Rational drug design

Animal testing, drug discovery, high throughput screening (HTS), investigational new drug (IND), new drug application (NDA), novel chemical entities (NCE), phase I studies, phase II studies, phase III studies, phase IV studies, rational drug design, serendipitous drug discovery.

The drug development process is where new drugs are currently discovered and developed, frequently using a rational approach involving experimental evidence. Often this process may begin with the screening of a multitude of compounds, selecting one that can inhibit (inactivate) certain molecular targets or receptors (structure or site on the surface or interior of a cell that binds with substances such as hormones, antigens, drugs, or neurotransmitters). Once a suitable compound is found, it can then be modified to enhance its effectiveness based on its interactions with the target. Molecular target screenings are increasingly utilized to study natural products for anticancer therapy, among other therapies.

Novel chemical entities (NCEs) are compounds that emerge from the process of drug discovery. These will have promising activity against a particular biological target thought to be important in disease processes. However, little will be known about the safety, toxicity, pharmacokinetics, and metabolism of this NCE in humans until clinical trials are performed.

Historically, most drugs have been discovered either by identifying the active ingredient from traditional remedies and manufacturing it, or by chance, known as serendipitous drug discovery.

The rational approach, which has much promise for the future, seeks to understand how disease and infection are controlled at the molecular (simple or basic structure or form) and physiological (entire living organism) level, and to target specific entities based on this knowledge, such as drug receptors on target tissues. This practical process includes identifying candidates, synthesis and characterization of the compound, and screening or testing for therapeutic efficacy. Another method of screening possible compounds includes the use of human cell lines. In cancer research, these cell lines have known characteristics regarding drug response, growth factor dependence, and oncogene (genes that may be related to cancer) expression. A comparison can then be made between the response patterns of the experimental compounds and other agents. If a compound proves valuable through these tests, it will then be further developed before clinical trials begin.

The theory behind much of today's drug discovery, known as rational drug design, is that if a target is known for a particular disease, different molecules that will interact with this target, altering the course of the disease can then be found. The process of finding a new drug against a chosen target for a particular disease usually involves high-throughput screening (HTS), involving large libraries of chemicals that are tested for their ability to modify the target HTS, also demonstrates how selective the compounds are for the chosen target. The goal of this process is to find a molecule that will interfere with only the chosen target, but not other, related targets. For this reason, other screening runs will be made to see whether the "hits" against the chosen target will interfere with other related targets. This is the process of cross-screening. Cross-screening is important because the more unrelated targets a compound hits, the more likely that off-target toxicity will occur with that compound once it reaches the clinic, thus increasing side effects and drug interactions.

Recent evidence supporting the theory of rational drug design is the discovery and design of imatinib, an anti-cancer drug. This drug specifically targets a fusion protein that is only present in the Philadelphia Chromosome, an abnormal minute chromosome found in white blood cells, in certain related leukemias. It is different from previous cancer drugs because it only targets cancer cells, rather than all rapidly diving cells in the body.

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

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Preclinical pharmacology: This phase of drug development involves animal trials, often using mice, rats, or dogs, in order to study the pharmacokinetic and pharmacodynamic processes of the experimental drug before initiating human testing. Pharmacodynamic studies involve the action or effects of drugs on living organisms. Pharmacokinetic studies focus on the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. These studies aim to determine a suitable dose for the drug, establish the minimum effective concentration, and the maximum tolerated concentration. They also look at drug solubility issues and how the drug will be delivered to the site of action. Pharmacodynamic studies involve processes that occur once the drug has reached the site of action up until it has initiated an effect on the body. Animal toxicology studies also occur at this time, to help ensure that the drug will not harm human subjects. Drug companies often determine the dose of the drug that is lethal to 10% of mice, which does not necessarily mean that it will be lethal in humans. Organ-specific toxicity is also studied in rodents. These toxicology studies must use the same drug schedule that will then be used in humans.

Investigational new drug (IND) application (FDA 1571): An IND application is a form (FDA form number 1571) that must be submitted by a drug company to the United States Food and Drug Administration (FDA) before human clinical trials can begin. This form contains all of the data obtained during the preclinical animal trials, a proposed clinical protocol for the drug, a brochure by the investigator and pertinent manufacturing information. After the submission of an IND, there is a waiting period of 30 days during which the FDA has a chance to ask the company for changes. If the FDA has made no requests during the 30 days after submission, the drug company may then begin clinical trials. In the case of life-saving therapies for refractory patients, an "emergency use" or "compassionate" IND may make the investigational drug available before approval of the IND. An institutional review board (IRB) must approve all phases of clinical drug trials. This board reviews clinical trial to insure a scientific basis for the research protocol, and to prevent patients from being exposed to unnecessary risks. The IND requires FDA approval before the drug is tested in humans.

Phase I studies: Phase I trials utilize the protocol for drug administration that was approved in the IND. An informed consent document is also required for all participants in this phase. Phase I trials generally use normal, healthy human subjects to study the drug's pharmacology, pharmacokinetics, pharmacodynamics, maximum tolerated dose and toxicity in humans. However, for Phase I oncology studies, the subjects are often patients with advanced cancer with normal organ function, who are non-responding to conventional treatment. Phase I studies for cancer drugs often start with a dose that is 1/10 the lethal dose to 10% of mice in the most sensitive animal model. The dose of the drug is then increased in a stepwise manner until over 1/3 of the study population experiences dose-limiting toxicity. This dose is then used in Phase II studies.

Phase II studies: Phase II trials look at drug safety and effectiveness in a group of patients with a disease the drug is intended to treat, as opposed to Phase I studies, which use healthy patients. Data is collected on adverse effects and response to the therapy. The starting dose is the safest dose found in Phase I trials.

Phase III studies: These studies involve a large group of patients with a particular condition. The patients are randomized to either the treatment being studied or a current standard of care or placebo. Data is then collected on the experimental drug's efficacy, safety, drug interactions and other aspects of the drug.

New drug application (NDA): The data collected from the clinical trials is combined and submitted to the FDA as a new drug application. After submission, the FDA is allotted 60 days to reject the NDA due to gross deficiencies in the data. It then has 180 days to complete a more thorough review of the new drug.

Phase IV studies: These post-marketing studies examine a drug's performance in clinical settings, such as hospitals. They are often large, multicenter studies examining the drug's use for a specific labeled indication. They are very valuable regarding long-term effects of the drug and potential adverse reactions that may not have been documented in the relatively small number of patients in the previous trials. These studies provide information on efficacy and safety in a wide population. Post-marketing surveillance also includes voluntary reporting of adverse drug reactions and drug recalls.

Accelerated NDA review: Regarding drugs with significant therapeutic gains, the FDA instituted short-track approval mechanisms to decrease the length of the approval process. In this accelerated review, the FDA and the drug's sponsor may begin to meet as soon as the Phase I trials are complete. NDA approval may then be based on expanded Phase II trials. Preclinical data from Europe or Japan may be utilized in some cases. The FDA oversees the entire process, regulating the drug development and manufacturing as well as sales and marketing.

The sponsor or person who takes responsibility for, and initiates, a clinical investigation often funds these studies. Clinical trials can be sponsored by an organization such as a pharmaceutical company, a federal agency (for example, the National Institute of Health) or an individual, such as a physician or health care provider. The results of clinical trials are often published in peer-reviewed, scientific journals. Peer-review is a process by which experts review the report before it is published to make sure the analysis and conclusions are sound. If the results are particularly important, they may be featured by the media and discussed at scientific meetings and by patient advocacy groups before they are published.