by Anne Monroe, M.D.
Almost 20 years have passed since Retrovir (zidovudine, AZT, ZDV) was approved as the first treatment for HIV. During that time, researchers have developed close to 30 HIV drugs, an amazing accomplishment.
The drug approval process starts with researchers who discover new compounds to fight HIV. It continues with people who are willing to advance medical research by participating in clinical trials. Finally, a review by the U.S. Food and Drug Administration (FDA) determines if the drug is safe for people to take and if it works.
With innovation, time, money, and a lot of paperwork, a new drug can move out of the lab and into the pharmacy.
The first step in drug development is basic science research. The National Institutes of Health (NIH) and pharmaceutical companies fund most basic science research in the U.S.
To develop a new HIV drug, researchers study the HIV life cycle. Their goal is to find new ways to prevent HIV from making copies of itself.
Researchers screen chemical compounds looking for one which may fight HIV. Any compound that is a candidate to become a new drug must be stable in a pill, liquid, inhaled, or injected form, and it must be fit for mass production.
The next step for a potential new drug is laboratory testing in animals to see how the drug is processed in a living being. One of the major reasons for animal studies is to look at safety and toxicity. The original dosing of the drug in humans is based on the results of studies in animals.
All told, the laboratory testing of a new drug can last three to six years. Of 250 chemical compounds identified, only five of them will move on to the next stage: clinical trials of the drug in humans.
New drugs must be reviewed by the FDA before they are approved for sale in the U.S. The FDA regulates both prescription and over-the-counter drugs. Currently, dietary supplements, including vitamins and herbals, do not need to be approved by the FDA before they are sold.
Once the laboratory and animal testing of a new drug is complete, the drug developer sends all the test results to the FDA in the form of an Investigational New Drug (IND) Application. If the FDA determines that the drug appears safe for human testing, clinical trials can proceed.
There are risks and benefits to people who participate in clinical trials. Risks include unknown side effects and the possibility that the new treatment may not work well. Benefits include access to new treatments and helping to advance medical research.
Clinical trials have strict guidelines for who may or may not participate, called inclusion and exclusion criteria. This helps to select people who are most suitable for the trial and screens out those most likely to be put at risk.
Any one who is considering enrolling in a trial must have the details explained to them in easy-to-understand language before starting the study. This allows people to make an informed decision as to whether they want to join. The process of explaining the trial is called informed consent and includes the following information:
- Potential risks and benefits
- The study procedures
- Alternatives to joining the study
- Letting the person know that they can quit at any time
There are several other safeguards in place for people who participate in clinical trials. These include the Institutional Review Board (IRB) and the Data Safety and Management Board (DSMB).
The IRB reviews the study plan and the informed consent paperwork before the study can begin enrolling volunteers at a particular hospital, clinic, or doctor’s office. The IRB checks that the informed consent paperwork is easy to understand and that it is available in different languages if the trial will enroll many non-English speakers. The IRB monitors the safety of study volunteers at a local level.
The DSMB, which is a group of people who have no role in the conduct of the study, reviews data from the trial to address safety concerns at the national level. The DSMB has the authority to stop a trial early if the study drug is shown to be too harmful or is not working as well as already approved drugs. The DSMB also stops a trial if the data show that the study drug is so good that everyone in the study should get it.
It is important to study new HIV drugs in women and minorities as drugs may have different effects in different populations.
In the past, women of childbearing age were blocked from some clinical trials because of fear of harm to the fetus if a woman in the trial became pregnant. However, since 2000, an FDA regulation prohibits excluding women of childbearing age from trials. The regulation did not go as far as to require a certain number of women to be enrolled in each trial; therefore women remain underrepresented in most clinical trials.
Minority enrollment in clinical trials is also very important. In 2004, the Adult AIDS Clinical Trials Group (AACTG), sponsored by the NIH, enrolled almost 6,500 patients in trials, 30% of whom were African American. However, close to 50% of all people with AIDS in the U.S. are African American. Researchers need to try harder to recruit people of color to clinical trials.
The clinical trial process starts with Phase 1 trials. Phase 1 trials are the first time the drug is tested in humans. They are closely controlled trials which require being admitted to the hospital for frequent laboratory tests of drug levels in the blood and intense monitoring for side effects.
Phase 1 trials are small studies (up to 100 people) of healthy volunteers that check the safety of a new drug. Phase 1 trials examine what dose of the drug should be used in future trials and how the drug is processed in humans.
Phase 2 trials of HIV drugs involve up to 300 HIV+ people. These studies are usually performed in an out-patient setting such as a clinic or doctor’s office. Lab tests are done to see how well the drug is working against HIV and frequent clinic visits are required to make sure that the drug is not causing any dangerous side effects.
Phase 3 studies enroll up to 3,000 people, and are long-term studies of drug safety and activity. Because Phase 3 studies are large, they may reveal less common side effects. The study visits occur in a clinic or doctor’s office, and the trial may last two to three years.
Once the first three phases of the clinical trials are complete and the data have been collected and analyzed, the drug company submits a New Drug Application (NDA) to the FDA. These applications are up to 100,000 pages long and take up to 16 months to review! The FDA reviews the data in order to decide if the benefits of the drug outweigh the risks and if the drug should be approved.
From start to finish, the new drug approval process costs approximately $802 million and lasts up to ten years! Of five compounds that make it to clinical trials, only one will make it through all three phases.
Phase 4 studies, called post-marketing studies, collect data about the safety, efficacy, and different uses of the drug after it is out on the market. Some side effects only occur in one out of 10,000 people who take a drug. Clinical trials are not big enough to reveal those rare side effects, which is why it is so important to keep collecting data after a drug is approved.
Now that you know everything that goes into the drug approval process, it may seem even more incredible that close to 30 drugs made it through! And thanks to the hard work of researchers, over 100 new compounds are in preclinical or clinical trials at this time, providing hope for future treatment options for HIV. But remember, without the continued participation of volunteers, drug development would not be possible.
Camp, R. (2006). 2006 antiretrovirals in development pipeline. Treatment Action Group: Retrieved August 2006 from http://www.thebody.com/tag/articles/pipeline.html.
U.S. Department of Health and Human Services. (2006). From test tube to patient: protecting America's health through human drugs: Retrieved August 2006 from http://www.fda.gov/fdac/special/testtubetopatient/default.htm.