Golden Rules of Drug Discovery
One must learn by doing the thing, for although you think you know it you may have no certainty until you try.
–Sophocles
The difficulty lies, not in the new ideas, but in escaping the old ones, which ramify, for those brought up as most of us have been, into every corner of our minds.
–John Keynes, English economist.
The three major functions of research and development groups in pharmaceutical companies are to discover drugs, develop drugs to reach the market, and protect and extend the scope of drugs that are marketed. This last function includes development of new indications, formulations, dosage strengths, routes of administration, and packages. Important principles (i.e., golden rules) of drug development are presented in Chapter 11. These golden rules differ from the mission, objectives, goals, strategies, or tactics of a research and development group [defined and described by Spilker (1991) and summarized in Chapter 20].
Drug discovery must be differentiated from drug development for this discussion. The preferred definition of drug discovery is that it includes preclinical activities leading to the identification of a specific compound that possesses a desirable profile of biological activity. At that time, a decision is made to undertake additional animal studies to ensure that the compound has adequate safety to be tested in humans and, also, to initiate or expand technical activities to generate data for regulatory approval to study the drug in humans, synthesize the drug in larger amounts, be able to measure the drug in biological fluids, and conduct a myriad of other required tests.
It is generally possible to determine the precise point at which the drug discovery phase is completed and the drug development phase begins. That point occurs when preclinical activities change from a search for an agent with the desired biological profile to the focused evaluation of a specific compound. This usually occurs at a management meeting where the decision is reached to initiate a large number of additional studies and to commit the company to taking that particular compound into the clinic. The safety and efficacy profiles will then be determined in greater depth in pharmacology, pharmacokinetic, and toxicology studies (and possibly in microbiology, virology, and other biological departments) to assure that the compound is acceptable for testing in humans. Even though the decision may be made on a specific day to move a compound into development, there is usually a transition period during which the drug discovery activities for a particular compound are ending and the development activities are building.
Safety testing in animals includes both toxicological evaluation and pharmacological studies. There is usually little or no toxicological evaluation of a compound during the discovery period. However, there is a growing tendency for more toxicological testing to occur earlier so that the results may be considered before a decision is made on whether to have the compound enter development.
The amount of pharmacological data collected that can be extrapolated to a specific disease using validated animal models during the discovery period is highly variable and depends primarily on the type and validity of the animal models available for testing. A lead compound is chosen based on the data obtained in a number of in vitro and in vivo animal tests demonstrating sufficient activity to encourage the chemists to create new molecules with structural modifications intended to improve activity or decrease toxicity. Studies that further refine the biological profile of a specific compound are conducted during early stages of drug development and often throughout the
development period as well (e.g., more extensive mechanism of action studies). Typically, 12 to 36 months of preclinical biological (e.g., toxicology, pharmacology) and technical tests (e.g., formulation, stability) are required before a compound entering the development phase can be tested in humans. Drug discovery may also occur in the clinic when a new use for a known drug is found. This type of drug discovery, usually resulting from serendipity or an investigator’s theory, is not discussed in this chapter.
development period as well (e.g., more extensive mechanism of action studies). Typically, 12 to 36 months of preclinical biological (e.g., toxicology, pharmacology) and technical tests (e.g., formulation, stability) are required before a compound entering the development phase can be tested in humans. Drug discovery may also occur in the clinic when a new use for a known drug is found. This type of drug discovery, usually resulting from serendipity or an investigator’s theory, is not discussed in this chapter.
Most principles of drug development are relevant (some with modification) to activities conducted during the drug discovery phase. Major differences exist, however, between the ways in which drug development and discovery are managed. Whereas drug development may be planned and controlled with a certain degree of assurance, attempts to plan and control drug discovery often stifle and destroy the creative process.
Golden rules of drug discovery have been grouped into five broad categories for ease of discussion.
CHOOSING THE APPROPRIATE DISEASE AND THERAPEUTIC AREAS TO RESEARCH AND THE METHODS AND STRATEGIES TO USE
Determine the specific therapeutic and disease areas to explore. Companies focus discovery activities in a few or larger number of therapeutic areas but cannot successfully conduct research and discovery activities in all therapeutic areas. By focusing efforts, companies develop areas of strength that enhance their drug discovery activities.
