Aaron: Have you ever taken an over-the-counter medication for heartburn? How about an antibiotic for an ear infection? At some point, pretty much all of us have visited a pharmacy to pick up a drug, but we likely don't consider where those drugs come from or how they're made. Whether you're talking about something for seasonal allergies or your grandparents' arthritis medication, the act of bringing a drug to market is long and complex. I'm not an expert, but Healthcare Triage intern Rachel Hoffman is, and with her help, that's the topic of this week's Healthcare Triage.

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Before you start making a drug, you need to make sure that there's a target for that drug. Drug targets can include things like cancer cells, viruses, enzymes, or receptors on the surface of our own cells. For example, drugs like morphine and hydrocodone interact with opioid receptors in the brain to decrease pain perception. Once a target has been identified, researchers can begin developing a new drug.

New drugs can be discovered in any number of ways.  Many of the drugs we use today are derived from natural products. Pyrethrin, a natural pesticide found in some lice shampoos, comes from the chrysanthemum flower, and exenatide, a drug used in treating Type II Diabetes, is a synthetic derivative of a substance found in Gila monster saliva. 

Drugs can also be developed in the lab to have specific chemical structures to fit a given target, similar to how a locksmith would design a key to fit a lock. This is called de novo drug design, meaning that the drug molecule is a new structure, never before seen in nature.  

The most common way new drugs are discovered today is by a process known as High-Throughput Screening, or HTS. HTS utilizes robotics and high speed computers to evaluate huge numbers of potential drug molecules quickly and efficiently. If a compound is found to be active for a given target, it may be considered for further investigation.  

Using any of these methods, an estimated 5,000 to 10,000 molecules may be identified for potential use at an established drug target. Once identified, potential drug compounds undergo rigorous pre-clinical studies. Researchers will use living cells, animals, and computer models to assess things like: 1) How a compound is absorbed, 2) Where it distributes throughout the body, 3) How and where it's metabolized, and 4) How the potential drug compound is excreted from the body.

The study of drug absorption, distribution, metabolism, and excretion is known as pharmacokinetics, a fancy-schmancy word that describes what the body does to a drug, and again, these tests are extensive.  

In the United States, the Food and Drug Administration, or FDA, requires that such studies be done for every compound before they can be tested in humans. These studies are critical for estimating safety and an appropriate starting dose for human trials. A large percentage of potential compounds are eliminated before and during this stage of drug development. The 5,000 to 10,000 compounds they may have started with will likely be reduced to five or fewer candidate drugs.  

Before a drug can be tested in humans in the United States, an investigational new drug, or IND, application must be filed with the FDA. This application includes a comprehensive report on all the data on animal studies, the chemical compositions of the drug, the drug's pharmacokinetic information and side effect profile, and a detailed account of the study design of the forthcoming clinical trials.

The FDA carefully reviews these applications before allowing trials to proceed, and it has the authority to halt trials at any time. This type of process in general varies from country to country. The European Medicines Agency, the PDMA of Japan, and Health Canada all have their own regulations and procedures regarding drug trials. Once allowed to proceed, clinical trials progress in three phases. In Phase One trials, researchers establish the safety of a drug by evaluating the pharmacokinetic profile and documenting any and all side effects. Dose escalation may also occur to establish the highest tolerated dose of the compound. Phase One trials usually involve roughly 20-100 healthy volunteers. An exception to this are trials investigating cancer drugs, in which seriously ill patients who are not responding to standard therapy are the study population. In Phase Two, the candidate drug is tested to establish safety and efficacy of the compound. Such tests are usually done in about 100-600 volunteers with the disease state under investigation. Pharmacokinetics and side effects are still monitored, but researchers are primarily interested in understanding if the drug has the effect we want on disease and its symptoms. Phase Two inquiries also focus on finding the optimal dose for sick patients.

Phase Three is very similar to Phase Two, in that its purpose is to establish safety and efficacy, but it's on a much larger scale. Thousands of volunteers with the disease state from all over the world are involved in these trials. The larger numbers allow researchers to present statistically significant data to the FDA about the drug's safety and efficacy. Information from Phase Three is also key in establishing the labeling data that will accompany the final drug product. You know those thin folded sheets of paper that come with your prescriptions that look like a Dickens novel printed in 2 point type? All of that stuff was figured out and finalized in Phase Three clinical trials.  

Okay, so after all this, should all go well, it's time to reassess. The drug is safe. The drug is effective. Now, we have a new drug ready to prescribed, right? No. Everything needs to be approved by a nation's regulatory body once again before the drug can be marketed. Throughout all the phases of clinical trials, investigators are constantly analyzing their data and compiling information for submission to regulatory bodies. In the United States at this point, a new drug application, or NDA, must be submitted to the FDA The FDA then reviews the data and decides whether or not to approve the drug. Submission of an NDA does not guarantee approval. The FDA may issue an "approvable" letter to the investigators, requiring additional studies, or they may deny approval of the drug altogether.  

But let's say the drug is approved. Then what? Well, naturally, the drug's gonna work perfectly. Nobody experiences any nausea or has dizziness when standing, and we all live forever, and Ned Stark turns out not to be dead after all, right? Guys? No? Of course not. Even though a drug may have been studied over decades and thousands of volunteers, it's impossible to know exactly how this drug will affect every single patient. That's why there's a fourth phase of drug research known as post-market surveillance. In post-market surveillance, drugs are continually monitored, and pharmaceutical companies often submit long-term safety data to the FDA. Consumers and practitioners can also participate in Phase Four by reporting adverse drug events to the FDA's MedWatch program.  

So to recap: The drug development process is complicated. You find a target, test for a compound to hit it, do preclinical studies, get approval for human trials, complete Phase One, Phase Two, and Phase Three, then get approval again, and finally, monitor the drug's use until forever to make sure it's still safe and working. This whole process of bringing a drug to market takes a really long time. From a drug's discovery to the point where you can finally find it in the pharmacy takes an average of 15 years, according to industry. Let's put that into perspective.  Fifteen years ago, Harry Potter and the Goblet of Fire was new on the shelves, the PS2 had just come out, and the only Marvel movie in theaters was X-Men, the original X-Men. Even then, we sometimes screw up. Some people claim it's too easy to get a drug approved. Others claim it's too hard. Debate should continue, and it will.

Healthcare Triage is supported in part by viewers like you through Patreon.com, a service that allows you to support the show through a monthly donation. We'd especially like to thank our honorary research associates, Cameron Alexander and Qadeem Salehmohamed.  Thanks, Cameron and Qadeem! Healthcare Triage will always be free to watch and share, but your support helps make it bigger and better.  

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