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.
The Institute of Medicine (IOM) called for a fixed time for review of risk/benefit (such as five years after approval). However,
the continued search for drug risks will increase the frequency with which new safety questions are discovered or verified.
For most drugs, the risk/benefit ratio will become steadily more unfavorable unless companies take steps to ensure that new
information about benefits is provided to balance or overcome new information about risks. The question is how to do that.
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.
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