The Drug Development Process

  Leo Borjon using the ARA centrifuge

Leo Borjon using the ARA centrifuge

  • HIV research begins with “basic” or “bench” science, seeking an understanding of the immune system and how HIV functions within that system.
  • Promising drugs go through pre-clinical testing—experiments in test tubes and animals—to test for safety and effectiveness.
  • Before getting final FDA approval, a drug must be tested in humans in Phase I, Phase II, and Phase III clinical studies.
  • Developing a new drug is complicated—only one in 5,000 compounds that begin in a lab ever receive FDA approval at the end of years of research.

Each step in the drug development process is focused on satisfying the regulatory requirements of the U.S. Food & Drug Administration (FDA), designed to ensure that new drugs are safe and effective in fighting the targeted disease.

The development of a new HIV drug once in clinical trials takes an average of nine years before the drug reaches your medicine cabinet.  This includes early work in the laboratory and animal testing, which is designed to identify any toxicities prior to experiments conducted in humans.  The process, however, can take up to twenty years. Then, the process continues with phased clinical trials using human research volunteers.  According to the FDA, only 1 in 1,000 compounds moves from the lab to clinical trials in humans.  And from there, the FDA approves only 1 in 5 new drugs.

Basic Science Research

In the case of HIV, basic science research begins with an understanding of the immune system and how HIV functions.  The questions that basic or bench science seek to determine are how a drug might be effective in preventing infection, treating HIV, or curing AIDS.  These questions provide researchers with a concept around which they can start to develop a drug for commercial purposes.

New HIV drug candidates are first identified by testing them for anti-HIV activity.  In test tube experiments called “assays,” new compounds are added one at a time to cell cultures or actual human cells grown in a laboratory.  The goal is to find a compound that shows new and promising anti-HIV effects under the microscope.  A related method is called “rational drug design,” where scientists “build” drug molecules specifically so they can fight HIV in targeted ways.  Computers can be used to simulate a chemical compound and to design chemical structures that might work against HIV.  While computers give organic chemists clues as to which compounds to pursue, a substance must still be tested within a living being.

Pre-Clinical Research

Once a promising drug has been identified, it goes through pre-clinical testing in test tubes and animal studies.  Generally, a substance is tested in two or more animal species.  Animal testing is used to measure how much of a drug is absorbed into the blood, whether the drug candidate causes any toxic effects, and what new chemicals—called metabolites—are formed when the drug candidate is broken down by the body.  Tests also determine how quickly the drug and its metabolites are excreted from the body.  Animal testing can range in length from a few weeks to several months, during which time researchers make every effort to use as few animals as possible and to ensure their humane care.

If results from pre-clinical experiments show promise, this data is submitted to the FDA in an Investigational New Drug (IND) application, which is essentially a formal request to proceed with human clinical trials.  The FDA reviews the preclinical research data and then makes a decision as to whether to allow in-human trials to proceed under strict guidelines that protect research volunteers.

Clinical Research

Once the FDA reviews the preclinical data and objections are answered, an ethics committee must grant its approval, too; these committees protect the rights of clinical trial participants.  Then, there are three clinical phases that every new drug must go through before it can receive final FDA approval. 

Phase I studies are the first time a new drug candidate is given to humans, possibly patients with the disease being targeted, but more often healthy research subjects with no disease.  These closely monitored studies are primarily designed to determine the safety of the new drug.  These studies examine the metabolic and pharmacologic actions of the drug in the human body, any side effects associated with increasing doses, and if possible, they try to gain early evidence on the effectiveness of the new drug.  The number of subjects and length of time needed for Phase I studies vary with the drug, but are generally in the range of 20 to 80 volunteers, usually lasting less than a year.

Once clinical researchers reach Phase II, they are ready to collect preliminary data on the effectiveness of the drug for a particular use in HIV/AIDS patients.  This phase of testing also helps determine the common short-term side effects and risks associated with the drug.  Phase II studies are typically well controlled, closely monitored, and usually involve several hundred trial volunteers.

If evidence collected during Phase II studies suggests the drug is effective, researchers can roll out Phase III studies, which involve significantly expanded trials.  These larger trials are intended to gather additional information about effectiveness and safety, which is needed to evaluate the ultimate risks and benefits of the drug.  Since Phase III studies usually include several hundred to several thousand subjects, they provide an adequate basis for extrapolating the clinical results to the general population.  The FDA requires two separate Phase III studies before approving any new drug.

Final Approval by the FDA

Once Phase III trials are successfully completed, researchers may submit a New Drug Application (NDA) to the FDA, seeking approval for use of the drug in the United States.  The NDA includes the results and related analyses from both animal and human experiments, as well as an indepth description of how the drug will be manufactured.  The FDA reviews the results from these studies to determine if a drug is safe and effective, whether its benefits outweigh its risks, whether the drug’s labeling information is appropriate, and whether the manufacturing methods are adequate enough to ensure the purity of the drug.

Collecting Long-Term Data on New Drugs

The last phase of the drug development process is the marketing or “commercialization” of the new drug once it has been approved.  The drug manufacturer must submit marketing authorization applications in every country or territory in which it wants to sell the drug.  Phase IV studies—also known as “post-marketing studies”—then begin.  These studies monitor long-term effectiveness, safety under “real world” conditions, and they are especially valuable for detecting long-term and uncommon side effects that did not show up in earlier trials.  Such post-marketing studies also compare the new drug to similar drugs on the market, and in some countries these studies are mandatory.

AIDS Research Alliance

Our scientists have conducted over 150 research studies, and these studies fall along every stage of the drug development process.  AIDS Research Alliance is currently conducting pre-clinical studies to test the compound, prostratin, to determine its effectiveness in eradicating HIV reservoirs—the latent virus not killed by existing therapies.  AIDS Research Alliance also conducts Phase I, Phase II, and Phase III clinical trials for major research universities, the world’s leading pharmaceutical companies, as well as the National Institutes of Health.  These studies keep our scientists at the forefront of HIV science and inform our cure research.

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