FDA proposes allowing off-label claims of risk reduction

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
JAMA Internal Medicine, August 15, 2014

In June 2014, the US Food and Drug Administration (FDA) for the first time issued draft guidance for the pharmaceutical industry on distributing scientific and medical publications about the risks of approved prescription drugs and biological products. In my view, the draft guidance, which is open for public comment until August 25, 2014, has the potential to undermine the FDA’s drug safety laws and regulations and should be substantially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As written, the draft guidance would allow pharmaceutical companies who believe that the FDA-approved drug-labeling information overstates the risks of their drug to tell physicians that the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The draft guidance states that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The draft guidance suggests that the agency has now tilted toward protecting industry’s commercial speech and away from protecting patients from the risks of prescription drugs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
Health Affairs, August 2014

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 of follow-up).

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 approval standards.


Trends in Boxed Warnings and Withdrawals for Novel Therapeutic Drugs, 1996 Through 2012

By Christine M. Cheng, PharmD1; Jaekyu Shin, PharmD, MS; B. Joseph Guglielmo, PharmD
JAMA Internal Medicine, August 15, 2014

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.



By Don McCanne, M.D.

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.

Draft Guidance;

Submit a comment on the guidance:!submitComment;D=FDA-2014-D-0758-0002