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The development process for a new molecular entity (NME) in humans proceeds over several phases of clinical trials (I through III) before it can be approved for marketing by national regulatory authorities (Figure 6–1). Once regulatory approval has been obtained, after undergoing all required trials over many years, NMEs translate into drugs that are used to treat specific conditions.

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Figure 6–1.
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Drug development process. The process of bringing a drug to market is a stepwise progression. AEs, adverse events; IND, Investigational New Drug application; NDA, New Drug Application.

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The first step in human drug development involves Phase I or “first-in-human” studies. These trials are an exciting milestone in the drug development process, because this is the first time an investigational drug is given to humans. Before human testing occurs, preclinical (animal and laboratory) work establishes the preliminary safety profile of the NME and a starting dose for use in humans. At the end of the preclinical phase in the United States, the drug's developer submits an Investigational New Drug application (IND) to the US Food and Drug Administration (FDA) to obtain permission to begin human testing of the compound. The performance of an NME in Phase I trials helps determine its progression through the drug development process.

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The primary goal of Phase I trials is to assess the safety of the NME in human subjects. In addition, the NME's pharmacokinetics (“what the body does to the drug”) are evaluated to determine the most appropriate dose and dosing regimen in humans. Phase I studies also can explore the effects of different formulations, different exposure routes, giving the drug under fasting or fed conditions, and drug–drug interactions. Because safety and pharmacokinetics are primary objectives of Phase I trials, they are usually conducted in healthy volunteers (often adult men). This strategy limits factors that can confound assessments of safety and pharmacokinetics, which are often present in patients with the disease of interest. However, in the case of significant toxicity concerns or a narrow therapeutic index of the NME, these trials may be conducted in actual patient populations.

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The design of Phase I clinical trials varies according to the primary objective and can range from open-label to blinded, randomized trials. Phase I trials must show that an investigational agent is safe enough to be used in humans and must generate enough pharmacokinetic data to permit the design and conduct of Phase II trials. Description of pharmacodynamics (“what the drug does to the body”) and early tests of efficacy can be secondary end points of Phase I trials, but the emphasis is on nontherapeutic objectives.

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Phase I studies present several practical challenges to drug manufacturers. For example, the compound might not be available yet in the optimal formulation for the patient population of interest. Manufacturing the compound for these studies also can be ...

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