Bench to Bedside: How does drug discovery work?


What is the largest animal you think you could beat with your bare hands?


I’ve spent a lot of time thinking about this. After much internal deliberation, I came to the conclusion that the largest animal I could beat with my bare hands would be a cougar. It’s not unheard of for a person to beat a cougar (it happened last year in Washington, actually). As long as I don’t let it get the drop on me (aka sneak up behind me and bite my neck), I think I have a pretty good shot at avoiding lethal bites or scratches and if equipped with at least a knife, I’d give this cat a run for its money.
— Blaide Woodburn

Big Pharma is pretty mainstream, often under the microscope of the general public and the topic of intense political discussion on Capital Hill. That said, not many people fully understand how the pharmaceutical industry works, and the intimate relationship that exists with academia. Photo credit: Joshua Coleman

Big Pharma is pretty mainstream, often under the microscope of the general public and the topic of intense political discussion on Capital Hill. That said, not many people fully understand how the pharmaceutical industry works, and the intimate relationship that exists with academia. Photo credit: Joshua Coleman

We hear the term “Bench to Bedside” a lot in the media when talking about drug discovery, but have you ever wondered exactly how a drug evolves from a molecule in a tube to a medical therapy that helps treat millions of patients? Sure, many people understand that it takes a lot of time and money to get a drug to market, but where that time and money is spent is often poorly understood. This article aims to provide an accurate, yet understandable, map of the drug discovery process.

Research and Discovery: In-vitro and in-vivo studies

The goal of research and discovery (R&D) within drug development is to identify new compounds that may help treat disease. These compounds range from natural compounds (for example, aspirin was derived from willow bark) to synthetic molecules whose production was informed through biochemical studies. Historically, this was a very slow and tedious process, but now, automation has allowed scientists to develop a process called “high-throughput screening,” by which hundreds of thousands of compounds can be screened in one experiment. Any “hits,” or compounds that may have therapeutic properties, are then further validated using additional experimentation.

For in vitro experiments, scientists can use cells in a dish to model a variety of different diseases. Often, cells cultured in a flask like the one shown in this picture. Photo credit: rawpixel

For in vitro experiments, scientists can use cells in a dish to model a variety of different diseases. Often, cells cultured in a flask like the one shown in this picture. Photo credit: rawpixel

R&D is a “bottom-up” process that explores the biology and treatment of disease by first using a simple model system (cells in a petri dish) and then moving into more complicated model organisms (mice, rats, or non-human primates), ending with human clinical trials. Specifically, research often starts by experimenting on cell lines that model the disease of interest, and this is termed an in vitro approach. As an example, let’s say we’re interested in lung cancer, a disease where lung cells divide uncontrollably to form tumors. Scientists use live lung cells, grow them in a petri dish, and introduce cancerous mutations to their DNA. These mutations result in uncontrolled cell division, and now scientists can treat the cells with various compounds to see if any have therapeutic effects i.e. can stop tumor formation. After identifying potentially therapeutic compounds, scientists will then explore the molecular mechanisms behind their action. For example, let’s say Compound A has been shown to decrease the rate of division in these cancer cells. The next step is to tease out exactly how this molecule is acting within the cell to halt tumor growth; this is referred to as a compound’s mechanism of action.

After identifying viable drug candidates, these experiments must be repeated in-vivo, or in animal models that more accurately represent human physiology. There is a collection of animal models, termed model organisms, used in scientific research, each having specific characteristics that make them desirable for different research questions. But, the one important commonality among model organisms is that their genome is very similar to the human genome. Specifically, their genes code for proteins that are very similar to human proteins, and this especially important in diseases like cancer where genetics often determine treatment viability. Some examples of common mammalian model organisms are mice, rats, and non-human primates, but researchers also use organisms such as fruit flies, zebra fish, and nematodes. So, continuing with our lung cancer example, the next step would be to use the compound hits from the in-vitro experiments to treat mice who have been bred to have lung cancer. This allows scientists to make conclusions that are more impactful as it relates to the human cancer. Ultimately, the efficacy data of in-vitro ­studies must be corroborated ­in-vivo, but in-vivo studies also aim to evaluate the compound’s safety, establish therapeutic concentrations, and determine the best route of administration. Yet, the results of these studies are useless if they are not validated in human clinical trials.

Human Clinical Trials

Let’s start with the regulating body of this process: The Food and Drug Administration, or FDA. The FDA is a government branch that regulates, you guessed it, food and pharmaceutical drugs that are marketed and sold in the United States. Concerning food, the FDA mandates that Nutritional Facts labels are printed on all commercially sold food products, ensures safety and labeling accuracy through random sampling, and works with Department of Agriculture to regulate farming practices. Yet, the FDA receives the most publicity within the public sphere for their role as the primarily regulators of pharmaceutical drugs within the United States.

Drugs are evaluated for efficacy and safety through human clinical trials which are comprised of four phases. These studies are usually double-blinded, meaning neither the scientists, doctor, or patient knows whether the patient was given the actual drug or a placebo. This prevents biases when evaluating the efficacy of the drug. Below is a breakdown of the four phases of a clinical trial.

Research Flow.png

Phase 1

This phase is focused primarily on safety, dosage, and route of administration/delivery. Phase 1 tends to last several months and is comprised of 20-100 healthy volunteers or people with the disease or condition. Of all the drugs that enter Phase 1 clinical trials, approximately 70% advance to Phase 2.

Phase 2

Phase 2 is meant to establish drug efficacy (does it actually work in humans?) and determine any side effects. This phase lasts several months to a year and includes hundreds of people with the disease or condition. Of all the drugs that enter Phase 2 clinical trials, only 33% proceed to Phase 3.

Phase 3

Phase 3 is meant to further establish drug efficacy and determine any side effects, but in a larger sample population. Phase 3 is where most drugs tend to fail. Phase 3 is the most expensive part of the FDA clinical trials, and often projects run out of funding before they are able to demonstrate that the drug is efficacious and safe in a large population of patients. This phase tends to last 1-4 years, and includes 300-3,000 people with the disease or condition.

Phase 4

Phase 4 takes place after the drug has been approved and is commercially available to treat patients. The purpose is to monitor the drug’s efficacy and safety in a population that would not be possible to achieve in a controlled study. This study is comprised of several thousand people who are using the drug after its approval.

Ultimately, drug development is a long, expensive process. Including in-vitro and in-vivo studies and clinical trials, it is estimated that $2-3 billion will be spent to bring a new drug to market. This somewhat explains the high cost associated with pharmaceutical drugs. Yet, the drug development process is a perfect example of the scientific process in action. From lab to clinics, drug development is a demonstration of how a basic scientific discovery grows to influence your everyday life.

Stay tuned for my next article where I’ll compare and contrast the regulatory processes required of pharmaceutical drugs to that required of nutritional supplements.

- Blaide


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