AIDS Community Research Initiative of America (ACRIA) - Winter 2002/2003
Liz Highleyman

It usually takes ten or more years for a promising candidate to wind its way through the drug development process (although activists have succeeded in speeding up development of medications for HIV and other life-threatening diseases). According to the Food and Drug Administration (FDA), only one in 1,000 compounds makes it from the laboratory to clinical trials in humans, and only one in five that enters human trials is ever approved. 

The earliest stage of drug development takes place in the laboratory. Traditionally, large numbers of candidate agents are screened by combining them with disease-causing organisms and cell cultures in a test tube or Petri dish to see how they interact. Such preclinical work is known as in vitro research (Latin for "in glass"). Today, drug companies increasingly use a process called rational drug design in which computers guide the construction of custom-made compounds that have a desired action.  

If a candidate shows good activity in the lab, preclinical testing continues with animal studies (in vivo research, Latin for "in a living organism"). Different tests are done to see what side effects an agent causes and what doses are safe. It is not unusual to see specific toxicities in animals but not in humans, and vice versa. 

If all goes well, the candidate then enters human clinical trials. Before a drug is approved for marketing, it is called an investigational new drug (IND). 

Phase I trials are usually conducted in a small number of healthy HIV-negative volunteers (typically 10-100); sometimes testing in people with HIV may begin in Phase I. These early trials establish the pharmacokinetics of a drug (how it is absorbed, processed, and excreted by the body), its safety and tolerability, and the best doses. 

Phase II trials involve a larger number of participants with the disease under study (typically 50-500). While researchers continue to look for toxicities, they also seek preliminary indications of effectiveness, or efficacy. Sometimes Phase I and II or Phase II and III trials are combined to speed the development process.

Phase III trials include the largest number of participants (typically hundreds or thousands). These trials are designed to determine whether a drug is effective. They also continue to monitor toxicity, especially longer-term side effects. Once Phase III trials are complete, a company may submit a New Drug Application (NDA) to the FDA. The agency uses results from these studies to determine whether a drug should be approved for marketing. 

Phase IV trials are post-marketing studies conducted after an agent has been approved. They are intended to further confirm efficacy and safety under "real world" conditions, and are especially valuable for detecting long-term and uncommon side effects that do not show up in Phase III trials. Since many HIV drugs have been given accelerated approval, activists have complained that companies often neglect to do these follow-up studies.

Traditionally, drugs are tested against a placebo (an inactive substance such as a sugar pill), but this is now less common in HIV trials. However, randomized, double-blind trials - in which participants are assigned by chance to receive different treatments and neither the researchers nor the participants know who is getting what - remain the "gold standard." New agents are often compared to an existing standard of care, such as the best currently available drugs.

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