Assessment of the Regulatory Dialogue Between Pharmaceutical Companies and the European Medicines Agency on the Choice of Noninferiority Margins.

Choosing a noninferiority margin is one of the main challenges when designing a noninferiority trial. The European Medicines Agency (EMA) published a guidance report on the choice of margins in 2005. Nonetheless, in 2008 and 2009 they did not accept 41% (35 of 86) of the noninferiority margins that were proposed by pharmaceutical companies in the context of scientific-advice letters. In this study, we focus on whether the EMA's recommendations were followed by pharmaceutical companies, and on a possible relationship with eventual drug approval. Five of the 35 unaccepted margins were equivalence margins; we considered only the 30 unaccepted noninferiority margins in our analysis. Twelve of these margins were defined based on clinical and statistical considerations (the approach recommended by the EMA) and were rejected due to unacceptable clinical considerations. The other 18 margins were rejected because they were considered too wide. The EMA's recommendations were followed in the cases of 10 of the 15 margins (67%) for which information on follow-through of recommendations was available. The main reason for ignoring the EMA's recommendation in the other 5 cases was that the margins had been accepted by the US Food and Drug Administration. The proportions of approved drugs for which recommendations were and were not followed were similar, yet numbers were too low for formal statistical testing. This study shows that the main concern of regulators with regard to noninferiority trials was the strictness of margins from a clinical perspective. Future studies using more recent data, including data on the US Food and Drug Administration, may help in assessing the impact of guideline recommendations on noninferiority margins used for drug approval and may assist in reaching consensus among regulators about the choice of margins.

Correction: A standardised framework to identify optimal animal models for efficacy assessment in drug development.

[This corrects the article DOI: 10.1371/journal.pone.0218014.].

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

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

A standardised framework to identify optimal animal models for efficacy assessment in drug development.

INTRODUCTION: Poor translation of efficacy data derived from animal models can lead to clinical trials unlikely to benefit patients-or even put them at risk-and is a potential contributor to costly and unnecessary attrition in drug development. OBJECTIVES: To develop a tool to assess, validate and compare the clinical translatability of animal models used for the preliminary assessment of efficacy. DESIGN AND RESULTS: We performed a scoping review to identify the key aspects used to validate animal models. Eight domains (Epidemiology, Symptomatology and Natural History-SNH, Genetic, Biochemistry, Aetiology, Histology, Pharmacology and Endpoints) were identified. We drafted questions to evaluate the different facets of human disease simulation. We designed the Framework to Identify Models of Disease (FIMD) to include standardised instructions, a weighting and scoring system to compare models as well as factors to help interpret model similarity and evidence uncertainty. We also added a reporting quality and risk of bias assessment of drug intervention studies in the Pharmacological Validation domain. A web-based survey was conducted with experts from different stakeholders to gather input on the framework. We conducted a pilot study of the validation in two models for Type 2 Diabetes (T2D)-the ZDF rat and db/db mouse. Finally, we present a full validation and comparison of two animal models for Duchenne Muscular Dystrophy (DMD): the mdx mouse and GRMD dog. We show that there are significant differences between the mdx mouse and the GRMD dog, the latter mimicking the human epidemiological, SNH, and histological aspects to a greater extent than the mouse despite the overall lack of published data. CONCLUSIONS: FIMD facilitates drug development by serving as the basis to select the most relevant model that can provide meaningful data and is more likely to generate translatable results to progress drug candidates to the clinic.

Alignment of European Regulatory and Health Technology Assessments: A Review of Licensed Products for Alzheimer's Disease.

Aims: To facilitate regulatory learning, we evaluated similarities and differences in evidence requirements between regulatory and health technology assessment (HTA) bodies of Alzheimer's disease (AD) approved products. Methods: The European marketing authorisation application dossiers and European public assessment reports (EPARs) of the licensed AD drugs were screened to identify the phase III randomised controlled trials (RCTs) and outcomes used. We also screened the assessment reports of the National Institute of Health and Care Excellence (NICE, England) and the National Health Care Institute (ZiN, the Netherlands) to identify the studies and outcomes used in HTA assessments. Results: The application dossiers of donepezil, galantamine, rivastigmine, and memantine contained 16 phase III RCTs in total. These trials were also included in HTA assessments except that NICE excluded studies that were not published (n = 2) or trials that included patients with other types of dementia (n = 3). In the regulatory assessments the focus was on cognitive and global outcomes, and to some extent on function. In the HTA assessments of clinical effectiveness other domains were also covered including: function, behaviour and mood, and, occasionally, quality of life. In the economic analyses of NICE the domains cognition, function, and quality of life were included. Conclusion: There was a large overlap in inclusion of trials in regulatory and HTA assessments, although the focus on specific outcomes slightly differed. Understanding the methods and perceptions of both authorities can stimulate regulatory and HTA cross-talk and further alignment, and therefore more rapid patient access to new treatments.

