Oct 2006 Newsletter
Special Focus: Drugs - From conception to market
In this newsletter, we will walk you through the complex process of developing small molecule drugs - from conception to market. Development of a drug takes 1-2 billion USD and is the result of hundreds of scientists - in both academia and industry including chemists, biologists, toxicologists, physicians - researching and experimenting for 10-14 years.
In the beginning
Drug discovery process typically starts when a protein (also called a target) that is believed to be the cause of the disease is identified. Target validation often includes generating targeted mutations and transgenes in mice to find specific genes, and pathways.
Established targets are those for which there is a good scientific understanding of both how the target functions in normal physiology and how it is involved in human pathology. Druggable targets are those that can be addressed with vaccines, small molecules, therapeutic antibodies or protein therapy approaches.
Goal of a drug discovery program
Goal of a drug discovery program is to find a novel compound that binds to the particular target protein, thus altering the disease causing behavior of the protein. For approval by regulatory agencies, it has to exhibit superiority compared to available treatments - either more effective, easier delivery mechanism, reduced dosage, or reduced toxicity.
An orally deliverable small drug is considered superior to alternate therapies such as injections because of the ease of transport and delivery of the drug and ease of administration to the patients. However, for a drug to be orally available in a small tablet format, it has to be a compound with relatively small molecular weight (typically, 200-600) and survive the stomach acids.
In the process of testing compounds to find potential drugs, scientists must ask several different questions. Is the drug candidate likely to be more effective than current therapies? Will it be possible to manufacture the molecule in bulk quantities? Does it have a reasonable dose range and delivery system (e.g., oral, inhaled)? Establishing answers to such questions involves testing the compounds - first, in vitro e.g. human cells in test tubes and then, in vivo e.g. rats and mice. Finally, large scale human trials are needed to establish effectiveness and safety.
Lead discovery and optimization
Once a target is validated, chemists typically screen hundreds of thousands of drug-like compounds (compounds that have similar physiochemical profile to known existing drugs) to identify active compounds i.e. ability of the compound to modify the target. This process is called High Throughput Screening (HTS). HTS is a highly automated process and enables screening of hundreds of thousands of compounds in a single day. A typical large pharmaceutical company has access to about a million drug like compounds.
While HTS is a commonly used method for novel drug discovery, it is not the only method. It is often possible to start from a molecule which already has some of the desired properties. Such a molecule might be extracted from a natural product or even be a drug on the market which could be improved upon (so-called "me too" drugs). Alternately, computational screening (or virtual HTS) involves using computational modeling of the protein and small molecule interaction to predict active compounds.
Whatever the screening method, it is unlikely that a perfect drug candidate will emerge from these early screening runs. Typically, the successful molecules have some desirable properties as a potential drug candidate but scientists must modify them to increase activity and decrease side effects.
Early screening typically yields 100 to 200 compounds that are further examined in the laboratory in order to perfect their physiochemical properties, their pharmacokinetic and pharmacodynamic behavior and the therapeutic effectiveness.
Pharmacodynamics studies the effects on an organism of a pharmaceutical compound and its metabolites (products derived from the impact of metabolic reactions on the molecule). It includes the study of uptake, movement, binding and interactions of agents at their tissue and cellular site. Pharmacokinetics studies the mechanisms of absorption of a pharmaceutic compound, its distribution in the organism, its metabolism (i.e., modifications by the liver, kidneys, lungs, skin, etc.), its storage (e.g., in adiposal or bone tissues) in an organism, and its excretion.
At the end of this stage, which can take 6 mo to 3 years, around twenty (20) compounds are selected for further testing on animals in the preclinical development stage.
Testing the drugs in animals (pre-clinical testing)
Once a drug candidates have been identified in the laboratory, it is tested in animal studies to evaluate its safety and demonstrate that it has biological activity against the disease target.
In addition to biological tests, researchers conduct a number of other preclinical studies. Chemistry tests establish the compound's purity, stability and shelf life. Manufacturing tests determine what will be involved in producing the medicine on a large scale. And pharmaceutical development studies explore dosing, packaging and formulation (e.g., pill, inhaler, injection).
The main goal of preclinical studies is to rigorously assess safety before human tests begin and this can take anywhere from 3-6 years. Some preclinical safety tests continue even after the start of clinical trials in people to determine if there are any long-term adverse effects researchers should look for.
Human (clinical) trials
In clinical trials teams of physicians carry out studies designed to determine if the drug is safe when administered to people and is indeed an effective treatment for the disease in question. In US, of the 250 compounds that enter preclinical testing, only five will make it this far. There are three phases of clinical trials:
Phase I: The medicine is tested in a small group (20-100) of healthy volunteers - often in a hospital setting - to determine its safety, the safe dose range, and identify side effects. Pharmacokinetic studies examine how a drug is absorbed, distributed, metabolized and excreted, as well as the duration of its action. Phase I studies can take from six months to one year to complete.
Phase II: Placebo-controlled trials involving approximately 100 to 300 volunteer patients who have the disease being studied. The goal of this phase is to establish the "proof of concept" - i.e., the medicine effectively treats the disease. Researchers continue to evaluate the drug's safety and look for side effects, and determine optimal dose strength and schedule (e.g., once or twice daily). Phase II studies can take from six months from one year to complete.
Phase III: The medicine is tested in large, randomized, placebo-controlled trials with much larger numbers of patient volunteers - from 1,000 to 3,000, in hospitals, clinics and/or physician offices - to generate statistically significant data. Researchers closely monitor patients at regular interviews to confirm that the drug is effective and identify side effects. At this stage, it is also compared with other commonly available treatments for the disease. Phase III studies are the most expensive, time consuming and difficult trials to design and run and can take from one to four years to complete, depending on the disease, length of the study, and the number of volunteers.
While Phase I-III studies are taking place, researchers also conduct a number of parallel studies: toxicity tests and other long-term safety evaluations; dosage forms; plans for full-scale production; package design; and preparation of the complex application required for government approval.
After the clinical trials
Once all three phases of the clinical trials are complete demonstrating both safe and efficacy of the medicine, the company files a "regulatory submission" with drug regulatory agency e.g. New Drug Application (NDA) is filed with Food and Drug Administration Agency (FDA) in US. NDAs are typically 100,000 pages or longer containing all the information about all the studies including pre-clinical testing, clinical trials, dosage information, manufacturing details and proposed labeling of the new medicine.
If the event that the medicine is approved for marketing, it becomes available for physicians and patients. In USA, it takes about 1.5 years for FDA to approve a medicine and the proportion of rejected applications is about 10%-15%.
Following the approval, engineers and scientists at the manufacturing plant scale up production to meet global demands. Facilities must meet inspection criteria for Good Manufacturing Practices to ensure quality control for the product. As the manufacturing ramps up, marketing for the product begins and in 3-6 months, consumers can start benefitting from the drug.
Footnote
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