Scientific Research (NWO, grant Mozaiek 017.003.084). RD Thijs and JW Sander are part of PRISM - the Prevention and Risk Identification of SUDEP Mortality Consortium which is funded by the NIH (NBIH/NINDS -1P20NS076965-01). The funders were not involved in: design, conduct of the study, collection, management, analysis, interpretation of the data, preparation, review or approval of the manuscript.

Correction: Differential Changes in QTc Duration during In-Hospital Haloperidol Use

There was an error in the published funding statement. The correct funding statement is: H.L. Tan was supported by the Netherlands Organization for Scientific Research (NWO, grant ZonMW Vici 918.86.616), the Dutch Medicines Evaluation Board (MEB/CBG), and the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement nr. 241679 - the ARITMO project. A. Bardai was supported by the Netherlands Organization for Scientific Research (NWO, grant Mozaiek 017.003.084). Both grants are unrestricted. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The proportion of patient reports of suspected ADRs to signal detection in the Netherlands: case–control study

To determine the contribution of patients' adverse drug reaction (ADR) reports to signals detection, through a study of the signals sent by Lareb to the Dutch Medicines Evaluation Board. The percentage of patient's ADR reports contributing to generate signals of adverse drug reactions was determined. A case-control design was used to study if the proportion of patient reports in associations that had been selected as 'signals' differed from non-signals. A logistic regression analysis was used to calculate the Odds Ratio with 95%CI for patient reports in the cases and controls. The number of patient reports which contributed to a signal has increased from 0 reports in 2003 to 31 reports in 2008 (9% of total). Since 2005 patient reports have triggered particular associations to be selected as a signal. In 2007, 28% of all trigger reports were reported by a patient. The case-control analysis showed that patient reports were equally present in the reports used in signal formation (cases) as in the controls, reports not contributing to a signal. Odds Ratio (OR) was 1.10 (95%CI 0.81-1.49) and OR = 0.96 (95%CI 0.50-1.87) for the 'trigger reports'. The proportion of patient reports contributing to generate signals was equal to the proportion of patient reports in the database. Patient's reports of adverse drug reactions can provide a valuable contribution to the detection of signals in addition to healthcare professionals' reports. In the Netherlands, direct patient reports have added to the signals of adverse drug reactions sent to the Medicines Evaluation Board.

Regulatory scientific advice in drug development: does company size make a difference?

PurposeTo assess whether the content of Scientific Advice (SA) questions addressed to a national drug regulatory agency is associated with company size. This may help to increase understanding about the knowledge, strategic, and regulatory gaps companies face during drug development.MethodologyA cross-sectional analysis was performed of SA provided by the Dutch Medicines Evaluation Board (MEB) in 2006–2008. Definition of company size was based on ranking by total revenues (Scrip’s Pharmaceutical Company League Tables 2008). The content of each SA question was scored according to predefined domains (quality, nonclinical, clinical, regulatory, and product information), their subdomains (e.g., efficacy), and a selection of additional content variables (e.g., endpoints, choice of active comparator).ResultsIn total, 201 SA documents including 1,087 questions could be identified. Small, medium-sized, and large companies asked for SA 110 (54.7%), 40 (19.9%), and 51 (25.4%) times, respectively. Clinical questions were asked most often (65.9%), mainly including efficacy (33.2%) and safety questions (24.0%). The most frequent topics were overall efficacy and safety strategy. Small companies asked quality and nonclinical questions more often (P < 0.001) and clinical questions less frequently than large companies (P = 0.004). Small companies asked significantly more clinical questions about pharmacokinetics, including bioequivalence, than medium-sized and large companies (P < 0.001).ConclusionThe array of topics addressed in SA provides an interesting outlook on what industry considers to be still unresolved in drug development and worthwhile to discuss with regulators. Company size is associated with the content of SA questions. MEB advice accommodates both innovative and noninnovative drug development.

