Phase III clinical testing

By the time a drug is in phase III clinical testing, the drug will have been in development for 2-5 years, extensive data will probably exist on the drug substance, and a final or close-to-final commercial formulation will be available. 

Phase II and III clinical testing then begins, and during this phase (preferably phase II) an order of magnitude formula is finalized. 

A water-solubilized texaphyrin based on gadolinium(III) (XCYTRIN ) is under current testing in a new Phase III clinical trial with the role to enhance the effects of radiation therapy for... 

The phase I clinical testing of enalapril began in 1980 in a study in which its efficacy to inhibit intravenously administered angiotensin I was determined. Oral doses as low as 2.5 mg produced a substantial decrease in ACE, activity and lowering was evident even 21-24 hours after the drug was given (129). Phase II and phase III trials began in 1981, and the first approval to use enalapril in hypertension came in 1984 and in heart failure in 1986. 

A second-generation compound, (79) (WIN-54954)also advanced into clinical tests, but had disappointing effieacy in Phase II trials, probably beeauseof extensive metabolism. Modifieation of the phenylisoxazole,guided by both structural and metabolic considerations (177), allowed the ereation of a stable and potent antiviral, the third-generation compound (80)(WIN-63 843, pleconaril, or Picovir) (178). This compound was evaluated in Phase III clinical trials and showed efficacy in humans. Oral dosing of virally infected patients with... 

Phase III clinical trials are critical and require full-scale treatment in several medical centers. The design of these trials compares the test candidate to known treatment and placebo in a double-blind manner. The dosage used in these trials is critical as these determine regulatory decisions and marketing. The number of patients can be several hundred to thousands, and assessments of drug interactions are made at this stage. 

However, other molecules are still in the race, including some natural products and others that are products of semi-synthesis and in two particular cases, total syntheses. Currently (July 2007) there are at least 16 molecular entities in varying stages of testing from biological testing through to Phase III clinical trials. Of these, four are in clinical trials in addition to ixabepilone. These are... 

Pharmaceutical executives claim that the number of people enrolled in clinical trials has increased dramatically over time. A rapid increase in trial sizes would be consistent with an increase in the estimated cost of phase III clinical trials from 5.7 million for each NCE entering the phase in Hansen s study to 14.3 million in DiMasi s study (in 1990 dollars). Part of the explanation for such an increase may be a change in the mix of drugs under testing from those for acute illness to those for chronic illness. Drugs for long-term use often require larger trial sizes. 

Once several batches of raw materials have been reviewed and tested to demonstrate that they will conform with the functional and quality requirements, the full excipient and packaging specifications can be finalised. Excipient and pack performance should be evaluated from a stability evaluation of the product and feedback from experience in clinical trials. Ideally, the specifications should be finalised for the start of Phase III clinical trials. If for some reason, the excipient or packaging material has to be changed for Phase III supplies, then some or all of the steps involved in the selection of materials, compatibility and stability studies may have to be repeated. 

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