immunotherapy
early-drug development
toxicology studies
dose determination
Early-drug development in the era of immuno-oncology: are we ready to face the challenges?
Summary
- The classical development of drugs is being replaced by a seamless drug-development process.
- First-in-human trials now often include large expansion cohorts to quickly identify early signs of activity and achieve rapid regulatory approval.
- Intense competition among pharmaceutical companies and the popularity of immune combinations necessitate a reevaluation of current drug evaluation methods.
- The review highlights critical issues and limitations in immunotherapy development, particularly in pre-clinical toxicology studies.
- Murine models and cynomolgus monkeys have been inadequate in predicting human toxicity.
- Issues surrounding dose determination in phase I trials, such as dose-escalation methods and flat versus body-weight dosing, are discussed.
- A proposal is offered to address these challenges, aiming to achieve maximum efficacy with minimal toxicity for patients.
During the past few years we have faced an unprecedented evolution in the design of immunotherapy phase I (Ph1) trials. This change is mainly due to the desire to facilitate patient’s access to drugs with promising activity from early stages of development, and also a consequence of pharmaceutical companies striving to obtain rapid regulatory approval of their drugs. These facts, added to the strong collaboration of the regulatory agencies, approving drugs based on data obtained from Ph1 trials, has made the number of early-immunotherapy trials increase notably.
The traditional trial design has progressively faded away, and in early-drug development (EDD) units we are currently facing rapid Ph1 dose escalation trials followed by strikingly large expansion cohorts. This is well illustrated with the development of pembrolizumab, an antiprogrammed cell death protein 1 (PD-1) monoclonal antibody (mAb). The initial Ph1 trial started in 2011, and in 2014 pembrolizumab obtained U.S. Food and Drug Administration (FDA) approval for metastatic melanoma patients. A 3-year period represents an exceptional time-line in comparison to the more than 10 years that it traditionally took old drugs to be approved [establishing a trend in EDD in immuno-oncology (IO) and being an example followed by many others.
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immunotherapy, early-drug development, toxicology studies, dose determination
