Phase 1 Studies

Phase 1 studies are the first studies performed in human subjects after an Investigational New Drug (IND) application has been submitted and approved (Fig. 5.1). Companies must wait r First studies in humans after obtaining IND

r Single-dose followed by short-term multiple dose studies -follow-up for days to weeks r Determine initial safety profile, maximally tolerated dose (MTD), and pharmacokinetic profile including ADME

r Usually 20-100 healthy volunteers r For studies of "toxic" therapies (e.g.,Oncology, AIDS studies), "volunteers" have disease r Duration ~1.5 years Fig. 5.1. Phase 1 Studies

30 days from filing the IND with regulatory authorities before starting any trials and will usually wait for their comments about their first human protocol in phase 1. Sufficient preclinical information including animal toxicology data are available to suggest that the new chemical entity or biologic may be effective and safe in humans for the proposed indication. The primary goal of phase 1 studies is to define the initial safety profile and the maximum tolerated dose (MTD).

The initial phase 1 studies use only a single-dose (often a likely no or minimal effect dose based on animal studies) and volunteer subjects. Follow-up is for days to weeks depending on the predicted pharmacokinetics. Subsequent phase 1 studies use multiple doses for several days to a week or two, with follow-up for days to weeks. The simplest dose-up schema in phase 1 studies is a doubling of the dose from the no effect dose until the MTD is achieved. These studies typically require frequent blood sampling for pharmacokinetic data. Monitoring is usually extensive in phase 1 work for various organ systems (e.g., full physical exams, blood pressure, and biological specimens), and is sometimes performed in a clinical research center in which the normal subjects are housed even overnight. Blood, urine, and other specimens are obtained to identify hematologic, hepatic, renal, and other adverse effects. If animal studies suggested any special tissue effects, extra specimens are collected and assessed to ensure subject safety. Additionally, pharmacokinetic studies are done along with the toxicology assessment, or in separate trials, to document the absorption, distribution, metabolism, and elimination (ADME profile) of the product. Pharmacokinetic differences between products in the same family of drugs can be major advantages (e.g., longer half-lives permitting less frequent dosing, nonre-nal elimination permitting use in renal failure, or distribution of the drug to a site where the disease is localized).

Phase 1 studies usually require 20 to 100 healthy volunteers. However, there are circumstances in which healthy volunteers are not used. Typically, this occurs when more "toxic" therapies are being tested, such as cancer chemotherapy and antivirals for the treatment of the human immunodeficiency virus (HIV). Under such circumstances, patients with the disease are the first individuals to test the new therapy. In these populations, there is a tendency to merge phase 1 studies with early phase 2 studies to minimize the total number of subjects r Determine effectiveness in condition or disease of interest r Define appropriate dose (dose-ranging studies)

r Begin to identify side effects / toxicity (over 4-6 weeks)

r Typically 100-300 patient volunteers r Highly controlled study design r Duration (overall) ~ 2 years

Fig. 5.2. Phase 2 Studies exposed to a potentially toxic treatment. In addition, the minimum pharmacokinetic work is done in patients to also reduce patient exposure to toxic products. It takes approximately 1.5 years to complete the phase 1 studies.

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