Ellen H.M. Moors

Clinical comparability and European biosimilar regulations

Clinical trials required by European regulators to compare biosimilar products with corresponding biologic brands are surplus to requirements and may even be a barrier for the development of biosimilars of more complicated biologics.

Traditional and Modern Technology Assessment: Toward a Toolkit

Abstract Technology assessment (TA) as a discipline includes rather different approaches and methods. Traditionally, the discipline has focused on forecasting, impact assessment, and policy studies. Later more process-oriented approaches, such as constructive technology assessment (CTA), were developed that were aimed explicitly at influencing the shape of new technologies. Although the new approaches have enriched the field of technology assessment, the scope and variety of the field has increased, particularly concerning its methods. These range from trend extrapolation and Delphis to interventions in innovation networks and consensus conferences. This article aims to classify the approaches and methods of TA into a common framework. Distinctions are made between methods of analysis and intervention methods, and between methods functioning as project layout and mere tools. Some criteria are formulated for the choice of methods. In this way, the article attempts to increase the coherence of the field of TA, and to make it more transparent to nonpractitioners such as scientists and engineers, government employees, and members of civil movements.

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.

Conditional Approval and Approval Under Exceptional Circumstances as Regulatory Instruments for Stimulating Responsible Drug Innovation in Europe

The need for fast drug innovation and the public demand for risk‐free drugs creates a dilemma for regulatory authorities: less restrictive procedures involve uncertainties about benefit/risk profiles of new drugs. The European Union has introduced two instruments that regulate early market access: conditional approvals (CAs) and approvals under exceptional circumstances (ECs). We have studied whether these instruments compromise the safety of new drugs and whether they lead to earlier access to innovative drugs. Our study shows that neither of these regulatory pathways accelerates the approval process for innovative drugs. However, the CA pathway shortens the clinical development period. Approvals under ECs are associated with longer clinical development periods, but this regulatory pathway may open up opportunities for specific drugs to be admitted into the market because less comprehensive data are required. Despite the fact that these advanced approvals are based on limited safety databases, there are no special safety issues associated with using these pathways.

The value of non-human primates in the development of monoclonal antibodies

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Towards a sustainable system of drug development

Drug development has become the exclusive activity of large pharmaceutical companies. However, the output of new drugs has been decreasing for the past decade and the prices of new drugs have risen steadily, leading to access problems for many patients. By analyzing the history of drug development and the pharmaceutical industry, we identified the main factors causing this system failure. Although many solutions have been suggested to fix the drug development system, we believe that a combination of reforms of the regulatory and patent systems is necessary to make drug development sustainable. These reforms must be combined with a larger, open-access role for public research institutes in the discovery, clinical evaluation and safety evaluation of new drugs.

The ability of animal studies to detect serious post marketing adverse events is limited

The value of animal studies to assess drug safety is unclear because many such studies are biased and have methodological shortcomings. We studied whether post-marketing serious adverse reactions to small molecule drugs could have been detected on the basis of animal study data included in drug registration files. Of 93 serious adverse reactions related to 43 small molecule drugs, only 19% were identified in animal studies as a true positive outcome, which suggests that data from animal studies are of limited value to pharmacovigilance activities. Our study shows that drug registration files can be used to study the predictive value of animal studies and that the value of animal studies in all stages of the drug development should be investigated in a collaborative endeavour between regulatory authorities, industry, and academia.

Measures of biosimilarity in monoclonal antibodies in oncology: the case of bevacizumab.

Biosimilars have been available on the European market since 2006 and experience with their use is increasing. The next wave of biopharmaceuticals that are about to lose patent protection consists of more-complicated products, including many monoclonal antibodies. Guidance has been released on the particulars of a biosimilarity exercise involving these products. Considerable challenges exist to establish biosimilarity for anticancer products. An especially challenging product is bevacizumab (Avastin(®)). On the basis of data available for the innovator product (bevacizumab) we will discuss strengths and weaknesses of preclinical and clinical models and explore the application of novel endpoints to the biosimilar comparability exercise.

Orphan drugs: Unmet societal need for non-profitable privately supplied new products

Abstract Due to the severity of rare diseases, the societal need for biopharmaceutical treatments for these diseases is high, despite low numbers of patients. Therefore, we investigated the barriers currently hindering the willingness to develop orphan drugs in the Netherlands. To this end, a robust, small sample, exploratory analysis of Dutch multi-actor development of orphan drugs was performed. Various factors that were expected to stimulate the adoption of orphan drug development were found to be important barriers. Concerted actions of producers, users, and especially regulators are necessary to overcome these barriers, but the prerequisite of a shared problem definition is lacking.

User-producer Interactions in Functional Genomics Innovations

Summary Now we are at the doorstep of the functional genomics era, lessons can be learned from the debates on risks, public acceptance and ethical aspects of biotechnology, by anticipating on users’ preferences and needs, and by involving users in the innovation process. Insights into the user—producer interactions are also important because developments in nutrigenomics and pharmacogenomics may cause a shift-towards an individualised consumer demand and a de-fragmented market. The relation between users and producers will alter when the genomics ‘products’ become customised (e.g. tailor-made drugs, functional foods). In order to get a better understanding of the interaction between users and producers in functional genomics innovations and to learn about a useful participation of users in genomics developments, this exploratory paper focuses on what we can learn from innovation studies about the role of users in functional genomics innovations. This leads to recommendations for governance of biotechnology in general and functional genomics in particular.