Pharmaceutical Applications:
Drug Discovery

Overview

Drug discovery is the process by which drugs are discovered and/or designed, in medicine, biotechnology and pharmacology. In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by unexpected discovery. A new approach has been to understand how disease and infection are controlled at the molecular and physiological level and to target specific entities based on this knowledge.
The process of drug discovery involves the identification of candidates, synthesis, characterization, screening, and assays for therapeutic efficacy. Once a compound has shown its value in these tests, it will begin the process of drug development prior to clinical trials.
Despite advances in technology and understanding of biological systems, drug discovery is still a long process with low rate of new therapeutic discovery. Information on the human genome, its sequence and what it encodes has been hailed as a potential windfall for drug discovery, promising to virtually eliminate the bottleneck in therapeutic targets that has been one limiting factor on the rate of therapeutic discovery. However, data indicates that "new targets" as opposed to "established targets" are more prone to drug discovery project failure in general. This data corroborates some thinking underlying a pharmaceutical industry trend beginning at the turn of the twenty-first century and continuing today which finds more risk aversion in target selection among multi-national pharmaceutical companies.

The Basic Idea

Traditionally, the design of novel drugs has essentially been a trial-and-error process despite the tremendous efforts devoted to it by pharmaceutical and academic research groups. It is estimated that only one in 5,000 compounds investigated in preclinical discovery research ever emerges as a clinical lead, and that about one in 10 drug candidates in development ever gets through the costly process of clinical trials. For each drug, the investment may be on the order of $600 million over 15 years from its first synthesis to FDA approval. In 2000, U.S. pharmaceutical companies spent more than $22 billion in research and development, which, after inflation adjustment, represents a four-fold increase from the corresponding figure some 20 years ago. In an attempt to counter these rapidly increasing costs associated with the discovery of new medicines, revolutionary advances in basic science and technology are reshaping the manner in which pharmaceutical research is conducted. For example, the use of DNA microarrays facilitates the identification of novel disease genes and also opens up other interesting opportunities in disease diagnosis, pharmacogenomics and toxicological research (toxicogenomics). The development of combinatorial chemistry and parallel synthesis methods has increased both the quantity and chemical diversity of potential leads against new targets. The ability to discover useful leads has been greatly enhanced through astonishing advances in high-throughput screening (HTS) technologies.
Through miniaturization and robotics, we now have the capacity to screen millions of compounds against therapeutic targets in very short period of time. Central to this new drug discovery paradigm is the rapid explosion of computational techniques that allow us to analyze vast amount of data, prioritize HTS hits and guide lead optimization. The advances and applications of computational methods in drug design are beginning to have a significant impact on the prosperity of the pharmaceutical industry.

How long does it take to develop new drugs?

* Pharmaceutical companies can often research and test 5,000 to 10,000 different compounds (or substances) before finding one that will actually become an approved drug. Each company employs thousands of scientists (also called researchers) to search for the right compounds that can help people with different diseases. In the beginning, scientists used 'trial and error' to find the right compound - today, they use sophisticated technology to discover and develop new drugs.
* It takes a long time for pharmaceutical companies to develop and test new drugs - on average it can take up to 15 years. This is mostly because each company is very careful to make sure that the benefits of the drug are greater than any risks. For example, they must make sure that the drug helps a patient more than it causes any unpleasant side effects.

The Development Process

Development of an Innovating Medicine (in Canada)
Researchers study thousands of different compounds. When a pharmaceutical company decides to develop a compound into a drug, the company must put the drug through a development process before the drug is approved. The process is as follows:
- Pre-clinical testing Once a new drug is discovered, it must be carefully tested before it can be given to people. These pre-clinical tests include laboratory tests done on human cells in test tubes and tests done on animals, to find out how the drug actually works. If the drug seems to work and be safe for animals, the pharmaceutical company asks for permission to test the drug in people.
- Investigational New Drug (IND) Application A pharmaceutical company submits an Investigational New Drug (IND) application, which shows:

results of previous tests;
how, where and by whom the new studies will be done;
the chemical structure of the compound;
how the researchers think it works in the human body;
any toxic effects found in the animal studies;
how the compound is made.

