New Drug Product Development Phases
Drug products containing NCE are developed sequentially in the following phases:
1. Preclinical
Animal pharmacology and toxicology data are obtained to determine the safety and efficacy of the drug. Because little is known about the human and the therapeutic/toxicologic potential, many drug products will not reach the marketplace. No attempt is made to develop a final formulation during the preclinical stage. Nonclinical studies are nonhuman studies that may continue at any stage of research to obtain additional information concerning the pharmacology and toxicology of the drug.
2. Phase I
a. An investigational new drug (IND) application for human testing is submitted to the FDA. Clinical testing takes place after the IND application is submitted.
b. Healthy volunteers are used in phase I clinical studies to determine drug tolerance and toxicity.
c. For oral drug administration, a simple hard gelatin capsule formulation containing the API is usually used for IND studies.
d. Toxicologic studies—including acute, chronic, subchronic, and mutagenicity—and other such studies in various animal species are planned during this phase.
3. Phase II
a. A limited number of patients with the disease or condition for which the drug was developed are treated under close supervision.
b. Dose–response studies, bioavailability, and pharmacokinetics are performed to determine the optimum dosage regimen for treating the disease.
c. Safety is measured by attempting to determine the therapeutic index (ratio of toxic dose to effective dose).
d. A drug formulation having good physicochemical stability is developed.
e. Chronic toxicity studies are started in two species; such studies normally last more than 2 years’ duration.
4. Phase III
a. Large-scale, multicenter clinical studies are performed with the final dosage form developed in phase II. These studies are done to determine the safety and efficacy of the drug product in a large patient population who have the disease or condition for which the drug was developed.
b. Side effects are monitored. In a large population, new toxic effects may occur that were not evident in previous clinical trials.
5. Submission of a new drug application (NDA)
An NDA is submitted to the FDA for review and approval after the completion of clinical trials that show to the satisfaction of the medical community that the drug product is effective by all parameters and is reasonably safe as demonstrated by animal and human studies.
6. Phase IV
a. After the NDA is submitted, and before approval to market the product is obtained from the FDA, manufacturing scale-up activities occur. Scale-up is the increase in the batch size from the clinical batch, submission batch, or both to the full-scale production batch size, using the finished, marketed product.
b. The drug product may be improved as a result of equipment, regulatory, supply, or market demands.
c. Additional clinical studies may be performed in special populations, such as the elderly, pediatric, and renal impaired, to obtain information on the efficacy of the drug in these subjects.
d. Additional clinical studies may be performed to determine if the drug can be used for a new indication or additional labeling indications.
7. Phase V
a. After the FDA grants market approval of the drug, product development may continue.
b. The drug formulation may be modified slightly as a result of data obtained during the manufacturing scale-up and validation processes.
c. Changes in drug formulation should always be within the scale-up and post-approval change (SUPAC) guidelines.
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