Skip to content

Inside Health Policy – Woodcock 'Lives In Fear' Outdated Labels Will Lead To Patient Harm

Inside Health Policy – Woodcock 'Lives In Fear' Outdated Labels Will Lead To Patient Harm

Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), said she “live[s] in fear” of providers using outdated treatment methods based on FDA-approved drug labels which, the director admitted, are updated less and less after FDA first approves a drug. Woodcock made clear that FDA cannot play an omnipresent role in making sure labels are up to date, but Friends of Cancer Research, in a new paper, says the agency should collaborate with developers of compendia and clinical guidelines to suggest updates to labeling.


Woodcock’s admission came during a congressional briefing on prescription drug information hosted by FOCR on March 20. The panelists all agreed that, after a drug is approved, FDA can be slow to approve new uses or generally update the drug label, which leaves health care providers to rely on other sources of information to keep current on the drug. This fact led some to question whether FDA can do more to publicize new research absent updating a label.


“An FDA label is the most helpful right when the drug gets approved,” said Angus Worthing, chair of the Government Affairs committee for the American College of Rheumatology (ACR). “But from that day on, as the label ages it’s not like fine wine, it doesn’t age well.”


For example, Worthing explained how new data might lead to new recommendations for different dosage levels of an immune system suppressive drug for patients about to have a major surgery, but that information might not make it onto an FDA label quickly enough for providers.


Josephine Torrente, partner at Hyman, Phelps & McNamara, emphasized that the original label requires a substantial amount of data, but a supplemental application can require just as much information. It usually takes FDA 10 months to review those applications, according to Torrente.


Instead of waiting that long, Worthing said, providers learn to use other resources to make prescription decisions, including electronic databases such as UpToDate and guidelines from specialty organizations such as ACR.


Angela Green, a research fellow at Memorial Sloan Kettering Cancer Center, said she and her fellow oncologists “rarely use the FDA label because it’s outdated and incomplete in comparison to the widely used cancer guidelines, called the [National Comprehensive Cancer Network].”


Green also emphasized that over half the drugs in oncology are used off-label.


Jeff Allen, president of FOCR, substantiated that claim with a paper his organization wrote on the issue. The paper includes a graph comparing the number of FDA-approved uses to the number of NCCN Compendium-approved uses for 43 cancer drugs approved between 1999 and 2011.


For many drugs, there are 10 or more times the number of compendium-approved uses than FDA-approved uses, FOCR finds.


Allen argued there are a number of reasons why off-label use is so common in oncology, including that the National Cancer Institute funds clinical research that “oftentimes is intended to help refine practice once a drug is on the market.”


Product liability concerns also confound the labeling issues. Torrente explained that generic drug manufacturers often can’t work to update a drug label without taking on product liability, and thus have to persuade brands to update their labels first — which is particularly a problem when the brand is discontinued.


“So now you have to ask the generics, if their innovator’s discontinued, to take on that product liability by fussing with their labeling in some way…so you can see the enormous disincentive to those companies to take this on,” she continued.


Despite the challenges of the current system of drug labeling, panelists agreed it would be impossible for FDA to maintain an omniscient presence for approving all new developments in prescription drug usage. “We can’t take care of the entire inventory of pharmaceuticals ourselves at the FDA,” Woodcock said. “We have lots of other jobs.”


However, the director did point out how FDA helped negotiate the omission of supplement fees–which manufacturers were required to pay to apply for updating a drug label–from the most recent Prescription Drug User Fee Agreement (PDUFA VI) “for the overt reason to encourage submission of efficacy supplements,” she said.


“There still is a substantial cost to put the information together and shepherd it through the FDA process,” Torrente said. “But the removal of that user fee is certainly a step in the right direction…because I think what’s missing is incentives.”


In the organization’s paper, FOCR suggested FDA play a more active role in promoting up-to-date drug labeling through “a collaboration between the FDA and the developers of clinical guidelines and drug compendia.” The groups could work together to evaluate existing evidence and suggest updates to labeling, which would allow manufacturers to reference those evaluations in supplemental applications, FOCR wrote. Such a collaboration, “would be far less resource-intensive than a program requiring FDA to update labeling on its own,” read the paper.


Still, Allen said there will need to be some way of categorizing the data circulated by clinical guidelines and drug compendia as either conclusive, reliable and reproducible or “more exploratory” in nature. “Having a framework in place I think will help people distinguish between the different potential uses for RWE rather than sort of aggregating it all into one comprehensive science,” he said.


The cancer research advocate told IHP FOCR’s suggestion is similar in spirit to the program the 21st Century Cures law directs FDA to establish. The program would evaluate the potential use of real-world evidence in support of the approval of a new indication for an approved drug or to help support or satisfy post-approval study requirements.


Allen said FDA’s framework could help distinguish what types of information would help refine dosage instructions or provide evidence for new indicators of efficacy or patient populations. “Where I see this related to some of the things that we’re talking about it is, if such a framework is laid out in terms of different uses of RWE, one component of that could be appropriate for label modifications.”


While FDA steers away from promoting off-label drug use, Allen believes FDA coordinating with compendia could cool the debate by more easily moving off-label uses on-label. “If there are easier processes to put that information into the label, maybe it will help alleviate some of the tension around what information really truly needs to be communicated,” he said.


Woodcock said in the briefing that FDA would be issuing a framework and holding public discussions on an RWE evaluation program soon. While an agency spokesperson could not give an exact date for the framework, he said it would be issued by the statutory deadline this December.…