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What It Takes

“I like to think about drug discovery as solving a very complex jigsaw puzzle with many thousands of pieces,” says Mark Noe, Vice President of Discovery Sciences in Pfizer’s Groton, CT Research and Development site. “The team arranges the pieces out in front of them, and they may start with a corner or with the edge pieces because you have some idea of where those pieces are supposed to go. And then you build the puzzle towards the middle as you progress. There are moments of exhilaration when you make an advance by finding some pieces that do fit together, but you often run into problems and need to rethink your approach in order to complete the puzzle.” Here’s the story of building that puzzle, and of some of the people who work toward putting it together:

Choose a Target

The drug discovery process begins with understanding how a disease chang¬es biological processes in the body, even if the exact cause isn't known. Re¬searchers hone in on the target, typically a protein that may be involved with this disease process. They then form a hypothesis that inhibiting or activating this protein will help treat the disease. Proteins are the most common drug targets because they play so many critical roles in the body, performing a variety of biological process from mounting an immune response to facilitating nerve and hormone responses. A drug target can also be DNA or RNA. A good target must be responsive to small molecules or biologics.


The Search

Scientists use several methods to nd a molecule that can serve as a potential starting point of creating a new medicine. Often this process begins with the company's compound library, a collection of millions of chemical compounds to screen against a biological target. They often begin by screening millions of these compounds for their ability to in¬teract with the intended target. Of the millions screened, the candidate pool will be narrowed down to about 5,000 compounds and eventually to one or more “lead” compounds that will continue to be optimized through safety and efficacy testing. A variety of screening methods are used in this stage, which is a cycle of designing and testing candidates for various properties. Many of the tools and methods used in this stage of drug discovery are used at different times--overall, the process of HIT identi cation is very dynamic, which makes it all the more momentous when scientists decide on a compound to advance to the next stages.

High Throughput


Screening

Scientists can quickly test millions of compounds from the library to zero in on a lead compound to advance to later stages of the drug discovery process. It's like launching millions of arrows at a target to see which ones land closet to the bullseye. High-throughput screening is used at several stages in the drug discovery process.

Rational Drug


Design

In contrast to the trial-and-error process of HTS, this method begins with knowledge of the shape of the protein target and then builds a compound that optimally fits that target. Computer- aided 3-D modeling is used to virtually screen and design these com¬pounds. In order to do structure-based design, scientists need to understand the form and function of a molecule. To do this, they use high-tech tools such as crystallography—the study of the arrangement of crystals to uncover the form and function of molecules—and electron microscopes to determine the 3-D structure of a molecule and where on the target protein the compound is binding.

Pharmacology

These stages together are critical for determining the right dose for the medicine – the sweet spot between the minimum dose at which you see a therapeutic effect and the maximum dose at which you don't see toxicity. Pharmacology encompasses pharmacokinetics and pharmacodynamics, that is, what the body does to the drug and what the drug does to the body. For example, does the drug has the properties to treat the disease? How it is absorbed, distributed, metabolized and excreted? Pharmacology testing happens at multiple stages in the drug discovery process, in both preclinical and clinical stages. This is another part of drug discovery where high-throughput screening is useful.

Candidate is Chosen

It works! Months or years of study, hundreds or thousands of tests, have led to a compound that can stop or reverse a disease that afflicts millions of people. It's exciting, but theory still needs to meet practice: It's time to learn, through a series of carefully managed clinical trials, if what works in the lab can be turned into a viable treatment for real people.

Toxicity Testing

Scientists use several methods to nd a molecule that can serve as a potential starting point of creating a new medicine. Often this process begins with the company's compound library, a collection of millions of chemical compounds to screen against a biological target. They often begin by screening millions of these compounds for their ability to interact with the intended target. Of the millions screened, the candidate pool will be narrowed down to about 5,000 compounds and eventually to one or more "lead compounds that will continue to be optimized through safety and efficacy testing. A variety of screening methods are used in this stage, which is a cycle of designing and testing candidates for various properties.

