Rewriting the Safety Equation

Currently, to have a new drug application (NDA) approved, a company has to demonstrate that the product's benefits (B) outweigh its risks (R), so B/R>1. In the new Culture of Drug Safety, more danger signals will be detected and more safety studies undertaken, not only for the drugs we are championing as if our livelihood depended on it (and, of course, it does) but also for other drugs both within and outside the class.

As a given drug moves through time, two things can happen:
» R or B may change due to the discovery or verification of new information (either positive or negative).
» The perception or interpretation of R or B may change, not because of new information about the drug but because of the context in which the information is conveyed. For example, a competitive drug for the same condition has been approved in the period between initial approval and the new risk/benefit analysis. Although comparative risk/benefit analyses are not supposed to influence drug safety analyses, they clearly do—and they will continue to influence safety decisions.

Currently, life cycle plans are viewed as a marketing-focused template that helps to identify sales and profit goals, new uses to be investigated, and long-term strategies to stave off therapeutic and generic competition. In the new Culture of Drug Safety, we will need to modify and adapt life cycle planning to meet the challenges posed by the continued discovery and analysis of drug risks. There are several goals we will need to integrate into our life cycle planning. These goals include benefit identification, benefit and risk quantification, and benefit augmentation.

Benefit Identification

In many instances, the intended uses of a drug are also its benefits. For example, if a drug is approved to treat pain, its benefit is that it treats pain. In cases like this, the benefit of a drug is said to have "face validity," and if there are no other effective drugs in a class, face validity is usually sufficient for approval.

But there are many effective drugs in many classes, and a manufacturer who wants to add an additional drug to the class must look to additional benefits. In the case of a pain drug, for example, the benefit may be that it treats pain more rapidly, more conveniently, with fewer minor side effects, or with less chance of addiction or abuse. These are clearly benefits, but they are much more difficult to analyze in a R/B equation.

In the past, manufacturers have argued successfully that providing an alternative treatment option is sufficient benefit to justify approval. Recent cases, however, suggest that that may no longer be true. During the FDA advisory-committee meeting to review Merck's proposed new COX-2, Arcoxia (etoricoxib), the company made just that argument. FDA and the committee, however, wanted evidence that people who have failed on one pain reliever would benefit from a new product. Without it, they were unable to quantify the benefit of the product. (Disclosure: I served on the Arcoxia advisory committee and voted against approval.)

How do we translate drug effects into benefits, and how do we make these benefits tangible? This will be a major problem for the industry. The most likely candidate for providing this perspective is some form of patient-reported outcome (PRO) or health-related quality-of-life (HRQL) measure. These scales are commonly used in clinical trials as secondary end points to help characterize the disease and the drug's impact on the disease. A new class of scales that can help capture drug effects—not necessarily disease impacts, as quality-of-life instruments currently do—will likely be needed to identify the meaning of the drug's benefits to patients.