An overview of the drug development process

Physician Executive, May-June, 2005 by Ross Tonkens

Pharmaceutical medicine uses all the scientific and clinical knowledge acquired by physicians in medical school and postgraduate training--combined with additional regulatory and business skills--to provide a challenging and rewarding career

Unlike clinical medicine, pharmaceutical medicine is part of an industry with huge up front investments for rewards that may or may not come years later. To develop new drugs takes a very, very long time--2 to 12 years from discovery to market, on average--and the cost is extremely high. It costs about $1.8 billion to take a new compound to market and success is quite limited.

Only one in 10,000 compounds ever reach the market. Of those only one in three ever recaptures its development costs. High risk indeed!

Drug development is a scientific endeavor that is highly regulated because of legitimate public health concerns.

Drug development phases

There are three major phases in drug development:

1. Pre-clinical research and development

2. Clinical research and development

3. After the compound is on the market, a possible "post-marketing" phase

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The pre-clinical phase represents bench (in vitro) and then animal testing, including kinetics, toxicity and carcinogenicity. In the U.S., an investigational new drug application (IND) is submitted to the Food and Drug Administration seeking permission to begin the heavily regulated process of clinical testing in human subjects.

The clinical research (IND) phase--representing the time from beginning of human trials to the new drug application (NDA) submission that seeks permission to market the drug--is by far the longest portion of the drug development cycle and can last from 2 to 10 years.

Phase I trials, sometimes called, "first in human" trials, are generally conducted on relatively small groups (typically 10 to 30) of healthy volunteers (except for oncology drugs or other potentially toxic compounds) in specialized units resembling small hospitals with 20 to 50 monitored beds.

The "inpatient" portion of Phase I trials usually lasts from a day or two to a week (though follow up can last up to about a month), and are designed to assess the safety of a compound and study its pharmacokinetics (Pk--what the body does to the drug) and pharmacodynamics (Pd--what the drug does to the body).

In some cases, human metabolism can differ markedly from animals so that a drug with a half life of a few hours in dogs may turn out to have a half life of several days in humans, or a compound with no animal toxicity may cause elevation in liver functions or a prolongation of QT interval in humans.

A rough idea of the maximum safe or tolerated dose, as well as a general side effect profile is obtained during Phase I trials. Many compounds never make it past Phase I, as they are found to have unacceptable side effects.

Assuming a compound is shown to be safe for healthy subjects and survives Phase I, then development proceeds to a series of Phase II trials. These trials typically enroll anywhere from about 20 or 30 patients up to a few hundred at most.

These patients usually have a relatively "pure" form of the disease for which the drug is intended. In other words, they suffer from as little other intercurrent disease as possible, and the list of concomitant medications they can be taking is usually restricted.

For example, patients with newly diagnosed, but untreated, diabetes, with no evidence of end organ damage, would be used to test a new antidiabetic agent.

Phase II trials tend to last only a few weeks to, at most, a few months. Initial Phase II trials (sometimes called, IIa) are pilot trials to determine dose range. They tend to be conducted at specialized centers, like university medical centers, by specialized investigators, such as medical school faculty.

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Subsequent Phase II trials (often called, IIb) are aimed at elucidating dose response relationships, safety and, for the first time, efficacy, of the compound treating the disease or condition for which it is intended.

Drug-drug interactions are also studied carefully during Phase II as well as Pk and Pd in diseased patients, which can sometimes differ markedly from what was observed in healthy volunteers.

Phase II can encompass anywhere from a few to 20 or more clinical trials, and the "development plug" can be pulled--and frequently is--after any of them. Once again, assuming the drug shows sufficient evidence of efficacy and no major safety concerns--whether purely from drug effect, or from drug-drug interactions--a go/no go decision will be made to proceed to Phase III.

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Phase III is where the "rubber meets the road." At least two pivotal Phase III trials demonstrating efficacy and safety in large numbers of patients, including special populations with all forms of the disease or condition to be treated, who may be on multiple other medications, are required for regulatory approval in the U.S.

Few drugs have been approved with data from less than two pivotal trials, and, if so, generally require post-marketing commitments to ensure that safety and efficacy is validated after marketing.