- Clinical Trials, Phase I During these tests, a small number of healthy volunteers (between 20 and 100 people) are given the drug to see what dose (or amount) of the drug is safe. The tests also determine how a person.s body absorbs and gets rid of the drug.
- Clinical Trials, Phase II In this phase, the drug is tested in about 100 to 300 people with the illness (for example, a new drug to cure cancer is given to people with cancer). The tests are done to find out how safe the drug is and how well it works.
- Clinical Trials, Phase III This phase usually involves 1,000 to 3,000 patients and is carried out in clinics and hospitals. During Phase III trials, doctors closely watch each patient to see if the drug is safe and effective, and to see whether the drug causes any side effects.
+ If a trial shows that the drug is neither safe nor effective during any phase of clinical trials, the trials are stopped.
- Once Phase III clinical studies have been done, the pharmaceutical company prepares and submits a New Drug Submission (NDS) application to the FDA and/or TPD to review the application and decide if the drug can be sold.
- Even after a drug is approved, pharmaceutical companies continue to do research and development on the drug. This is called Phase IV research and is focused on two key issues:
1. Keeping track of how safe a drug is once it is being sold and used by many people, and 2. Doing more clinical studies to determine alternative uses for the drug - i.e. other conditions.

How Companies Test their Drugs

* Pharmaceutical companies conduct clinical trials to test whether the drug can prevent, diagnose, or treat different diseases. A clinical trial is a test, or experiment, using a drug on people. Clinical trials are performed to find out if new drugs are safe and how well they work, and also to see if drugs would be effective for other conditions. There are many types of clinical trials, such as treatment trials, prevention trials, screening trials, and quality of life trials.
* Pharmaceutical companies are conducting more clinical trials than ever before and more patients are participating in these trials. By doing more clinical trials and with more people, the company can find out more information on the benefits and risks of each drug. These trails also allow clinical researchers to have early experience with the new drugs, as well as giving early access of potentially life-saving therapies to patients with serious conditions.
* Safety is the most important concern to pharmaceutical companies. In fact, pharmaceutical companies and government organizations work very hard to make sure new prescription drugs are safe and effective - from the point when they are discovered to the time when the drug is being sold to patients.
* Although each drug is tested on thousands of patients, there is no guarantee that a drug will be risk-free. This is because drugs are chemical substances that have many benefits but also potential risks. However, government organizations do not approve a drug unless it determines that the benefit of using the drug is greater than any risks, and that it will improve life for people living with an illness. Still, there will always be some risks to some patients.
Graphs and Stats for R&D of Drugs

Reducing Time to Drug Discovery

Combinatorial chemistry is the art and science of synthesizing and testing compounds for bioactivity en masse, instead of one by one, the aim being to discover drugs and materials more quickly and inexpensively than was formerly possible. It has been the hottest approach to drug discovery long enough now that researchers have recognized some of its limitations and are developing strategies to address them.
Expert scientists said that "Going from data to wisdom is the real issue. There is a huge amount of data out there - hundreds of databases related to human genome project and associated areas - and so there has been a great need for tools to not only generate data but to organize it and cross reference the data, and of course to cross-reference different types of data."
Researches clain that "Technologies today generate a lot of data but it needs identification and analysis to put any meaning to the results. What is needed is software that gives you the statistically relevant information with an easy to use interface. In addition, it has to be able to interrogate results from a number of platforms and correlate them to give researchers the meaningful results they are looking for."
According to the "Next Generation Pharmaceuticla Article," there are two types of technology which are having a huge impact on the drug discovery process. Microarrays (or gene chips) are allowing people to look at tens of thousands of gene or other DNA sequences (and now sometimes protein sequences) in parallel. Imaging technologies are used for this too, but the more interesting applications of imaging technologies are looking directly at biological specimens - in some cases for high-throughput cellular analysis, and in other cases for looking at tissues through a microscope; and analyze the structure by looking at the morphology, or by looking at the patterns of staining with various antibodies. Together, those approaches are first of all allowing scientists to look at tens of thousands of genes at once; and second, to look at many more specimens at a time. This ultimately saves time and development costs.

Pharmaceutical Applications: Drug Discovery