Early development involves laboratory and animal studies. Small animals such as albino rats and mice are the most frequently used to ensure that the investigational product is safe for use in humans. The use of animals has diminished over the years as new bench-based techniques have become available. However, animal testing can be eliminated only for a minority of non-clinical studies and animal toxicology tests are still considered essential to drug development, and are required by government regulators before they will allow human testing. A large proportion of candidate compounds fail animal testing, leading to attrition in the pipeline. Sometimes development efforts have to be abandoned and discovery work re-initiated because all concurrent candidates failed non-clinical testing.
Candidates that prove successful in non-clinical testing are prepared for human testing. A drug formulation such as tablets, capsules, or injection, is produced and tested, and an application, known as the Investigational New Drug (IND) application is filed for regulatory approval in anticipation of permission to conduct human studies.
All potentially unsafe molecules are identified early in laboratory and animal studies so that only those molecules that are relatively safe and effective reach the stage of clinical testing. Government regulators thoroughly scrutinize the results of non-clinical testing and approve, for human testing, only those candidates for which experts feel that the potential benefits in patients will be greater than any potential risk of side-effects.
Human testing begins with Phase 1 studies in a small number of healthy volunteers who are given very small doses of the test compounds in specialized Phase 1 laboratories, in the presence of experienced doctors who have expertise in first-in-man studies. Volunteers are told about the study and all its risks. They are paid a participation fee if they decide to participate. The dose of the test compound is slowly increased over a period of several days till the frequency of minor side-effects reaches the upper end of the acceptable range, or the full dose is reached. The nature of any side effects, and the drug concentration in the body are documented. The investigational compound enters Phase 2 studies only if the potential benefits to patients continue to outweigh the risk of side effects in the opinion of government regulators and independent experts.
Phase 2 studies are conducted in a few hundred volunteer patients suffering from the disease for which the investigational compound is being developed. Patients are explained about the study and the investigational medicine, including potential benefits and all potential side effects. Those who wish to participate in the study are enrolled. Patients receive free treatment, and all blood, urine, and other diagnostic tests are paid for by the sponsor company. However, unlike volunteer subjects in Phase 1 studies, patients are usually not paid for participation in the study. The informed consent document and patient recruitment procedures are reviewed by government regulators and the Ethics Committee of the hospital in advance. Patients are free to withdraw consent at any time during the study. Phase 2 studies help in confirming that the medicine works and in determining the exact dose at which it works best. The new medicine is compared with dummy tablets, usually given on top of standard medicines for the disease so that patients are not harmed even if the experimental treatment does not work.
Many investigational drugs do not work well in these studies. Some are shown to have side effects that occur in more patients than is the case with the older medicines. In many cases the overall cost of using the new medicine works out to be too high when compared to the benefits, and therefore may not sell in preference to older, cheaper drugs. Many investigational compounds are dropped from further development for one or the other of these reasons.