Thankfully, given the volume of new chemical entities and drugs approved each year by the FDA, and despite extensive in vivo and in vitro testing, this is a relatively rare occurrence. However, it does happen for a number of reasons.
The Food and Drug Administration has strict guidelines for human new drug approvals (NDAs). Before a new chemical entity enters into one of four phases of in vivo clinical trials (see below), it undergoes extensive in vitro testing in the laboratory against dangerous microorganisms in a controlled environment under conditions that mimic a human’s physiology.
Working under controlled settings in a laboratory, researchers focus on small samples of harmful microorganisms that cause disease in humans. This is a very complex process that involves first isolating and identifying the proteins, cells and genes that are causing a particular microorganism to act the way it does and then applying and testing various reagents and chemicals against this microorganism, recording any notable changes in them. This trial and error period often times takes years to perfect, and many times researcher, despite their best efforts, come up empty-handed in fully reversing the deleterious effects of these new microorganisms. In many cases chemists will settle for reducing the harmful effects of a particular microorganism in lieu of a cure. This is particularly true for difficult diseases that have one or more microorganism creating a negative reaction in humans like cancer, diabetes, Alzheimer’s disease, muscular dystrophy, ALS, and any other number of other chronic and potentially fatal disorders currently without a cure.
If the in vitro testing of a particular chemical entity against a microorganism was successful in the laboratory, this newly developed chemical entity must then be formulated into a delivery system that would distribute the drug properly in a human’s circulatory system. In other words the drug may be formulated into either an oral dose, such as a capsule, tablet, liquid, or an injectable such as IV, IM, SQ, etc. Other delivery systems include transdermal (generally through a patch), topical (ointment or cream), or inhaled with a inhalator. Whatever the method of delivery, the desired endpoint would be to deliver a drug in a proper safe dose to the areas of the body that would most benefit from its effects without causing dangerous adverse reactions or side effects. This requires additional extensive trial and error testing in humans. This testing is generally carried out in four phases during which time results are recorded and studied. At each stage researchers determine whether to continue to the next stage based on the results of the previous stage.
- Phase I: Researchers test a new drug or treatment in a small group of patients for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
- Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
- Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
- Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long-term use
Even if a chemical entity or drug makes it through this rigorous series of testing, during Phase IV, when the drug is already approved and marketed to millions of people, will the true results be known? It is generally during this period that possible side effects and adverse events occur that were not seen in the much smaller population testing group.
At this point the data would be gathered, and either the drug would be recalled and sent back to the testing phase with alterations to it, or the withdrawn for the market permanently.
Even drugs that performed particularly well during the extensive testing cycle may exhibit negative pharmacological behavior when given to the general population. Relative to how many drugs have been approved over the years, this is a rare occurrence. Some of the withdrawn drugs may actually be reformulated and brought back to market sometimes months or years later.
Overall though, exhaustive testing of new chemical entities and approval of new drugs has proven to be quite effective over the years, and relatively few drug approvals without documented side effects and adverse reactions have caused a major health risk to humans.