New pharmaceutical drugs and medical devices are required to have rigorous testing to ensure that they are safe for humans and that they do what they claim to do. In the U.S., potential drugs have to go through rigorous testing in what are called clinical trials in order to gain approval from the Food and Drug Administration (FDA). However, lets step back a bit and start from the beginning.

How Were Drugs Discovered?

In the past, drugs were originally discovered by scientists studying bacteria or fungi. Penicillin, the world’s first antibiotic, was discovered accidentally in 1928 when Dr. Alexander Fleming returned from vacation and found that some of his petri dishes were growing mold. He examined it and found that this particular mold, Penicillium notatum, had inhibited growth of Staphylococcus, a genus of bacteria. Dr. Fleming published a paper about the finding and is credited with the discovery of penicillin, but it wasn’t until about ten years later when Dr. Howard Florey found Dr. Fleming’s paper in a journal by chance and decided to get funding to develop this idea further. Dr. Fleming and Dr. Ernst Chain worked earnestly until they were able to purify penicillin in mass quantities. They tested on animals then on humans to great success, and in 1945, Fleming, Florey, and Chain were awarded the Nobel Prize in Physiology or Medicine. Many other antibiotics have been discovered since then, and due to drug resistance, researchers are still looking for new antimicrobials.

Statins, which are lipid lowering medications used to lower risk of cardiovascular disease, were also discovered by investigating fungi. In 1976, Akira Endo, a biochemist working with Sankyo Company, isolated a factor from Penicillium citrinum that was found to inhibit HMG-CoA reductase.This first statin became known as compactin. It showed promising results in animal testing, however clinical trials had to be halted due to serious toxicity. In 1978 Merck Research Laboratories discovered another similar molecule that also inhibited HMG-CoA reductase from bacteria Aspergillus terreus, and they called this drug lovastatin. Within the year, Akira Endo also discovered this same compound independently. Lovastatin eventually became the first statin to be approved in the U.S. by the FDA for the treatment of hypercholesterolemia (high amounts of cholesterol in the blood). Several other statins and lipid lowering drugs have been discovered since then, and research is still ongoing for new measures or treatments.

While designing drugs from molecules isolated from plants, animals, bacteria, or fungi is still viable, many pharmaceutical or academic researchers use computer modeling in order to design drugs. First, they set a target molecule which ideally has key involvement in a disease process. Then a “drug” or ligand, is designed to affect that target molecule by either enhancing or inhibiting the function of the target molecule. There are many aspects of drug design involving biochemistry processes, pharamacokinetics, pharmacodynamics, and molecular biology. Overall, researchers are focused on developing a drug that will work as intended with the least amount of complications due to the incredibly high cost of animal and clinical trials.

Drug Development

After looking through the thousands of possible molecular compounds, researchers pick a much smaller group of potential drugs to follow through to pre-clinical testing and development. Pre-clinical testing is typically done through animal models that are genetically engineered to mirror the human disease process. Although this practice is somewhat controversial, many researchers agree that animal testing allows the development of basic knowledge of a treatment. In the U.S., any animal testing that is federally funded has to get approved by the Institutional Animal Care and Use Committee (often abbreviated as IACUC) in order to ensure animal welfare. During this process, many drugs are dropped from further development due to various reasons ranging from complications to low efficacy.

Following that, clinical research for the molecule can begin. Now to be clear, clinical research involves studies, or trials, that are done on people (humans). Approval of these human trials is a highly regulated process by the FDA, and they also have to be approved by an Institutional Review Board (IRB), whose purpose is to protect the rights and welfare of human subjects involved in research activities being conducted under its authority. (The IRB heavily relies on medical ethics, which I wrote about in this post!) We will talk about the IRB in a later post. Clinical trials are planned and designed well before they start. Researchers have to define the population they are interested in, the amount of subjects the trial will possibly include, the selection criteria, the type of study, the type of drug dosage and delivery, what data would be examined and the reasoning for it, and many other points. Usually, all these details are written in what appears to be a small booklet. Each phase of a clinical trial is typically it’s own separate trial, and each one of them have to be approved by the FDA.

Phases of Clinical Trials

Phase 0 trials are relatively recent in their designation by the FDA, and not all drugs go through this phase. This phase is conducted on a very small group of healthy people (< 10) with very small doses in order to ensure that the drug behaves as expected in human subjects. This is done by pharmaceutical companies to rank the different possible drugs they are testing. Next, phase 1 clinical trials are done in a group of up to 100 subjects. Typically, these people are healthy and this testing is done in a special clinic where they stay and are monitored 24/7 to ensure their safety. This phase is used to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and dose-ranging. Phase 2 clinical trials have a larger size of around 200 people with the disease that is being treated. This phase is used to test for side effects and effectiveness at treating the disease (if the treatment will affect the disease). This phase is not used to measure a drugs therapeutic effect. Phase 3 trials are much larger and can involve a few thousand people with the specific disease. This phase is used to measure a drug’s therapeutic effect and continues to monitor for efficacy, effectiveness, and, of course, safety. After a successful Phase 3, the FDA can approve the drug for the market, and physicians can prescribe it if necessary. Phase 4 goals are for post marketing surveillance to ensure long term safety in the general public.

So what happens when a drug fails one of these steps? Any issues are recorded as an adverse event or serious adverse event, reported to the FDA, and then an investigation is started to see whether testing needs to be halted or not. One of the biggest cases recently was when the then FDA-approved drug Rofecoxib (Vioxx) was pulled from the market due to concerns about increased risks for heart attack or stroke. It was ruled that Merck, the drug company that developed Vioxx, withheld information from the general public concerning this drug.

As you have learned, the path for drug development is difficult. The image on the right emphasizes the amount of failures that precede one approved drug. There is a large cost associated with that one approved drug, and that is one of the reasons why new drugs have a high cost. Here is some more information if you are interested in looking more into the drug development or clinical trials. Please consult your physician for any medical concerns or advice.