Drug development process clinical phase

The partition coefficient and aqueous solubility are properties important for the study of the adsorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) of drugs. The prediction of the ADME-Tox properties of drug candidates has recently attracted much interest because these properties account for the failure of about 60 % of all drug candidates in the clinical phases. The prediction of these properties in an early phase of the drug development process could therefore lead to significant savings in research and development costs. 

The period in the drug development process at which results of these studies are required varies somewhat from country to country, but recommendations are made in the ICH guidelines. In most instances, Stage B studies are required prior to phase 2 clinical studies, the Stage A study is required prior to phase 3, and the Stage C study is needed for the NDA. Circumstances for an individual drug or requirements of certain countries may warrant a modification of this schedule. 

The clinical drug development process required by the US FDA, arguably the most stringent in the world, starts with the investigational new drug (IND) application prior to human testing. It reveals information about all known compounds to be used and includes the description of the clinical research plan for the product as well as the protocol for phase I studies. Preclinical study results also need to be revealed. 

The second gap in the drug development process occurs when pre-clinically validated candidate drugs fail to enter the clinical study phase because of profit-minded choices made by pharmaceutical companies. While it is not as expensive to develop drugs as the pharmaceutical lobby claims, it is still a costly and risky business (MSF 2001 17). Where a substantial reward at the end of the development process is clearly absent, corporate decision-makers are ill disposed to incur this risk. 

The drug development program is divided into preclinical development, clinical development, and post-approval surveillance. Several preclinical and clinical trials are conducted during this program. In the following the phases of the clinical drug development process are described with a special focus on the data available for modeling and simulation and some objectives are exemplarily listed for the respective phases. 

Quality assurance activities actually begin early in the drug development process—in the analytical phase. United States requirements5 are established as early as non-clinical laboratory studies. At this early phase, the audit program concentrates on in vivo and in vitro experiments, focusing on early drug entities. These drug entities are tested under laboratory conditions to determine their potential safety risk. At this phase, human subjects (e.g., clinical studies) or field trials in animals are not involved. 

The pre-clinical drug development process has as its end product a drug candidate that is suitable for testing in human clinical trials. To achieve this, the candidate must pass pre-clinical toxicology testing, have its adsorption, distribution, metabolism and excretion understood in suitable animal models, and have good scientific evidence that it will provide medicinally beneficial effects. The latter normally requires showing efficacy in animal models of the disease. The early phase discovery process has usually... 

The nomenclature for early clinical studies is not fully standardized. In addition to first-in-human evaluations, Phase I trials are appropriate throughout the drug development process as specific issues arise that require clinical pharmacologic investigation. Further, some exploratory hrst-in-human studies are currently being described as "Phase Zero," in which the goals are somewhat different from classic Phase I trials. 

As described in Chapter 31, Phase I includes first-in-human (FIH) trials to provide information about the safety (tolerability) and pharmacokinetics of a new drug. These trials are usually conducted in healthy volunteers unless the trials involve certain cytotoxic drugs such those used in cancer and HIV treatments. It should be noted that Phase I-type clinical pharmacology trials, such as those to study pharmacokinetics in special populations, can and do occur throughout the clinical drug development process (see Chapter 1, Figure 1.1). 

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