Drug Discovery and The People Behind The Scenes



“The number of people involved in getting a drug to the first patient is a small phonebook. It’s hundreds to even a thousand or two thousand, depending on the nature of the work. It requires people from a whole set of different disciplines, ranging from a geneticist who may be that person who makes the first link of a gene with a disease, to the chemist who tried to understand how to make a chemical that will interact with a protein, that a biochemist will have isolated, to a pharmacist who will figure out how to take that chemical and put it into some kind of delivery device, what we call a pill or injection, who work to try to predict how that drug is going to behave in a patient or in a large population, and so on. The set of disciplines is immense.”
                                                                                                                                             John Leonard, M.D., Abbott

Modern drug discovery is the product of cooperation. Many sectors contribute, particularly in building the basic science foundations. Both public and private organizations play unique but increasingly interdependent roles in translating basic research into medicine.


Understand the disease
Before any potential new medicine can be discovered, researchers work to understand the disease to be treated as well as possible, and to unravel the underlying cause of the condition. They try to understand how the genes are altered, how that affects the proteins they encode and how those proteins interact with each other in living cells, how those affected cells change the specific tissue they are in and finally how the disease affects the entire patient. This knowledge is the basis for treating the problem.

Target Identification
Choose a molecule to target with a drug
Once they have enough understanding of the underlying cause of a disease, pharmaceutical researchers select a “target” for a potential new medicine. A target is generally a single molecule, such as a gene or protein, which is involved in a particular disease. Even at this early stage in drug discovery it is critical that researchers pick a target that is “drugable,” i.e., one that can potentially interact with and be affected by a drug molecule.
Target Validation
Test the target and confirm its role in the disease
After choosing a potential target, scientists must show that it actually is involved in the disease and can be acted upon by a drug. Target validation is crucial to help scientists avoid research paths that look promising, but ultimately lead to dead ends. Researchers demonstrate that a particular target is relevant to the disease being studied through complicated experiments in both living cells and in animal models of disease.
Drug Discovery
Find a promising molecule (a “lead compound”) that could become a drug
Armed with their understanding of the disease, pharmacists are ready to begin looking for a drug. They search for a molecule, or “lead compound,” that may act on their target to alter the disease course. If successful over long odds and years of testing, the lead compound can ultimately become a new medicine.

Early Safety Tests
Perform initial tests on promising compounds
Lead compounds go through a series of tests to provide an early assessment of the safety of the lead compound. Pharmaceutical Researchers test Absorption, Distribution, Metabolism, Excretion and Toxicological (ADME/Tox) properties, or “pharmacokinetics,” of each lead. Successful drugs must be:
• absorbed into the bloodstream,
• distributed to the proper site of action in the body,
• metabolized efficiently and effectively,
• successfully excreted from the body and
• demonstrated to be not toxic.
These studies help researchers prioritize lead compounds early in the discovery process. ADME/Tox studies are performed in living cells, in animals and via computational models.

Lead Optimization
Alter the structure of lead candidates to improve properties
Lead compounds that survive the initial screening are then “optimized,” or altered to make them more effective and safer. By changing the structure of a compound, scientists can give it different properties. For example, they can make it less likely to interact with other chemical pathways in the body, thus reducing the potential for side effects.

Preclinical Testing
Lab and animal testing to determine if the drug is safe enough for human testing
With one or more optimized compounds in hand, researchers turn their attention to testing them extensively to determine if they should move on to testing in humans. Pharmacists carry out in vitro and in vivo tests. In vitro tests are experiments conducted in the lab, usually carried out in test tubes and beakers (“vitro” is “glass” in Latin) and in vivo studies are those in living cell cultures and animal models (“vivo” is “life” in Latin). Scientists try to understand how the drug works and what its safety profile looks like. The U.S. Food and Drug Administration (FDA) requires extremely thorough testing before the candidate drug can be studied in humans.
During this stage researchers also must work out how to make large enough quantities of the drug for clinical trials. Techniques for making a drug in the lab on a small scale do not translate easily to larger production. This is the first scale up. The drug will need to be scaled up even more if it is approved for use in the general patient population. At the end of several years of intensive work, the discovery phase concludes. After starting with approximately 5,000 to 10,000 compounds, scientists now have winnowed the group down to between one and five molecules, “candidate drugs,” which will be studied in clinical trials.


Investigational New Drug (IND) Application and Safety
File IND with the FDA before clinical testing can begin; ensure safety for clinical trial volunteers through an
Institutional Review Board Before any clinical trial can begin, the researchers must file an Investigational New Drug (IND) application with the FDA. The application includes the results of the preclinical work, the candidate drug’s chemical structure and how it is thought to work in the body, a listing of any side effects and manufacturing information. The IND also provides a detailed clinical trial plan that outlines how, where and by whom the studies will be performed. 

