If the Drug Works, It’s Ok Not Knowing the Mechanism of Action
[Posted on: Thursday, August 4, 2016]

For many drugs, the mechanism of action is either unknown or not confirmed. In an assay published in The Scientist, three case studies were used to emphasize why it is not critical, if not required, to know the mechanism of action of a given drug. Three drugs used as case studies were the CNS drug lithium, the analgesic acetaminophen, and the sleep disorder drug modafinil. All three drugs have a long history of use and benefit to patients with few side effects, and the mechanism of action of all three is not defined. The assay makes an important point about drug development that are lost on even the most experienced and proficient developers. While it is important to explore the mechanism of action of a given product, many a times products are approved based on safety and efficacy even if the mechanism of action is not well-understood. There is sound scientific justification for this regulatory model. For any drug, the safety is defined via monitoring for adverse effects. The safety profile of a drug is established via adverse effects caused in animal models and clinical trials. Regulatory guidelines list required nonclinical and clinical studies based on historical experience and scientific logic. These studies are designed to capture most plausible risk of administering a given drug. The guidelines acknowledge the limitation of knowing all risks with a given drug based on sample size and population tested. Similarly the efficacy of a drug is based on controlled studies to compare the benefit of the new drug compared to that of the standard of care or no treatment, i.e., placebo. Just like the safety profile, efficacy is a statistical justification for a given drug based on limitations of the testing, and not based on knowing mechanism of action. While toxicity studies and clinical trials are required to meet strict quality requirements under GCP and GLP, mechanism of action studies can be conducted in less controlled settings. The universally accepted regulatory requirement of benefit over risk, and does not include mechanism of action as a criteria for approval. Regulators expect the developers to impart reasonable efforts to understand the mechanism of action but are willing overlook this aspect if the safety and efficacy data is satisfactory. This is even truer for biological products and botanical drug products where the inherent nature of the product makes it impossible to pinpoint the mechanism of action. Coming back to the original issue raised in the assay, that many drugs are used without understanding the mechanism of action; it does not matter how it works, if it does.