Drug approval process

“FDA Approval Process: Abandon Hope All Ye Who Enter”

I think that if you and your doctor are considering consenting to a clinical trial you should be somewhat familiar with some of this information, language and the overall process of drug approval by the Food and Drug Administration (FDA). By happenstance I have becoming increasingly interested in clinical trials for new Crohn’s medications (particularly non anti-TNFs) because nothing seems to be working for me. At times I just feel like tossing my hands in the air and saying screw it when it comes to Crohn’s drugs. The sense of futility at times can be pretty difficult to deal with for me.

Interestingly, I was on the researcher side of this whole clinical trials equation for 4 years prior to medical school. We discussed and tried to understand the perspective of the patient considering entering a trial but honestly its something you can’t appreciate until you’re actually considering the risks for yourself. All this stuff scares me at times and I think that’s okay to admit. Anyways I don’t want this to be super long so I will go ahead and define the various “phases” of clinical trials so that we are all on the same page moving forward.

1. Pre-clinical studies are first performed in specialized cells grown in laboratories ( by lowly interning undergrad students like me back in the day) and then in animal models These studies are critical because they help establish the safety, toxicity, therapeutic doses, lethal dose, effects on reproduction, carcinogenicity (will it cause cancer?) of the drug. These studies are TIME CONSUMING (taking up to 5 years to collect and analyze data) and EXPENSIVE (averaging around 40 million dollars per successful drug)!

2. Once the drug is ready for testing in humans, an IND (Notice of Claimed Investigational Exemption for a New Drug) is filed with FDA. This IND includes: the molecular structure (what is in the drug and/or the source of the drug), the animal data, design/protocols of clinical trials and a bunch of other stuff. If IND granted proceed to 3, if not return to 1 and repeat.


3. Clinical trials begin: Usually take 4-6 years of running the studies to acquire all the data that the FDA needs, and they start up basically immediately after the animal toxicity studies have completed and the IND is filed.

a) Phase 1 trials: Short term studies that are conducted in a small number of healthy folks (usually less than 50 volunteers). These studies determine the safe clinical doses, how long the drug stays in your body, what the drug does to a healthy body, what your body does to the drug etc.

Main question of a phase 1 trial: What are the side effects? Is it safe to test?

b) Phase 2: The first time the drug will see patients who have the condition in question. These are smaller numbers of patients (several hundred at the most). These patients are usually the healthiest (among the diseased) and middle aged (because the companies want easy to treat people to maximize results). Usually this group will have the highest likelihood of a positive response to the drug.

Main question of a phase 2 trial: Does it work at all? What is the appropriate dose?

c) Phase 3: If the drug reaches phase 3 it now is given to several thousand patients. Here the efficacy (number of people who respond well to the drug) and safety are clarified further. Response rates generally drop from those reported in the Phase 2 data because sicker patients, more variability among the cohort etc. These studies are conducted in multiple locations (and even countries).

Main question of a phase 3 trial: Better than placebo and/or other treatments? Side effects?

4. After the 3 phases are completed, companies file a New Drug Application (NDA) which reports ALL PRE-CLINICAL AND CLINICAL TESTING for the drug. The approval process is in the ballpark of a 1-3 years.

5. Phase 4: After the drug is on the market these look at long term safety and adverse drug reactions. Also they will test in different like special populations.

Companies screen millions of compounds from chemical libraries (worth millions of dollars) using automated methods searching for candidate drugs and of these basically 1 or 2 may become a drug. The FDA screening is rigorous and the VAST MAJORITY OF DRUGS ARE NOT APPROVED due to liver toxicity and other reasons. Most trial information is all publicly available on pharmaceutical company websites, if you search some of the big players you will see that they excitedly publish all their  preclinical and phase 2 data no doubt to to stir up investments. Then the drug usually gets shot down in phase 3…that’s the way of the world folks.

Have any of you been in a clinical trial? Were you nervous/concerned about it like I am feeling? What pushed you to consent in the end? I would really like some advice in this area. Thanks.

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