How does a drug or vaccine get approved: a description of clinical trials

There seems to be a lot of misunderstanding of the long and complex process that a drug or vaccine has to go through in order to be approved here in the US. Its much more involved than the company just presenting data or applying to the FDA for approval. Drugs and vaccines go through years long testing that while not perfect (see Vioxx) certainly are pretty strict.



These regulations have been in place as we know it currently since 1978 when Good Laboratory Practices, Good Clinical Practices, and Good Manufacturing Practices were established to insure that the testing practices were closely monitored and standardized to some extent.



Initially there is an R+D period called "Discovery" where the basic composition of the product is established. This can be as much as 3-4 years.



Next there is the initial or pre-clinical testing. This is where animal studies are done to establish two things:

A) The properties and reactions of the product, especially what the therapeutic value is.

B)Toxicological studies are done with the animals to see what side effects are possible, and what the safe dosages may be (note: with vaccines toxicity studies are also done with various adjuvant and vaccine combinations to see which works best..therefore anyone who claims that they can't find adjuvant safety study data is looking in the wrong place. Its such standard work that you don't find it in scientific journals but in clinical trial data available from the FDA under the freedom of information act)

This stage can be anywhere form 1-4 years.



Then comes Phase I studies. This is usually the shortest stage of the study. It has a small amount of healthy volunteers to determine the most effective dose, and with drugs it also looks at how the drug is metabolized and excreted. It also looks for acute or harmful side effects. If nothing harmful is seen, this particular phase can be as short as 6 months.



Next is Phase II. Now the clinical trial starts to get into the heavy duty part of the study. The target population for the drug or vaccine is used. The number of test subjects is much larger and the length of the study is much longer than Phase I. It also establishes dose ranges and provides both safety and efficacy studies.



Next is Phase III. This is an even longer term study to get info for dosages and labelling purposes. An even larger group of targeted individuals is used. Critical large scale efficacy and safety studies are completed. The data is compared (if applicable) with standard therapies or perhaps a placebo (note: with vaccines that usually means giving the "placebo" group the adjuvant only to establish that the vaccine is actually creating antibodies to the pathogen it protects against because if it is only giving a generic antibody response, the vaccine is next to useless against the pathogen-this is called vaccine specificity).

Combined Phases II and III can often last between 4-7 years.

After Phase III is completed the data is submitted to the FDA for regulation review. The FDA then looks through and evaluates the data. This process can take anywhere from 6 months to 2 years. The FDA scientific advisor committees then decide whether to recommend the product or not based on the scientific data. If they don't recommend the product 90% of the time the FDA will not market the product. If they do recommend it 90% of the time the FDA will allow the product to be marketed.

Here is where politics come into play in the process. Sometimes political pressure is applied to approve a drug that perhaps should not have been approved (Avandia) and SOMETIMES believe it or not a drug is rejected for political reasons because the FDA is trying to do some PR work to protect its image. For example, recently a new drug of a similar class to Vioxx was rejected by the FDA but many on the advisory committees felt that it was a pretty safe and effective drug and that the FDA was being overly cautious in an effort to not look like they were simply being a rubber stamp for the pharmaceutical industry.

Finally, there is Phase IV- what is commonly known as the post marketing phase. If a drug/vaccine is approved and marketed, it is considered to be in Phase IV clinical stage-INDEFINITELY. In order to insure safety and because clinical trials are somewhat limited in the total amount of people and data they can collect, widespread distribution and use is likely to find what if any flaws there might have been in the trials. Also if there are similar type products on the market this is also when the efficacy of the new compound is compared with the other products. It also looks to see if new labels or warnings for a new drug or vaccine are needed as well as looking to see if its beneficial economically compared to other products.

Gardasil is in this Phase. But this is NOT an experimental phase as some claim (ie, the people now getting their vaccines are NOT guinea pigs). It is merely a recognition that its possible for even perfectly run clinical trial to miss something and this allows the FDA to keep track of new products and either relabel or change recommendation of use, or even yank the the product off the market.

Is this system perfect? No. Certainly there are ways to fudge data but the regulations are pretty tight when enforced. And the FDA has the right (and often does this) to conduct surprise inspections at any time with little or no notice. These days, however the FDA has had its staff and funding cut significantly so they don't have the resources needed to ensure full compliance.
However, most manufacturers have no desire to face multimillion dollar lawsuits so many will voluntarily conform. Also, even just getting a warning letter from the FDA can so damage a companies reputation that it can permanently hurt it (yes, I know of companies who have gone out of business because of this). Also all GLP/GMP companies must by law have a independent QA department whose so job is to make sure that a company is totally compliant with FDA regulations and that also helps keep most companies honest.