Identify the therapeutic areas to explore at four levels: (a) general therapeutic area (e.g., central nervous system, cardiovascular, gastrointestinal), (b) specific diseases, (c) targets (e.g., physiological and/or biochemical mechanisms such as inhibiting a specific enzyme) within each therapeutic area, and (d) specific approaches and methods to follow to seek compounds that have the mechanism for each target identified.
Determine whether the company should seek to discover drugs that are chemically or functionally similar to existing drugs. The second or third drug marketed of a new class often attains significant sales. Clarify the type and number of “me-too” drugs that are desirable or acceptable to seek. This may be determined by establishing the minimally acceptable criteria that each research project must meet to be judged successful (see Chapter 50).
Establish the types of criteria for each potential drug to meet. Three types of criteria that may be used for this purpose are ideal, realistic/desirable, and minimally acceptable criteria. For each characteristic of a compound for which criteria are established, determine which specific criteria the compound must achieve and which criteria the compound should achieve. Criteria should be written to facilitate management review and so that characteristics of compounds proposed for study in humans may be compared with this list.
Use the most highly validated animal models and tests to search for and choose drugs to develop. Organize the various tests in a logical sequence to develop the profile of the compound (see Chapter 8). In some cases, this involves progressing from tests that serve as broad filters to those that serve as specific ones, while in other cases, the opposite approach will be used. If some important test systems are unavailable in-house, then work should be contracted to scientists or to government agencies that have appropriate facilities or equipment.
Use rational approaches (e.g., molecular modeling) to drug discovery whenever possible. Do not forgo or minimize the other major approaches of drug discovery: empirical trial and error and the “greatest method of all”—serendipity. Be receptive to the unexpected. Carefully consider the role of high throughput screening of large libraries of compounds and targeted screening of selected types of compounds that may be chosen based on their structure.
Use animals bred by reputable suppliers in all but unusual situations. Avoid using animals from pounds or shelters. Choose the lowest species on the evolutionary scale consistent with objectives of the research. Use in vitro tests whenever possible. All protocols involving animals must be reviewed to ensure that currently acceptable ethical standards are followed. Treat all animals with respect and appropriate care.
Develop one-, three-, and five-year plans to implement research projects and achieve realistic goals. For example, a goal could be to explore the anti-X activity of chemical series A and B. Review these plans at least annually. Terminate nonviable research projects as soon as possible. This type of “sunset provision” for all research projects helps prevent some discovery projects from continuing for decades.
Create an international research plan for each site that is attempting to discover drugs. Minimize any unnecessary duplication of effort between sites, but maintain supplementary programs. Develop programs and systems that facilitate cooperation among researchers at all discovery sites. These goals are best met through periodic meetings (e.g., face-to-face, telephone or video conferencing) to develop and implement an effective international discovery strategy in each disease area.
Create and use those systems and standard operating procedures that the discovery scientists believe assist the discovery process. Do not allow systems to become bureaucracies, restrain creativity, or compromise efficiency. This is often a difficult goal to achieve because systems that improve efficiency (e.g., through standardization) may do so at the expense of scientific creativity. Utilize computer systems that are either identical or compatible among all major sites of a company that are seeking to discover drugs.
Develop a portfolio of research projects that balances high- and low-risk projects. Include projects that will probably require long-term as well as short-term completion cycles. Attempt to include some projects that have a chance of becoming breakthrough drugs. If there is a paucity of such ideas or an insufficient number of such compounds to develop, then hire more scientists who are known to be creative or license-in compounds with great potential to help the company or new technologies that will assist discovery research.
Develop a clear licensing policy and strategy that allows all research or technological opportunities to be reviewed and assessed rapidly for possible benefit to the company. Establish alliances with other companies (e.g., joint ventures) that enhance research activities of great interest. Caution must be used to avoid antitrust conflicts in establishing business
relationships. Many ideas for compounds that have never been made or compounds that have been made but never tested to demonstrate proof of principle are available for licensing. These compounds often require a significant amount of additional work in the discovery phase before it is known whether they have sufficient activity to pursue further or are candidates for development.
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