December 03, 2025
5 min read
Key takeaways:
- Citizens can petition the FDA to update an approved drug’s label, including removing a boxed warning.
- Successful petitions need to make a “compelling case” that the proposed action is justified.
PHILADELPHIA — Health care professionals can have a powerful impact on labeling requirements for drugs by formally petitioning the FDA for changes that improve public safety.
A citizen petition is a way for individuals, regulated industry or consumer groups to petition the FDA to use, change or cancel a regulation, Sean Hennessy, PharmD, PhD, professor of epidemiology, systems pharmacology and translational therapeutics and director of the Center for Real-World Effectiveness and Safety of Therapeutics at the University of Pennsylvania Perelman School of Medicine, said during a keynote presentation at the Dermatology in Pharma Educational Collaborative. There have been several high-impact changes to drug labels after successful citizen petitions to the FDA, Hennessy said, including relabeling over-the-counter cough and cold medicines to exclude their use in children aged younger than 2 years and the relabeling of gadolinium, a contrast agent used during MRIs, to note the risk for nephrogenic systemic fibrosis. The obesity drug sibutramine was voluntarily withdrawn from the U.S. market in 2010 after multiple citizen petitions citing data that showed an increased risk for heart attack or stroke, Hennessy said.
Hennessy was a senior author for a citizen petition to the FDA, which ultimately led to the relabeling of metformin, a first-line treatment for type 2 diabetes. In 2016, the FDA updated metformin’s label to reflect it is safe for people with diabetes and mild to moderate renal impairment.
The FDA receives about 200 such petitions yearly, according to the agency.
“One of the biggest health impacts I’ve made was through a citizen petition rather than through research,” Hennessy, also past scientific chair and past president of the International Society for Pharmacoepidemiology, said during the presentation. “Citizen’s petitions to the FDA are a mechanism by which citizens — all of us — can petition the FDA to make changes. [This process] permits any person to request that the FDA commissioner issue or manually revoke a regulation or order to take or refrain from taking any other form of administrative action. Anything that the FDA can do, we as citizens can ask the FDA to do or not to do. This is based on the First Amendment rights of citizens to petition the government for regressive grievances.”
Healio spoke with Hennessy about some of the unintended consequences of boxed warnings on drugs and the process to update a label when data suggest a change is needed.
Healio: What is a boxed warning and how does a drug approved by the FDA receive one?
Hennessy: A boxed warning — formerly known as a black box warning — is an elevated warning that is issued when either the company or the FDA, or both, thinks that it deserves this higher level of attention. It is the highest safety-related warning assigned to a medication by the FDA and it is intended to convey a major risk. Boxed warnings can be added, taken away or updated when new data suggest a change is needed.
Healio: In your keynote, you discussed some of the unintended consequences of a boxed warning when real-world data do not reflect the label’s stated risk. How might patients and physicians perceive these warnings?
Hennessy: My impression is that boxed warnings make people more concerned about the use of a drug, both from a clinical perspective and a medical-legal perspective. Physicians, pharmacists and other health care professionals may worry about getting sued if they do not follow a drug’s boxed warning. It increases the perception of liability, and perhaps the reality.
With metformin, as an example, the drug received a boxed warning about risk for lactic acidosis because of phenformin, a drug in the same pharmacologic class. Phenformin was taken off the market because it caused cases of lactic acidosis, some of which were serious and some of which were fatal. When metformin was considered for approval, it was painted with the same brush as phenformin. FDA took precautionary action and warned people against something that they thought might cause harm. Metformin received a boxed warning contraindicating its use for people with chronic kidney disease (CKD) and heart failure, since many of the people who developed lactic acidosis from phenformin had either heart failure or CKD. The FDA eliminated the heart failure contraindication for metformin back in 2006, but the contraindication for CKD remained on the label. In that case, the real-world evidence did not support the hypothesis that metformin increased the risk for lactic acidosis.
Healio: You highlighted several cases, like metformin, where data suggested a boxed warning should be updated or removed. What can be done in those instances?
Hennessy: For drugs that are on patent, there is a negotiation between the sponsor and the FDA. Sponsors need to provide the FDA with good reasons to change the label in the form of evidence — evidence that the drug does not cause the effect [noted in the boxed warning] and evidence that the warning label is resulting in clinical and public health harm because of underutilization of the product.
Individuals sometimes submit citizen petitions to the FDA, but most come from regulated industry, consumer groups or even state governments. Petitions to the FDA must contain several components, including the action requested; the factual and legal grounds for the petition, including all supporting material; the environmental impact, if any; a certification statement; and identifying information.
With the updated metformin label, there is evidence that the label change in 2016 did make a difference. According to a study, the label change increased the size of the population that was eligible to get metformin by something like 1 million to 2.5 million, depending on what numbers that you want to look at.
Healio: What makes for a successful citizen petition? What does one need to keep in mind when filing one?
Hennessy: The citizen petition asks FDA to do something specific, like change a label. It needs to provide a scientific and clinical basis for that.
In the case of metformin, that included providing evidence that people with diabetes taking metformin have the same rate of lactic acidosis as people with diabetes who do not take metformin. Then, we tried to quantify the number of people who are precluded from getting the drug, in our case metformin, because of the box contraindication, which was mild to moderate renal insufficiency.
So, our petition was not just providing evidence for the safety of the drug but providing evidence for the harm of the warning.
Healio: Anything else you want to add?
Hennessy: One, successful citizen petitions can have very large effects on the regulatory landscape, on drug use, and presumably on clinical care and public health. Two, successful petitions are most often led by health care professionals, academics, public health officials and those without a financial conflict of interest. Third, successful petitions need to make a compelling case that the proposed action is justified and will improve public health.
Finally, you need patience. The FDA is a big bureaucracy, and it does not move particularly quickly.
For more information:
Sean Hennessy, PharmD, PhD, can be reached at hennessy@pennmedicine.upenn.edu; X: @HennessySean.
Sources/Disclosures
Source:
Hennessy S. Improving the FDA label through real world data and public advocacy. Presented at: Dermatology in Pharma Educational Collaborative; Nov. 14, 2025; Philadelphia.
References:
Disclosures:
Hennessy reports no relevant financial disclosures.
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