Phase I Clinical Trials

The main goal of a Phase I trial is to test the safety of a medicine in healthy volunteers at the predicted e ective dose. Additional pharmacological research happens here to determine what happens in the body when you take a medicine--what the medicine does to the body and what the body does to the medicine. To determine what is known as the maximum tolerated dose at which it doesnt produce unacceptable side effects, the medicine is tested in small groups of healthy volunteers, typically 20 to 100 people.

Formulations/Bottling


and Packaging

The active ingredient is turned into a medicine that can be taken during the next clinical phases. Important to this stage is optimizing the therapeutic effect of a drug by delivering it in the proper way. For example, the rate at which a drug needs to be delivered (slow release vs. quickly) determines the inactive ingredients it's packaged with. And the metabolic properties of the drug also determine how it should be packaged — it needs to be delivered to the bloodstream in a way that balances absorption, metabolism, and excretion.

Phase II Clinical Trials

Only now is the safety and efficacy of the drug ready to be tested in patients with the disease or condition. In Phase II, the drug is tested for side effects and to determine whether and how it helps the condition being studied in up to several hundred people. In both Phase II and Phase III, the new drug is compared to an existing drug, if available. Phase III, which includes 300 to 3,000 volunteers, is used to determine how the new drug may fit into the treatment of the condition being studied.

Phase III Clinical Trials

Only now is the safety and efficacy of the drug ready to be tested in patients with the disease or condition. In Phase II, the drug is tested for side effects and to determine whether and how it helps the condition being studied in up to several hundred people. In both Phase II and Phase III, the new drug is compared to an existing drug, if available. Phase III, which includes 300 to 3,000 volunteers, is used to determine how the new drug may fit into the treatment of the condition being studied.

Final Registration

Regulatory Affairs is involved in the entire process of drug development, in order to make sure that the research plan for a potential medicine is in line with what regulatory agencies like the U.S. Food and Drug Administration (FDA) require. Regulatory Affairs is instrumental in the process of getting the potential medicine ready for approval at the various stages of clinical trials. For example, before Phase I clinical trials can begin, Regulatory A airs must submit an Investigation¬al New Drug (IND) application to the regulatory agency, such as the FDA. After Phase III, Regulatory A airs submits a New Drug Application (NDA) to the regulatory agency. The NDA includes data on the drug's safety and efficacy in its proposed use, and on the risks and benefits of using that drug. The NDA also includes data on a drug's proposed labeling, and on proposed manufacturing methods that are expected to preserve the drugs strength, quality, and purity. Regulatory A airs also combines data into a dossier for use in communicating the potential new medicine's value for reaching an unmet medical need.

Conclusion

YEARS AGO, the many people involved in developing a new medicine had a vision: A new treatment for an illness that might once have been thought incurable. Success required weeks, months, and eventually years of persistent work. It called on scientists, physicians, programmers, managers, investors, salespeople, manufacturers, marketers, and the best kind of bureaucrats to work together. It couldn’t have happened without hundreds of patients who volunteered for trials. The path from idea to pharmacy shelf is long, and it’s never a straight one. It doesn’t always reach the nish line. But when it does, and thousands or millions of people live better, longer lives, there’s one fact that no one involved doubts: It was all worth it.

Formulations/Bottling and Packaging Candidate is Chosen Toxicity Testing Phase I Clinical Trials Rational Drug Design The Search High-Throughput Screening What It Takes to Discover and Develop a Medicine Phase II Clinical Trials Final Registration Phase III Clinical Trials Conclusion Choose a target Pharmacology
Formulations/Bottling and Packaging Candidate is Chosen Toxicity Testing Phase I Clinical Trials Rational Drug Design The Search High-Throughput Screening What It Takes to Discover and Develop a Medicine Phase II Clinical Trials Final Registration Phase III Clinical Trials Conclusion Choose a target Pharmacology