Wednesday, January 08, 2014

How the FDA approves drugs

I gave a lecture at the AACI Netanya on the subject of "How the FDA approves drugs." This arose out of the "Health Day" that AACI had in Nov, which was very successful, but, most of the material presented there was for so-called "alternative medicine" and less for standard or "scientific" medicine. I thought there should be a presentation about the way that the FDA approves drugs, since there is a lot of ignorance and misconception about this. But, by then it was too late to be included, so I gave the lecture now.

First, FDA stands for the Food and Drug Administration, the agency that is given the responsibility of checking and approving all food and drugs sold in the USA for human consumption. Without FDA approval it is illegal for doctors to prescribe a drug, although any individual may take anything he/she likes at their own risk. How did the FDA come about? It's precursor was the Chemistry Division of the US Department of Agriculture that was originally founded in 1883. In 1906 Upton Sinclair published his novel "The Jungle" about the meat processing plants in Chicago, and it caused a sensation with its expose of the terrible practices of animal slaughter, hygiene and treatment of the workers. As a result Pres. Theodore Roosevelt introduced the "Food and Drug Act" of 1906 that required all food and drugs for human consumption in the USA to be approved by a US Government agency that became the FDA.

If we look at a graph of the life expectancy of people in the USA we see two things, first the graph keeps climbing, from an average expectancy of less than 50 years in 1900 to an average of ca. 80 nowadays. There is no doubt that improvements in scientific medicine and hygiene are responsible for this almost doubling of the age at mortality. Also, we see that the life expectancy for men lags behind that for women, men die about 5 years earlier than women. But, I won't go into that now since it's too controversial.

How are drugs discovered? Most of the drugs we use are derived from plants or animals and are called "natural products." They are chemicals produced by organisms usually to protect themselves against predators. People scour the world looking for trees, animals and insects that might produce a new chemical that might be a useful human drug. The first important drug discovered was aspirin, found in the bark of the willow tree. It was a folk remedy that was used by a doctors to help their patients deal with pain. Eventually the active ingredient was isolated and synthesized by Bayer in Germany in 1853. It was the first mass produced drug in the world.

Drugs are discovered now with what is called high throughput screening. Extracts of tissues from plants and animals are put into an automated process in a machine run by computers. A certain number of selected cancer cells are pipetted into the wells of a microtiter plate (a plastic plate with small wells in it). Then various solutions are added, including a dye substance and the compound to be tested, in escalating amounts. After a certain time for incubation, the amount of dye coloration is automatically measured. If the candidate drug kills the cells then its contents are released (a process called lysis) and these react with the dye substance to produce a color which can be measured. If small concentrations of the substance kill enough cells, then this becomes a candidate drug. Less than 1% of the substances tested in this way become candidate drugs.

Those selected as candidate drugs or "New molecular entities" (NMEs) are given a code number by the FDA and enter the process of testing for clinical use. This is the crucial part of the process. First there is Preclinical testing in animals to determine toxicity and pharmacokinetics (how fast the drug appears in the tissues) and to see how the drug affects an experimental animal model, such as tumors in mice. Then if it passes those tests the drug is tested in humans and all human subjects must sign informed consent forms. There are three phases of clinical testing , Phase I consists of testing for toxicity of the drug in patients who are usually terminally ill, using drug doses based on an escalating Fibonacci scale, i.e. 1,1,2,3,5,8,13...If there is no overt toxicity then the drug goes into Phase II, in which the drug is tested for efficacy against the chosen medical condition in a small number of human patients. Once again, only if the drug passes this test does it goes to Phase III, which is a multi-center trial with a large cohort of patients, usually ca. 100 in each center. Since this requires a large staff of nurses and doctors and many patients, drugs which do not show efficacy or show toxicity up to this stage are not tested further. The total Clinical Trial for a new drug can cost ca. m$250 and only one or two in ten that get this far are finally approved for human use by the FDA.

All Clinical Trials require suitable controls, and the most widely used is a randomized double blind study. What this means is that neither the doctor, nor the patients, know whether they are getting the actual drug being tested or a placebo (a null substitute). Since it has been found that the "placebo effect" is real, namely patients feel better even if they are given the placebo, it is necessary that the patients don't know what drug they are getting, and since the doctors have a lot at stake (fame and fortune) the clinical trial must be randomized and double blinded. Each hospital has its own Institutional Review Board (IRB, also known as a Helsinki Committee) that runs all clinical trials, thus making it independent, thus there is very little chance of bias or chicanery. Note that the FDA itself does not do the testing, it only reviews the results presented to it. Also, the pharmaceutical company may pay for the trial and supply the drug being tested, but has no control whatsoever in the actual trial. Also, all participants in the trial are required to sign a "conflict of interest" statement declaring any and all commercial interests they have. Failure to declare a true conflict of interest may result in loss of job and possible criminal charges.

Chemotherapy in cancer treatment relies on drugs which are toxic to cells and humans. The drugs are not actually anti-cancer but rather they kill dividing cells. Since cancer cells are rapidly dividing they are most susceptible to these drugs, but other human tissues with dividing cells are also killed by these drugs, including mouth mucosa, skin and hair follicles. This explains why cancer patients lose their hair and develop skin and mouth lesions.

The number of new drug applications being made to the FDA are gradually declining, down from ca. 40 in 1996 to ca. 20 in 2010. As a result scientists are trying to develop drugs by so-called "rational drug design" in which X-ray crystallography and molecular modelling with computer aided drug design (CADD) play a role. Other approaches include gene therapy and antisense, but so far natural products are still the main source of drugs in the world. Any drug must be regarded with scepticism, particularly those that are not subject to the rigorous approval process of the FDA.
Note: The Powerpoint presentation of my actual lecture is available on my web site (


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