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Cited by 4 publications
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Strength and weakness of phase I to IV trials, with an emphasis on translational aspects
Although phase I to III trials represent the standard for introducing new drugs to clinical therapy, there has been increasing demand for translational research in oncology over the past decade. Thus, for most novel therapies such as 'targeted agents', a critical aspect for drug development in oncology has been to select the right patients for therapy. Translational research plays a pivotal role, not only in phase II trials but also in phase I and III and even in phase IV trials. The importance of distinguishing between our translational 'aims' in phase II and phase III trials is emphasized. Although translational research in phase III trials aims to identify optimal markers for clinical use, phase II studies may represent an optimal setting to explore tumour biology and the mechanisms of drug resistance in depth. IntroductionThe roles of phase I to IV trials are now well defined. However, the concept of translational research is not part of this progression, simply because the need for translational research -as part of therapy development -became evident long after the concepts of phase I to III trials were defined. For many anticancer therapies, such as targeted therapies, identification of predictive markers for proper patient selection is mandatory. Use of therapies that are directed at well defined targets, such as trastuzumab and lapatinib, by definition require measurement of specific molecular targets. Although no proof for such a concept exists at present, we can envision that the efficacy of other therapies -such as antiangiogenic treatment -may partly depend on molecular markers such as vascular growth receptors [1].Considering chemotherapy in general, we lack key information about the mechanisms of drug resistance in vivo [2]. Yet, the clinical observation of lack of cross-resistance between different compounds such as taxanes and anthracyclines [3] indicates that different mechanisms are involved. Hence, identification of these mechanisms through predictive testing may help to define the optimal therapy in the individual patient. Turning our attention to endocrine therapy, substantial therapeutic opportunities may result from uncovering the mechanisms of acquired resistance among receptor-positive tumours. Over the past decade we have witnessed a dramatic increase in our fundamental biological knowledge, as well as significant improvements in analytical methods. Thus, the potential for improved predictive testing has never been better. This being so, we must examine how translational research can best be fitted into our general clinical trial programmes. Phase I studiesThe aim of phase I studies is to explore drug toxicity. Traditionally, such studies may involve about 12 to 20 patients who are treated with the drug under investigation at escalating doses. This may be achieved either through dose escalation in the same individuals or by increasing doses between patient cohorts, for instance by using a Fibonacci approach [4]. Often, such studies involve a pharmacokinetic component, in which ...
Strength and weakness of phase I to IV trials, with an emphasis on translational aspects
Although phase I to III trials represent the standard for introducing new drugs to clinical therapy, there has been increasing demand for translational research in oncology over the past decade. Thus, for most novel therapies such as 'targeted agents', a critical aspect for drug development in oncology has been to select the right patients for therapy. Translational research plays a pivotal role, not only in phase II trials but also in phase I and III and even in phase IV trials. The importance of distinguishing between our translational 'aims' in phase II and phase III trials is emphasized. Although translational research in phase III trials aims to identify optimal markers for clinical use, phase II studies may represent an optimal setting to explore tumour biology and the mechanisms of drug resistance in depth. IntroductionThe roles of phase I to IV trials are now well defined. However, the concept of translational research is not part of this progression, simply because the need for translational research -as part of therapy development -became evident long after the concepts of phase I to III trials were defined. For many anticancer therapies, such as targeted therapies, identification of predictive markers for proper patient selection is mandatory. Use of therapies that are directed at well defined targets, such as trastuzumab and lapatinib, by definition require measurement of specific molecular targets. Although no proof for such a concept exists at present, we can envision that the efficacy of other therapies -such as antiangiogenic treatment -may partly depend on molecular markers such as vascular growth receptors [1].Considering chemotherapy in general, we lack key information about the mechanisms of drug resistance in vivo [2]. Yet, the clinical observation of lack of cross-resistance between different compounds such as taxanes and anthracyclines [3] indicates that different mechanisms are involved. Hence, identification of these mechanisms through predictive testing may help to define the optimal therapy in the individual patient. Turning our attention to endocrine therapy, substantial therapeutic opportunities may result from uncovering the mechanisms of acquired resistance among receptor-positive tumours. Over the past decade we have witnessed a dramatic increase in our fundamental biological knowledge, as well as significant improvements in analytical methods. Thus, the potential for improved predictive testing has never been better. This being so, we must examine how translational research can best be fitted into our general clinical trial programmes. Phase I studiesThe aim of phase I studies is to explore drug toxicity. Traditionally, such studies may involve about 12 to 20 patients who are treated with the drug under investigation at escalating doses. This may be achieved either through dose escalation in the same individuals or by increasing doses between patient cohorts, for instance by using a Fibonacci approach [4]. Often, such studies involve a pharmacokinetic component, in which ...
The US Food and Drug Administration (FDA) has proposed new labelling regulations that describe alternative approaches for providing additional information to support labelling a drug, already approved for use in adults, for use in children. Therefore, the study of drugs in paediatric populations may now be encouraged. Paediatric pharmacokinetic studies are an important part of these trials. This action by the FDA may help resolve the ethical and technological concerns about the performance of clinical trials in children, and may render paediatric clinical trials more feasible. Most investigations in children are opportunistic in nature and their design is often constrained by a requisite noninvasive approach. Appropriately applied population-based techniques for both pharmacokinetic and pharmacodynamic data analysis may represent the most robust approach for generating a sufficiently large and accurate database for the use of new or old drugs in paediatric patients. Accordingly, this information, which is crucial for paediatric labelling of any drug product, must be obtained in infants and children if we are to truly individualize therapy for paediatric patients. The funding of 6 Pediatric Pharmacology Research Units by the US National Institutes of Health, and guidelines for application of pharmacokinetic methods to children may further contribute to the performance of paediatric clinical trials.
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