Friday, August 15, 2014
JAMA Internal Medicine
August 15, 2014
Proposed US Food and Drug Administration Guidance for Industry on
Distributing Medical Publications About the Risks of Prescription Drugs
and Biological Products
A Misguided Approach
By Sidney M. Wolfe, MD
In June 2014, the US Food and Drug Administration (FDA) for the first
time issued draft guidance for the pharmaceutical industry on
distributing scientific and medical publications about the risks of
approved prescription drugs and biological products. In my view, the
draft guidance, which is open for public comment until August 25, 2014,
has the potential to undermine the FDA's drug safety laws and
regulations and should be substantially changed.
As written, the draft guidance would allow pharmaceutical companies who
believe that the FDA-approved drug-labeling information overstates the
risks of their drug to tell physicians that the risks are, in fact,
lower. Companies could inform physicians of the purportedly lower risks
by distributing peer-reviewed articles and instructing their sales
representatives to discuss the information they contain about the lower
risks. Laws and regulations requiring FDA approval of the drug label
would have little meaning if a company, without the agency either
reviewing the data or approving it, can detail this information. In
analogy to the off-label promotion of unapproved uses of drugs, this
activity might be referred to as "off-label risk reduction."
The draft guidance states that
"FDA does not intend to object to the distribution of new risk
information that rebuts, mitigates, or refines risk information in the
approved labeling, and is distributed by a firm in the form of a reprint
or digital copy of a published study, if the study or the analysis and
the manner of distribution meet the [specified] principles…."
The agency guidance was issued in response to petitions from 11
pharmaceutical companies seeking clarification and expansion of the
limits on industry for communications with physicians and others without
risking FDA enforcement action for off-label promotion of unapproved
indications. Since 1991, pharmaceutical companies have paid tens of
billions of dollars to the United States for criminal and civil legal
violations. Two of the common forms of illegal activity have been
off-label promotion of unapproved uses of drugs and understating the
risks of approved uses.
The draft guidance suggests that the agency has now tilted toward
protecting industry's commercial speech and away from protecting
patients from the risks of prescription drugs and biological products.
Unfortunately, the draft guidance strikes the balance more toward the
industry's view of its First Amendment right to commercial speech than
toward the agency's mandate for patient protection.
The longer a drug is marketed, the historical pattern is for information
to develop about an increase in the risk to patients, not a decrease in
risk. FDA-approved labeling changes about risk are rarely about
reductions in risk. More commonly, labeling changes incorporate
information about increased risk, including many new boxed warnings. For
example, a 2005 FDA guidance that is frequently referred to in the 2014
draft guidance discusses, almost in its entirety, the various kinds of
post-marketing surveillance that result in information about increased
risks. Between 1975 and 2009, the FDA approved 748 new drugs; 114
(15.2%) received 1 or more boxed warnings after approval, and 32 (4.3%)
were withdrawn from the market for safety reasons.
To protect patients and the public health, the FDA should substantially
revise its draft guidance for industry on distributing medical
publications about the risks of prescription drugs and biological
products. When new information supports a reduction in risk, the company
should inform the FDA and provide the evidence, as is required under
current regulations; if the agency is convinced, the label can be
changed. Off-label risk reduction is a misguided approach.
Era Of Faster FDA Drug Approval Has Also Seen Increased Black-Box
Warnings And Market Withdrawals
By Cassie Frank, David U. Himmelstein, Steffie Woolhandler, David H.
Bor, Sidney M. Wolfe, Orlaith Heymann, Leah Zallman and Karen E. Lasser
After approval, many prescription medications that patients rely on
subsequently receive new black-box warnings or are withdrawn from the
market because of safety concerns. We examined whether the frequency of
these safety problems has increased since 1992, when the Prescription
Drug User Fee Act, legislation designed to accelerate the drug approval
process at the Food and Drug Administration, was passed. We found that
drugs approved after the act's passage were more likely to receive a new
black-box warning or be withdrawn than drugs approved before its passage
(26.7 per 100.0 drugs versus 21.2 per 100.0 drugs at up to sixteen years
The Prescription Drug User Fee Act (PDUFA)—first enacted in 1992 and
renewed in 1997, 2002, 2007, and 2012—authorizes the FDA to collect fees
from drug companies to expedite the drug approval process. Congress
enacted the PDUFA in response to widespread concerns that the process
was taking too long.
New drugs have a one-in-three chance of acquiring a new black-box
warning or being withdrawn for safety reasons within twenty-five years
of approval. We believe that the ultimate solution is stronger US drug
JAMA Internal Medicine
August 15, 2014
Trends in Boxed Warnings and Withdrawals for Novel Therapeutic Drugs,
1996 Through 2012
By Christine M. Cheng, PharmD1; Jaekyu Shin, PharmD, MS; B. Joseph
Our study demonstrates that boxed warnings are common, affecting more
than one-third of recent drug approvals. While nearly three-quarters of
boxed warnings had been applied to novel therapeutics at the time of
approval, more than 40% acquired the warning after a median market
period of 4 years. Clinicians should be aware of the prevalence and
growing numbers of boxed warnings and the importance of continued
adverse event reporting for identifying new safety concerns.
Comment by Don McCanne
The Food and Drug Administration (FDA) protects the public from
pharmaceutical firms that increase their drug sales by not being totally
forthcoming about both the effectiveness and safety of their drug
products. The required drug labeling is based on the best information
available. History has repeatedly confirmed that such oversight is
essential even now with the pharmaceuticals firms having paid tens of
billions of dollars in penalties for these continuing violations.
Yet the FDA seems to be allowing the pharmaceutical firms more leeway.
An example is that the FDA allows the firms to pay fees for the purpose
of expediting the consideration of new drug applications. Allowing them
to buy their way to the front of the queue is not only a compromise of
justice, much more importantly it has allowed new products to be
introduced to markets prematurely. This has resulted in an increased
need to add post-marketing black box warnings about more serious adverse
effects of the drugs. Of even greater concern has been the increased
need to withdraw drugs from the market, raising concern that the
accelerated approval process may have allowed the release of drugs that
never should have been on the market in the first place.
The current request pending before the FDA to allow pharmaceutical firms
to distribute studies that have not been cleared by the FDA that show
that their products are safer than the required labeling would indicate
should raise concerns since the first draft of this FDA guidance would
allow such activity. Although it proposes some guidance on how this
information would be distributed, based on previous behavior of the
pharmaceutical firms, there is absolutely no doubt that they would abuse
this process by supporting studies done by researchers who are friendly
to the industry, and by selecting only the favorable studies and burying
those that are less favorable.
Those who are concerned about this ill-advised FDA guidance, and we all
should be, can read the full draft of the guidance and then submit a
comment to the FDA. Public comments are open only until Aug. 25.
Submit a comment on the guidance:
at 12:24 PM