The regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials that typically use a valid comparison to an internal concurrent control. However, when it is not feasible or ethical to use an internal control, particularly in rare disease populations, relying on external controls may be acceptable. To better understand the use of external controls to support product development and approval, we reviewed FDA regulatory approval decisions between 2000 and 2019 for drug and biologic products to identify pivotal studies that leveraged external controls, with a focus on select therapeutic areas. Forty-five approvals were identified where FDA accepted external control data in their benefit/risk assessment; they did so for many reasons including the rare nature of the disease, ethical concerns regarding use of a placebo or no-treatment arm, the seriousness of the condition, and the high unmet medical need. Retrospective natural history data, including retrospective reviews of patient records, was the most common source of external control (44%). Other types of external control were baseline control (33%); published data (11%); and data from a previous clinical study (11%). To gain further insights, a comprehensive evaluation of selected approvals utilizing different types of external control is provided to highlight the variety of approaches used by sponsors and the challenges encountered in supporting product development and FDA decision making; particularly, the value and use of retrospective natural history in the development of products for rare diseases. Education on the use of external controls based on FDA regulatory precedent will allow for continued use and broader application of innovative approaches to clinical trial design, while avoiding delays in product development for rare diseases. Learnings from this review also highlight the need to update regulatory guidance to acknowledge the utility of external controls, particularly retrospective natural history data.
Legislative initiatives have been successful in increasing the availability of approved therapies for paediatric patients. However, additional measures to ensure the timely completion of paediatric studies are necessary to further increase the number of medicines available to children. Over the last 3 years, international experts convened to revise the ICH E11 guideline on clinical investigations of medicinal products in paediatric populations to harmonize approaches to paediatric extrapolation, striving to reduce substantial differences between regions in the acceptance of data for global paediatric medicine development programmes. Several areas of therapeutics development in children, such as human immunodeficiency virus and partial-onset seizures, have been streamlined and require fewer children enrolled in clinical trials because of the appropriate application of paediatric extrapolation. Based on this experience, it is clear that for paediatric extrapolation strategies to reach their full potential there is the need to understand the quality and quantity of data, often collected in adult patients, that will inform the appropriateness of the use of paediatric extrapolation, as well as to identify gaps in knowledge with respect to disease pathophysiology, organ maturation or drug target ontogeny. The generation of information that enhances our current understanding of these gaps in knowledge can further decrease the need for larger, paediatric clinical trials and can increase the efficiency of paediatric therapeutics development as well as protect children from participation in unnecessary studies. We hope that this publication will increase awareness, input and support from all the stakeholders involved in paediatric therapeutics development.Over the last 20 years, paediatric drug development has advanced from routine exclusion of paediatric patients from clinical trials to early consideration of paediatric studies during adult development when use in paediatric patients is anticipated. This shift has been driven by legislation both in the USA and EU and has led to a change in paradigm-that paediatric patients can be treated with drugs for which effectiveness and safety have been demonstrated, rather than reliance on often misleading assumptions of effectiveness and/or safety from adult data. Progress in paediatric drug development brings changes to the current paradigm, and is teaching us a few lessons about drug development in general while, out of necessity, paving the way for more efficient clinical trials.Regulatory standards for approval of drugs, vaccines and biological products (medicines) are the same for adult and paediatric patients. Approval must be based on evidence obtained, in general, from adequate and wellcontrolled investigations. Often, drug development proceeds in adults first and, once approved in adults, medicines are prescribed as off-label to children, out of need, long before establishment of effectiveness and safety and appropriate dosing of a medicine in the paediatric populations. ...
Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have legal force and alternative approaches may be taken, but these obviously require more justification. This new series of the BJCP, developed in collaboration with the EMA, aims to address this issue by providing an annotated version of some relevant EMA guidelines and regulatory documents by experts. Hopefully, this will help in promoting their diffusion and in opening a forum for discussion with our readers. BACKGROUNDFor a medicine to be authorised, clinical efficacy and safety should be established, usually through robust and relevant clinical trial data.The conduct of paediatric clinical trials is, however, fraught with hurdles related to operational practicalities, regional differences in standards of care, lack of standard of care, cultural expectations, and ethical challenges. Additional complexities relate to the rarity of the diseases and gaps in knowledge about the pathophysiology and epidemiology of diseases across paediatric age subsets, particularly in neonates and children less than 2 years of age. These challenges lead to concern internationally that despite the implementation of the legal framework in the United States and from the first 10 years of the Paediatric Regulation in the EU, depending on the disease and age of the child, 50% to 80% of children are still treated off-label. [1][2][3] Often, drug development proceeds in adults first, and once approved in adults, medicines are prescribed off-label to children, out of need, long before an evidence base establishes efficacy, safety, and appropriate dosing. This is particularly of relevance for the youngest age ranges, as typically, for these groups, dosages are more difficult to predict, and both the disease and the response to the drug may differ, to at least some extent. For the last decades, when a medicine is not authorised for children, paediatric clinical practice will rely on
The genetic diversity among epidemiologically unrelated strains of"the human pathogenic fungus Scedosporium apiospermum or its teleomorph, Pseudallescheria boydii, from different areas in Europe, was investigated by multilocus enzyme electrophoresis (MLEE) and random ampli®cation of polymorphic DNA (RAPD). Fourteen enzyme activities were analysed by starch gel electrophoresis, corresponding to 27 polymorphic loci and 43 iso-enzymes. Among the enzymes studied, propionate esterase, carboxyl esterase, superoxide dismutase, carbonate dehydratase and malate dehydrogenase were the most polymorphic, allowing the classi®cation of the strains into 6±11 groups each. Combination of the data obtained for the different enzyme activities studied allowed differentiation of the strains. Similarly, a high polymorphism was also revealed by each of the 20 RAPD primers tested, but no single primer was able to differentiate all the strains. The most ef®cient primers were GC70, UBC-701 and UBC-703, which revealed 17 distinct genotypes each, and combination of the results obtained with this threeprimer set allowed complete discrimination of the strains. The dendrograms obtained from MLEE or RAPD by the unweighted pair-group method using arithmetic average cluster analysis did not reveal any clustering according to the geographic origin of the strains or their pathogenicity.
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