How to Get a Drug Approved?

When your head hurts and you reach for a bottle of aspirin to sooth your aching head, do you ever wonder why the pill you’re taking is considered medicine with actual therapeutic benefit and not some kind of snake oil sham pill? Well the answer to that, is that it’s gone through rigorous testing and has obtained approval from the FDA (Food and Drug Administration) here in the United States. Quite frankly, I’m not as clear on the history of aspirin as it is a drug that has been around for a while now, since 1899 to be exact. The landscape of pharmaceuticals has changed drastically over the years, perhaps more than you’d think (I’d like to write about that in another post someday). We live in a society where we do not have to worry about taking pills that advertise to do more than can, nor do we have to worry about taking pills that may harm us (within a tolerable range). A big reason why that is so, is due to the drug approval process within the U.S — it’s quite stringent and if you want to start selling a brand-new pharmaceutical product to the public, you’d better be prepared to do a ton of work to prove to the FDA that your drug is not only effective but safe was well.

Within drug development there are six phases:

  1. Pre-Clinical
  2. IND Submission
  3. Clinical Studies
  4. NDA Submission
  5. FDA Review
  6. FDA Action

Pre-Clinical

The pre-clinical phase takes place in the lab and consists of the drug discovery process and animal testing. Typically once a mechanism of action or drug target is identified, many compounds are screened through a process to identify compounds that show the greatest potential for therapeutic benefit. These compounds are then tested either within the lab or within animals such as mice, dogs, pigs, monkeys, etc… to gather information regarding the safety and efficacy of the compound. Test tube testing, or in vitro testing, is testing with cell cultures. I often visualize it as exposing a bunch of cells on a petri dish to a solution of the drug and observing what happens (does the drug kill the cancer cells on the plate?) The in vitro environment is one where the effect can be magnified and more easily detected. In vivo testing, the counterpart of in vitro testing, involves the use of live specimens, whether that be human or animal, but since we are unsure of the detrimental effects a drug may have at this point, everything is just animal testing for now. Proper animal testing would require the animal model to possess disease characteristics that are similar to the human disease, which is not always available. Safety testing, on the other hand, is much more straightforward and involves dosing the animals with the drug at levels that are usually expected to be magnitudes greater than the expected treatment dose within humans.

“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.”

Paracelsus (1493–1541)

Since time is limited, this is unfortunately necessary to identify any safety concerns to watch out for should clinical trials on humans begin. One of the most important assessments is the determination of the no-observed-adverse-effect-level (NOAEL), which is the highest dose at which there was not an observed toxic or adverse effect and can be used to estimate the maximum safe starting dose for a trial.

IND Submission

Once all that data has been collected and things are looking good, the next step you’ll have to take is notify the FDA that you will be proceeding to the next step of testing on humans. To do that, an Investigational New Drug (IND) application will have to be submitted. The IND must contain information on the animal toxicology studies, manufacturing information, and planned clinical protocols and investigator information. Once submitted, you have to wait 30 days before starting any trials.

Clinical Studies

Clinical studies are experimental designs with the purpose of ascertaining the efficacy and safety of an intervention (whether that be pharmaceuticals, biologics, or medical devices). They start off with phase I trials, before moving on to phase II trials, and finally phase III trials. The number of patients in each phase’s trials grow successively larger, as the collected data from earlier trials should provide confidence in treating more patients effectively and safely. Larger populations are also needed to tease out any rare problems with the drug and offer greater statistical confidence in the final results obtained.

What makes clinical trials special is the experimental design involved — meaning that the participants in the study are allocated to different groups and treated in a manner that seeks to minimize any differences except for the factor under study, which in our case would be the drug. A good experiment would then be one that allows one to confidently conclude that any differences between group is caused by the difference in intervention and nothing else.

 “Medicine is no hard and thorny science like mathematics and metaphysics, so I soon made great progress; I became an excellent physician and began to treat patients using approved remedies”

Avicenna (980-1030)

NDA Submission/FDA Review/FDA Action

Once your studies have completed and things look good. You would then have to send your data and findings to the FDA in the form of an NDA (New Drug Application). The application is a comprehensive package containing the findings of the clinical studies, pharmacokinetic and pharmacodynamic findings, and manufacturing information regarding the drug. The FDA aims to finish reviewing NDAs and respond within 10 months, for priority review drugs, that time is shortened to months. The package is reviewed by a team of physicians, statisticians, chemists, pharmacologists, and other scientists, who will determine whether or not a drug is approved. Once it is approved, you can then start selling your drug to the public!

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