A Decade of Safety-Related Regulatory Action in the Netherlands

As pre-approval trials are inherently limited in assessing the complete benefit-risk profile of a new drug, serious safety issues may emerge once a drug gains widespread use after approval. Regulators face the dilemma of balancing timely market access with the need for complete data on risks. This challenge has led to a life-cycle approach but, so far, few data are available on post-approval safety issues requiring regulatory action. The aim of this study is to determine the frequency, timing and nature of safety issues that necessitated safety-related regulatory action in the form of a Direct Healthcare Professional Communication (DHPC) issued by pharmaceutical companies in collaboration with the Dutch Medicines Evaluation Board during the past decade. All DHPCs issued in the Netherlands from 1 January 1999 to 1 January 2009 were retrospectively collected from the national regulatory authorities. Elapsed time between the approval date and the issue of the DHPC was determined. Characteristics of the action including the nature of the safety issue (according to Medical Dictionary for Regulatory Activities [MedDRA] terminology), type of drug and procedural aspects of the regulatory action taken were reviewed. DHPC characteristics were tabulated and explorative non-parametric tests were performed to study the effect of safety issue, drug class, drug type, orphan drug and first-in-class status on elapsed time from approval to the DHPC. 157 DHPCs were issued concerning 112 different active substances, approximately 9% (112/1200) of active substances available in the Netherlands in 2007. The number of DHPCs issued increased by 2.1 (95% CI 1.2, 3.1; p < 0.001) DHPCs per year over the past decade, reaching a total of 25 in 2008. The median time between approval and DHPC was 5.3 years (range 0.13-48 years). No significant trend in elapsed time to DHPC was observed in relation to the studied years (p = 0.06). One-third of all DHPCs were issued in the first 3 years after approval, but 27% (n = 43/157) of the DHPCs were issued 10 or more years after approval. Timing of DHPCs differed depending on safety issue, drug class, drug type and orphan drug status. DHPCs mostly concerned adverse events in the system organ class of 'cardiac disorders' (15%), 'injury, poisoning and procedural complications' (13%) and 'general disorders and administration site conditions' (10%). In ten cases the drug was eventually withdrawn. Withdrawal occurred a median duration of 2.4 years after registration (range of 1.5-48 years) and was most frequently due to cardiac disorders (including QT interval prolongation; four occasions) and hepatobiliary disorders (two occasions). In the past decade, the number of DHPCs has increased over time. This is likely caused by a multitude of factors: increased risk awareness by the public, media, regulators and other stakeholders; the type of drugs approved, such as orphan drugs and biologicals; and the regulatory process, including conditional approvals. The number of DHPCs may in the future increase further with the possibility of screening large epidemiological databases proactively for adverse drug events. Nine percent of all marketed drugs required a safety-related action. Regulatory action is taken shortly (<3 years) after market approval nearly as often as after intermediate (3-10 years) and long-term (>10 years) market exposure. These findings underline the need for risk management during the whole life cycle of a drug.

Evaluation of serological trials submitted for annual re-licensure of influenza vaccines to regulatory authorities between 1992 and 2002

Background As part of the regulatory requirements, serological evaluation of trivalent inactivated influenza vaccines must be performed before annual re-licensure in the European Union. These studies are typically set up as uncontrolled, open label trials including 2 groups of at least 50 healthy adults and healthy elderly. Methods The serological data submitted to the Dutch Medicines Evaluation Board (MEB) for annual re-licensure purposes between 1992 and 2002, were analysed with respect to their ability to assess the immunogenic properties of the vaccines. The trials in this meta-analysis were selected by strictly applying the inclusion and exclusion criteria described in the Committee of Human Medicinal Products (CHMP) Note for Guidance on harmonisation of requirements for influenza vaccines. To select the final dataset additional exclusion criteria were defined: age outside the inclusion criterion of the trial, incomplete demographics, co-morbid conditions, antibody determination by SRH assay, incomplete dataset and sample size smaller than 50 subjects. Results Out of 51 trials retrieved from the archives, 48 age-defined trials including 2510 adults and 2008 elderly fulfilled all the in- and exclusion criteria. A large proportion of vaccinees already met the threshold for seroprotection at baseline. Post-vaccination, the serological response was shown to be age dependent. Previous influenza vaccinations significantly affected pre-vaccination but not post-vaccination titres. Conclusions The annual update trials performed for regulatory purposes have serious methodological limitations, which affect their ability to identify influenza vaccines with low immunogenicity. To establish clinical (protective) efficacy different trials and different assessment criteria are needed.

Psychopharmacology for children: From off label use to registration

Pharmacological treatment of children and adolescents is largely based on evidence from adults' studies. There is, however, growing awareness that this evidence cannot simply be extrapolated to children. The Dutch Medicines Evaluation Board (MEB) in collaboration with the Child and Adolescent section of the Dutch Association of Psychiatry and the National Expertise Centre Child and Adolescent Psychiatry have organised a workshop to discuss the kind of evidence that would be necessary and the methods involved. There was consensus about the need to demonstrate efficacy in targeted disorders as well as symptoms within specific disorders and about the need for separate evidence for children and for adolescents. In addition, too little is known about safety, especially long-term safety, as consequences of treatment. Main issues are effects on growth, cognitive, motor, emotional, and sexual development, metabolic symptoms, cardiotoxicity, and dependence. Specific methodological issues were discussed, such as the role of different informants and the high rate of comorbidity.

Comparative Course and Outcome of the Mutual Recognition Procedure with Two Related Progestagen-Only Contraceptive Products: Cerazette® and Implanon®

In 1998, NV Organon successfully completed two Mutual Recognition Procedures (MRPs) for two progestagen-only contraceptive products: Cerazette® (tablet) and Implanon (subdermal implant). Two different reference member states (RMS) were involved. For Cerazette® the Swedish Medicines Product Agency acted as the RMS, whereas the Dutch Medicines Evaluation Board acted as the RMS for Implanon’. This article compares the two MRPs. It discusses the progress and contents of the two procedures in terms of the approval times needed for the products in each RMS, the validation process, the start of the actual procedure, the number and types of questions raised by the concerned member states, and the results of the break-out session. Further-more, the effect of each MRP on the outcome of the contents of the Summary of Product Characteristics (SmPC) and the time required for issuing the national marketing authorizations will be discussed. Based on the experience of NV Organon, it is concluded that the MRP is a mature European registration procedure, providing that good cooperation between the RMS and the pharmaceutical company is established.