Human Drug Testing Phase II: Finding Out About the Drug’s Performance

By John Pezzullo

After the Phase I trials of human drug testing, you’ll have a good estimate of the maximum tolerated dose (MTD) for the drug. The next step is to find out about the drug’s safety and efficacy at various doses. You may also be looking at several different dosing regimens, including the following options:

  • What route (oral or intravenous, for example) to give the drug

  • How frequently to give the drug

  • For how long (or for what duration) to give the drug

Generally, you have several Phase II studies, with each study testing the drug at several different dose levels up to the MTD to find the dose that offers the best tradeoff between safety and efficacy. Phase II trials are called dose-finding trials; at the end of Phase II, you should have established the dose (or perhaps two doses) at which you would like to market the drug.

A Phase II trial usually has a parallel, randomized, and blinded design, enrolling a few dozen to several hundred subjects who have the target condition for the drug (such as diabetes, hypertension, or cancer).

You acquire data, before and after drug administration, relating to the safety and efficacy of the drug. The basic idea is to find the dose that gives the highest efficacy with the fewest safety issues. The situation can be viewed in an idealized form as shown.


Efficacy is usually assessed by several variables (called efficacy endpoints) observed during the trial. These depend on the drug being tested and can include:

  • Changes in measurable quantities directly related to the target condition, such as cholesterol, blood pressure, glucose, and tumor size

  • Increase in quality-of-life questionnaire scores

  • Percent of subjects who respond to the treatment (using some acceptable definition of response)

Also, safety has several indicators, including

  • The percent of subjects experiencing various types of adverse events

  • Changes in safety lab values, such as hemoglobin

  • Changes in vital signs, such as heart rate and blood pressure

Usually each safety and efficacy indicator is summarized and graphed by dose level and examined for evidence of some kind of “dose-response” association. The graphs may indicate peculiar dose-response behavior; for example, efficacy may increase up to some optimal dose and then decrease for higher doses.

The figure shown, in which an overall safety measure and an overall efficacy measure are both shown in the same graph, is useful because it makes the point that (ideally, at least) there should be some range of doses for which the efficacy is relatively high and the rate of side effects is low. That range appears to lie between 150 and 350 milligrams:

  • Below 150 milligrams, the drug is very safe (few adverse events), but less than half as effective as it is at higher doses.

  • Between 150 and 300 milligrams, the drug is quite safe (few adverse events) and seems to be fairly effective (a high response rate).

  • Above 300 milligrams, the drug is very effective, but more than 25 percent of the subjects experience side effects and other safety issues.

The “sweet spot” for this drug is probably somewhere around 220 milligrams, where 80 percent of the subjects respond to treatment and the side-effects rate is in the single digits. The actual choice of best dose may have to be thrashed out between clinicians, businesspeople, bioethicists, and other experts, based on a careful examination of all the safety and efficacy data from all the Phase II studies.

The farther apart the two curves are in the figure, the wider the range of good doses (those with high efficacy and low side effects) is. This range is called the therapeutic range. But if the two curves are very close together, there may be no dose level that delivers the right mix of efficacy and safety. In that case, it’s the end of the road for this drug.

The majority of drugs never make it past Phase II.

Between the end of Phase II and the beginning of Phase III, you meet again with the FDA, which reviews all your results up to that point and tells you what it considers an acceptable demonstration of safety and efficacy.