Expect more physicians to wait for a new drug to establish a safety record before prescribing it. What's old and established
is in, what's new—and once interpreted as "better"—is out. Currently, the industry thinks large postapproval safety studies
pay off only if they don't show a risk. In the future, the reduction in uncertainty gained by doing these studies will be
the payoff. Ironically, marketing advantage will go to drugs with a safety benefit as opposed to an efficacy advantage.
Under this paradigm, companies must move away from trying to reach peak sales as quickly as possible. Instead, they must learn
to build drug adoption slowly and steadily while increasing physicians' and patients' confidence that they understand a product's
risks. And though this method means companies will have to rethink their classical approach to life cycle marketing, the bright
side of this new culture of safety is that it will also be harder for the competition to gain acceptance for a substitute
In the new Culture of Drug Safety, FDA will perform formal drug safety reviews after approval. Look for scheduled reviews
of drug risks every three to five years. Companies will need to formally demonstrate product benefits both before and after
approval to receive a fair review of drug safety. (We'll have more to say about reviews in the next installment of this series.)
With more pharmacoepidemiologists sitting on FDA advisory committees—per IOM's recommendations—expect more requests for postmarketing
safety studies. Companies will continue to conduct postmarketing commitments in the form of small studies, database analyses,
and registries. The big difference is that companies will have to deliver what they promise. In 2006, the inspector general
reported that about one-third of the annual company-submitted reports used to track these commitments were entirely missing
(presumably not submitted) and that more than one-third of those present lacked required information. In total, FDA could
not track whether companies had followed through on postapproval promises 74 percent of the time.
Expect FDA to do more thorough follow-up to ensure that Phase IV and other study commitments are kept. Bills currently before
Congress grant FDA new authority to enforce commitments and delineate processes leading to fines and new drug application
(NDA) withdrawal if they are not met.
FDA has already taken steps to improve drug safety by controlling postapproval use. Under a May 2005 guidance, FDA may ask
companies (or companies may volunteer) to prepare a Risk Minimization Action Plan (RiskMAP) when new risks are discovered.
These plans specify what companies will do and what tools, such as Medication Guides or restricted distribution, they plan
to use to mitigate known risks.
The Senate and House bills, however, go a step further and include the requirement that companies submit a Risk Evaluation
and Mitigation Strategy (REMS) for all drugs. Like a RiskMAP, a REMS includes plans for continued risk assessment. But a REMS also includes a plan for a postmarketing
research agenda to track drug safety.
The Culture of Drug Safety has spoken: Risk-management programs will become the norm. The key for marketers is to find the
holy grail of risk mitigation: risk-management tools that protect patients, but whose restrictions don't kill the drug. After
all, certain risk-management interventions have been interpreted by doctors as an attempt to transfer liability for drug safety
from drug company to physician. That happened with GlaxoSmithKline's Lotronex (alosetron). When physicians were required to
sign an agreement stating that they would fully warn the patient—and get the patient to sign an agreement stating that they
had—gastroenterologists refused to prescribe Lotronex, and sales plummeted. We are now likely seeing similar liability concerns
In addition to risk-management programs, FDA is looking at new ways to discover drug safety risks at an earlier stage of marketing.
For example, FDA recently held hearings on sentinel networks—mechanisms to receive and investigate very early cases that may
signal safety concerns.
The problem for drug safety, however, is not usually the identification of new safety signals. Rather, it's qualifying and
quantifying these signals so we can understand, or at least hypothesize, which are real concerns and which are only "noise
in the system."