The FDA reviews the application to make sure people participating in the clinical trials will not be exposed to unreasonable risks. In addition to the IND application, all clinical trials must be reviewed and approved by the Institutional Review Board (IRB) at the institutions where the trials will take place. This process includes the development of appropriate informed consent, which will be required of all clinical trial participants.

Statisticians and others are constantly monitoring the data as it becomes available. The FDA or the sponsor company can stop the trial at any time if problems arise. In some cases a study may be stopped because the candidate drug is performing so well that it would be unethical to withhold it from the patients receiving a placebo or another drug. Finally, the company sponsoring the research must provide comprehensive regular reports to the FDA and the IRB on the progress of clinical trials.

Phase 1 Clinical Trial
Perform initial human testing in a small group of healthy volunteers
In Phase 1 trials the candidate drug is tested in people for the first time. These studies are usually conducted with about 20 to 100 healthy volunteers. The main goal of a Phase 1 trial is to discover if the drug is safe in humans. Researchers look at the pharmacokinetics of a drug: How is it absorbed? How is it metabolized and eliminated from the body? They also study the drug’s pharmacodynamics: Does it cause side effects? Does it produce desired effects? These closely monitored trials are designed to help researchers determine what the safe dosing range is and if it should move on to further development.
Phase 2 Clinical Trial
Test in a small group of patients
In Phase 2 trials researchers evaluate the candidate drug’s effectiveness in about 100 to 500 patients with the disease or condition under study, and examine the possible short-term side effects (adverse events) and risks associated with the drug. They also strive to answer these questions: Is the drug working by the expected mechanism? Does it improve the condition in question? Researchers also analyze optimal dose strength and schedules for using the drug. If the drug continues to show promise, they prepare for the much larger Phase 3 trials.
Phase 3 Clinical Trial
Test in a large group of patients to show safety and efficacy
In Phase 3 trials researchers study the drug candidate in a larger number (about 1,000-5,000) of patients to generate statistically significant data about safety, efficacy and the overall benefit-risk relationship of the drug. This phase of research is key in determining whether the drug is safe and effective. It also provides the basis for labeling instructions to help ensure proper use of the drug (e.g., information on potential interactions with other medicines).
Phase 3 trials are both the costliest and longest trials. Hundreds of sites around the United States and the world participate in the study to get a large and diverse group of patients. Coordinating all the sites and the data coming from them is a monumental task. During the Phase 3 trial (and even in Phases 1 and 2), researchers are also conducting many other critical studies, including plans for fullscale production and preparation of the complex application required for FDA approval.

New Drug Application (NDA) and Approval
Submit application for approval to FDA
Once all three phases of the clinical trials are complete, the sponsoring company analyzes all of the data. If the findings demonstrate that the experimental medicine is both safe and effective, the company files a New Drug Application (NDA) — which can run 100,000 pages or more — with the FDA requesting approval to market the drug. The NDA includes all of the information from the previous years of work, as well as the proposals for manufacturing and labeling of the new medicine.

Going from small-scale to large-scale manufacturing is a major undertaking. In many cases, companies must build a new manufacturing facility or reconstruct an old one because the manufacturing process is different from drug to drug. Each facility must meet strict FDA guidelines for Good Manufacturing Practices (GMP).
Making a high-quality drug compound on a large scale takes great care. Imagine trying to make a cake, for example, on a large scale — making sure the ingredients are evenly distributed in the mix, ensuring that it heats evenly. The process to manufacture most drugs is even more complicated than this. There are few, if any, other businesses that require this level of skill in manufacturing.
Ongoing Studies and Phase 4 Trials
Research on a new medicine continues even after approval. As a much larger number of patients begin to use the drug, companies must continue to monitor it carefully and submit periodic reports, including cases of adverse events, to the FDA. In addition, the FDA sometimes requires a company to conduct additional studies on an approved drug in “Phase 4” studies. These trials can be set up to evaluate long-term safety or how the new medicine affects a specific subgroup of patients.

“My calling to the pharmaceutical industry has been a personal one. When I was a child, I had a disease called rheumatic fever that came from strep throat. It had an effect on my heart and, as a child — in third grade for me — I was unable to play with other children. In fact, I had to lie in a bed for months and be carried. It was a medicine that I took that allowed me to get up again, and it was a medicine that the company that I work for today made. That’s why I joined the pharmaceutical industry.

Andrew Dahlem, Ph.D.
Eli Lilly and Company


The whole drug discovery process takes an average of  10 – 15 years. There are people from many disciplines that are striving hard for discovery of single drug molecule. Pharmaceutical industry plays a major role in the process. The definition of a pharmacist is definitely not limited to “the one who dispenses a drug”. It is much more than that. BE PROUD TO BE A PHARMACIST

Thanks for installing the Bottom of every post plugin by Corey Salzano. Contact me if you need custom WordPress plugins or website design.

This site uses Akismet to reduce spam. Learn how your comment data is processed.