Phase IV: the opportunity and the challenge

Abstract

As we lack important knowledge about every drug at the time of its initial introduction on to the market, the post-registration phase is of infinite length (unless the drug is withdrawn from the market) and of infinite opportunity. Consider the deficiencies that typically are present at the time of initial regulatory approval:

• 1. The necessarily limited clinical data accumulated by then will not have revealed rare but serious side-effects, the picture of gross overdosage in human beings, teratogenic and carcinogenic potential, and the possibility of abuse of the drug for non-medical purposes.

• 2. Because, for obvious reasons, pre-registration studies tend to avoid the co-administration of multiple drugs, there will be little information about significant drug-drug interactions.

• 3. A paucity of information will be available on the relative safety or efficacy of the new drug vis-à-vis the available alternative forms of treatment.

• 4. Most of what we know about the drug’s clinical performance will be of the type that might be characterized as ‘aggregate’, meaning what it does when given to a group of patients studied qua group. There will be little insight into the response of individuals or the function of baseline variables. Because of the desire to achieve homogeneous groups and to minimize confounding variables, we will tend not to know the importance of age or co-morbid states, for instance.

• 5. There will be a disproportionate amount of experience in the use of the drug when prescribed by expert physicians to carefully observed patients, whereas after registration the drug will be prescribed by physicians of greatly varying expertise to more heterogeneous populations taking the drug (and other drugs as well) in less supervised circumstances.