Regulatory scientific advice on non-inferiority drug trials.

The active-controlled trial with a non-inferiority design has gained popularity in recent years. However, non-inferiority trials present some methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how a non-inferiority trial should be conducted. Moreover, in a scientific advice procedure, regulators give companies the opportunity to discuss critical trial issues prior to the start of the trial. The aim of this study was to identify potential issues that may benefit from more explicit guidance by regulators. To achieve this, we collected and analyzed questions about non-inferiority trials posed by applicants for scientific advice in Europe in 2008 and 2009, as well as the responses given by the European Medicines Agency (EMA). In our analysis we included 156 final letters of advice from 2008 and 2009, addressed to 94 different applicants (manufacturers). Our analysis yielded two major findings: (1) applicants frequently asked questions 'whether' and 'how' to conduct a non-inferiority trial, 26% and 74%, respectively, and (2) the EMA regulators seem mainly concerned about the choice of the non-inferiority margin in non-inferiority trials (36% of total regulatory answers). In 40% of the answers, the EMA recommended using a stricter margin, and in 10% of the answers regarding non-inferiority margins, the EMA questioned the justification of the proposed non-inferiority margin. We conclude that there are still difficulties in selecting the appropriate methodology for non-inferiority trials. Straightforward and harmonized guidance regarding non-inferiority trials is required, for example on whether it is necessary to conduct such a trial and how the non-inferiority margin is determined. It is unlikely that regulatory guidelines can cover all therapeutic areas; therefore, in some cases regulatory scientific advice may be used as an opportunity for tailored advice.

Immunogenicity of mAbs in non-human primates during nonclinical safety assessment.

The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies.

From molecule to market access: drug regulatory science as an upcoming discipline.

Regulatory science as a discipline has evolved over the past years with the object to boost and promote scientific rationale behind benefit/risk and decision making by regulatory authorities. The European Medicines Agency, EMA, the Food and Drug Administration, FDA, and the Japanese Pharmaceutical and Medical Devices Agency, PMDA, highlighted in their distinct ways the importance of regulatory science as a basis of good quality assessment in their strategic plans. The Medicines Evaluation Board, MEB, states: 'regulatory science is the science of developing and validating new standards and tools to evaluate and assess the benefit/risk of medicinal products, facilitating sound and transparent regulatory decision making'. Through analysis of regulatory frameworks itself and their effectiveness, however, regulatory science can also advance knowledge of these systems in general. The comprehensive guidance that is issued to complete an application dossier for regulatory product approval has seldomly been scrutinized for its efficiency. Since it is the task of regulatory authorities to protect and promote public health, it is understood that they take a cautious approach in regulating drugs prior to market access. In general, the authorities are among the first to be blamed if dangerous or useless drugs were allowed to the market. Yet, building a regulatory framework that is not challenged continuously in terms of deliverables for public health and cost-effectiveness, might be counterproductive in the end. Regulatory science and research can help understand how and why regulatory decisions are made, and where renewed discussions may be warranted. The MEB supports regulatory science as an R&D activity to fuel primary regulatory processes on product evaluation and vigilance, but also invests in a 'looking into the mirror' approach. Along the line of the drug life-cycle, publicly available data are reviewed and their regulatory impact highlighted. If made explicit, regulatory research can open the door to evidence based regulatory practice and serve the regulator's contribution to innovative drug licensing today.

Determinants for successful marketing authorisation of orphan medicinal products in the EU.

In 2010, the European Regulation for Orphan Medicinal Products (OMPs) was in force for ten years. In this study we assessed possible determinants of applications for OMPs in the EU since 2000 that are associated with a successful marketing authorisation. Our analysis shows that clinical trial characteristics such as demonstrating convincing evidence of a beneficial effect on the primary endpoint, the selection of a clinically relevant endpoint, providing RCT data as pivotal study evidence and the submission of sound dose finding data are critical success factors. In addition, high medical need seems to counterweigh uncertainties about the scientific evidence in the benefit-risk assessment of OMPs.

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

PURPOSE: To 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. METHODOLOGY: A 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). RESULTS: In 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). CONCLUSION: The 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.