What is drug development?
Pfizer Inc discovers, develops, manufactures, and markets leading prescription medicines for humans and animals and many of the world's best-known consumer brands. Our innovative, value-added products improve the quality of life of people around the world and help them enjoy longer, healthier, and more productive lives. The company has three business segments: health care, animal health and consumer health care. Our products are available in more than 150 countries.
Drug discovery begins with chemists and biologists working on new chemical entities or molecules that, based on their research, they hope will be active against (or influence) certain biological targets. Once the molecule reaches rigorous standards or quality guidelines they nominate it for further testing in living organisms. This is the beginning of the pre-clinical phase of drug development.
Preclinical research involves testing the candidate molecule in animals, a step required by regulatory agencies around the world to establish the safety of the experimental drug for human testing. In addition to basic safety data, scientists garner vitally important metabolic information from these animal tests. The new molecule must be safe at a dose that enables an effective amount of the experimental drug to reach the target site. This must be achieved through a convenient route of administration, by mouth, a patch, or perhaps by inhalation. The new molecule must 'behave' in the body as well. It must be absorbed and distributed in a predictable manner, broken down. When a promising candidate emerges from preclinical testing, additional refinements or analogues will be created and tested, in the search for the optimal combination of activity and safety in the lead compound. At the same time, specialists in drug manufacturing are seeking to create larger amounts of the promising compound. The synthetic approach used in the discovery chemists' laboratory is seldom workable to produce the larger quantities required for pre-clinical and clinical testing. Sometimes this research effort fails as well, perhaps because the solvents required in the 'scale-up' process are too dangerous environmentally.
About half of the molecules tested in the preclinical phase are eliminated because of safety or metabolism issues. When the results of the testing look promising, the project team gathers all its data and submits an Investigational New Drug (IND) application to the Food and Drug Administration (FDA), requesting permission to begin initial human testing.
Clinical Trials
FDA approval of the IND sets the stage for Phase I safety testing of the experimental drug in healthy volunteers. These are the first of many 'clinical' studies or 'trials' conducted during the Development phase. A clinical trial is an experiment designed to prove or disprove an 'end-point,' that is the assertion that the experimental drug will produce a given effect. This effect, perhaps something as clear as reducing blood pressure, must be agreed on ahead of time as must the method of 'measurement' of the effect. Because blood pressure is measured in widely recognized and standardized ways, measuring the effect of a new medicine on this 'end-point' would be relatively simple. In many cases, however, defining an end-point to measure objectively is extremely difficult. How to determine objectively the degree to which 'pain' is reduced for an arthritis sufferer? Or 'anxiety' reduced? The goal of pharmaceutical clinical trials is to demonstrate, with a high degree of statistical 'certainty', that a positive effect, if one is seen, is attributable to the experimental drug being tested, and not to chance. Statisticians calculate how many patients need to be studied to achieve a given level of certainty about the results. Studies are frequently conducted with 'controls', i.e., with some number of subjects receiving a placebo or another drug, and are also blinded or 'double blinded', with neither physician nor subject aware of which ingredient the subject is receiving during the study. This approach to the creation of 'evidence-based' medical value is a revolution in health care, one that has become the standard only in recent decades.
Phase I Studies
In the first clinical trials for an experimental drug, small numbers of healthy volunteers are recruited to take single low doses of the drug under the close supervision of a physician. As in animal testing, safety is the number one consideration, although much important information is also gathered from the healthy subjects about how the drug is absorbed, distributed, metabolized, and eliminated by the body. If a series of gradually larger single doses does not cause problems, another study is undertaken in which a wider range of doses is administered to healthy volunteers over several days. Once again important safety, toleration, and pharmacological information is obtained. About one experimental drug out of three fails during these Phase I studies, which overall require about one year to complete.
Phase II Studies
For a compound that meets the Phase I testing hurdle, the next challenge is most eagerly awaited by the project team, the Phase II 'proof of concept' study. Here for the first time, after several years of difficult work, the team will arrange to administer the experimental drug to carefully selected patients suffering from the disease being targeted. Patients are recruited at research hospitals and centers through their physicians who agree to serve as clinical investigators. The research team educates these investigators in detail about the experimental drug, and they in turn educate selected patients who meet the entry criteria for the study. Only after all the risks of participation in the study have been explained to patients, who are required to sign 'informed consent forms' acknowledging their understanding of the risks, can the trial get underway. Patients in these studies are frequently hospitalized or very closely monitored under controlled circumstances. Generally 100 to 300 patients are enrolled in these Phase II studies. Each receives the experimental medication (or a 'control') for a period of time sufficient to produce measurable 'improvement' (however the protocol defines this) if the drug is effective. If a signal of efficacy is achieved in Phase II, there is much excitement and new studies are designed to test a range of doses of the experimental drug. The goal is to determine the amount and frequency of dosing that provides the optimal benefits with the smallest number of side effects.
A Word About Dosing
While the above description focuses on designing and conducting well-controlled clinical trials, the technical challenges associated with producing the correct dose strengths and dosage forms that make the trial possible are also formidable. Pharmaceutical scientists must manufacture quantities of the active ingredient in the experimental drug, but also formulate it into a capsule, tablet, or some other form. This form must be stable, easy to swallow, pure, and contain precisely the right amount of active ingredient, usually in combination with several other ingredients required to produce the stable form. For controlled trials, these same specialists must formulate the control as well, either by manufacturing a placebo identical to the study drug or by blinding a competitor's drug to match the study drug form. All these forms and doses must be tested for purity, labeled to preserve the blind, and shipped to the right investigators at the right time (and any unused drug must be 'recaptured' and accounted for following the completion of the study).
Phase III Testing
Phase III clinical testing is the most expensive and time consuming part of the drug development process. In these studies, the experimental drug is administered to hundreds and frequently thousands of patients throughout the world. The patients take their trial medication under the supervision of their physician, with whom the pharmaceutical company has contracted to conduct the clinical investigation. Patients visit the doctor regularly to receive physical examinations and provide laboratory samples during the trial, but otherwise lead their lives in the manner that is typical of those suffering from the disease being studied. Statisticians and clinical research specialists design these studies (the number of patients, the study length, and the analytical methods) to ensure that if the experimental drug does provide a benefit, this benefit will be clearly demonstrated. Experts at the regulatory agencies are consulted to ensure agreement on the proposed strategy. The FDA requires two such positive, well-controlled studies for any claim that a pharmaceutical company wishes to make in the label of a drug.