Many people don’t realize that drugs are approved by the FDA not based on a firm understanding of how they work, but based on whether they work and are safe. Efficacy and safety are both (at least up until now) statistical claims based on the effects on hundreds to thousands of subjects during phase I-III trials. If you give a particular drug to a large number of people, and if the adverse events are “tolerable” (by some reasonable definition, often in the context of how bad the disease is) and the drug has a positive effect, then the drug will be approved.
This FDA approach has been the right one for many decades–our scientific understanding of why drugs work often lags far behind the demonstrations that people can benefit from them. We may never have had access to many great medications if we insisted that we know how they work before we approved them.
However pharmacogenomics challenges this paradigm, because fundamental to pharmacogenomics is an understanding AT LEAST of the genes that are involved in either the way the drug works (pharmacodynamics, PD) or how the drug is absorbed, distributed, metabolized and eliminated from the body (pharmacokinetics, PK). Thus, the “black box” model of how a drug works erodes as you gain pharmacogneomics knowledge. Is this good or bad?
Well, the good part is that most will agree that it certainly seems beneficial to understand how a drug works (its mechanism), and to know what it interacts with. We can use this knowledge to reason about potential opportunities for new drugs that interact with similar biological processes, for modifying existing drugs with new chemical properties that may improve their interactions, and to predict which other drugs might have unexpected interactions with our drug because they work in similar biological pathways. As the noted founder of Faber College said “Knowledge is good.”
On the other hand, we do not have good knowledge of mechanism for many drugs, and that is a major barrier to the rapid application of pharmacogenomics. Which genetic variations should we assess for relevance to a drug response? The lack of this information has lead to great interest in genome-wide association studies (GWAS) to broadly search for genes that impact drug response. The problem, of course, is that these studies are essentially trying to define the mechanism of drug action (both PK and PD, kind of rolled into one) with a somewhat crude tool. The pitfalls of GWAS for picking up subtlety are pretty well chronicled. Are there better ways to uncover drug mechanisms so that genetics can be used with surgical precision instead? I think that this is what we call “good old-fashioned science.” To be sure, we need to use modern technologies to make the experiments faster, cheaper and more accurate, but I think there needs to be an investment in drug mechanism. It will make the pharmacogenetic task easier, but will also lead to a more profound understanding of how drugs work and how new drugs may work better.