General Drug Development Methodology

Assume you are a successful IT project manager who has been assigned to work for a new client; or youre a consultant and you find employment at a pharmaceutical company, where you are to head up a large multinational team of chemists and doctors to develop a new revolutionary drug. Can you do it? Yes, if you have a thorough grasp of project principles, understand process, and are able to learn quickly.

A new drug development methodology is best defined as a process followed for all those project activities and tasks from the identification of a lead compound to the approval by a regulatory agency for marketing a new drug. The project management methodology is surely one of the most crucial aspects for taking the new drug development through to its conclusion (see Figure 4.15).

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Figure 4.15: New drug development methodology. Source: FDA requirements, Overview of the drug development process, www.fda.gov/cder/handbook/develop.htm. Reprinted with permission.

Many drug and pharmaceutical companies rely on the research and development of new drugs to prevent life-threatening diseases and viral outbreaks throughout the globe. Engaging in any new drug project is a comprehensive task and should not be taken lightly. It requires considerable investment and resources, and may take up to fifteen years to get approval by monitoring agencies, such as the Federal Drug Agency (FDA). Even getting the IT systems in place to support the drug development process is audited by the FDA and also requires formal methodologies, which necessitate formal documentation and regulatory requirements.

New drug development is an R&D project, where the risks are notably high and can cost from the tens to hundreds of millions of dollars to develop and market. The research costs are astronomical during clinical trials. Therefore, drug companies want not only the best pharmaceutical and medical minds developing these vital drugs, but also a structured project methodology for this effort. Without a development process, the process simply will not work.

Many drug-related projects face failure because of the high risks and research involved. The success rate is small. After a drug has been registered and approved, the sponsoring drug company will have applied for a patent. Modern-day patents for drugs are limited to a 20-year period, thus limiting their product earnings capability. This leaves manufacturers with only a short time to commercialize and recover the research and development costs before

the patent expires. Competitors quickly start developing generic equivalents after the patent elapses and offer the drugs at much lower costs than the original manufacturer, which forces prices down dramatically.

More importantly, these pharmaceutical companies adhere to certain standards and guidelines. The new drug development methodology is an example of such a process. It divides new drug development into the following main categories:

Concept.

Preclinical research. Clinical studies. NDA review.

Concept

After a concept has been identified and presented, new compounds must be identified before the project can proceed. Literally thousands of compounds can be selected at this stage, and the concept phase is an important one to consider before moving to the preclinical research phase.

This is the early phase of the overall drug/biologic development process dealing with the synthesis of and search for compounds and the screening processes developed to identify lead compounds. The discovery phases relate to the research component of research and development.

Preclinical Research

In this phase, chosen compounds are studied to determine their bioavailability, absorption, distribution, metabolism, and elimination. The necessary tests are carried out in cells and in animals to establish preclinical parameters for safety and efficacy.

Under FDA requirements, a sponsor must first submit data showing that the drug is reasonably safe for use in initial, small-scale clinical studies. Depending on whether the compound has been studied or marketed previously, the sponsor may have several options for fulfilling this requirement:

Compiling existing nonclinical data from past in vitro laboratory or animal studies on the compound.

Compiling data from previous clinical testing or marketing of the drug in the United States or another country whose population is relevant to the U.S. population.

Undertaking new preclinical studies designed to provide the evidence necessary to support the safety of administering the compound to humans.

During preclinical drug development, a sponsor evaluates the drugs toxic and pharmacological effects through in vitro and in vivo laboratory animal testing. Genotoxicity screening is performed, as well as investigations on drug absorption and metabolism, the toxicity of the drugs metabolites, and the speed with which the drug and its metabolites are excreted from the body. At the preclinical stage, the FDA generally asks, at a minimum, that sponsors: (1) develop a pharmacological profile of the drug; (2) determine the acute toxicity of the drug in at least two species of animals; and (3) conduct short-term toxicity studies ranging from two weeks to three months, depending on the proposed duration of use of the substance in the following proposed clinical studies:

Synthesis and purification. The research process is complicated, time-consuming, and costly; and the end result is never guaranteed. Hundreds and sometimes thousands of chemical compounds must be made and tested in an effort to find one that can achieve a desirable result.

The FDA estimates that it takes approximately eight and a half years to study and test a new drug before it can be approved for the general public. This estimate includes early laboratory and animal testing, as well as later clinical trials using human subjects.

There is no standard route through which drugs are developed. A pharmaceutical company may decide to develop a new drug aimed at a specific disease or medical condition. Sometimes, scientists choose to pursue an interesting or promising line of research. In other cases, new findings from university, government, or other laboratories may point the way for drug companies to follow with their own research.

New drug research starts with an understanding of how the body functions, both normally and abnormally, at its most basic levels. The questions raised by this research help determine a concept of how a drug might be used to prevent, cure, or treat a disease or medical condition. This provides the researcher with a target. Sometimes, scientists find the right compound quickly, but usually hundreds or thousands must be screened. In a series of test tube experiments called assays, compounds are added one at a time to enzymes, cell cultures, or cellular substances grown in a laboratory. The goal is to find which additions show some effect. This process may require testing hundreds of compounds as some may not work, but will indicate ways of changing the compounds chemical structure to improve its performance.

Computers can be used to simulate a chemical compound and design chemical structures that might work against it. Enzymes attach to the correct site on a cells membrane, which causes the disease. A computer can show scientists what the receptor site looks like and how one might tailor a compound to block an enzyme from attaching there. But even though computers give chemists clues as to which compounds to make, a substance must still be tested in a living being.