Translating Research into Health Policy: The Citizen Petition Experience with the Food and Drug Administration

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Translating research findings into policy is important. Health policy researchers often testify before Congressional subcommittees and provide background on health policy issues. A rarely used, but important, tool for facilitating translation of research into policy is via filing a Citizen Petition.

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The United States Constitution protects the right of citizens to petition the government for “a redress of grievances.” This right has important implications for citizens desiring to advance the public health by petitioning administrative agencies, such as the Food and Drug Administration, to take safety actions. We examined a total of 1,915 petitions filed between 2001 and 2013 to investigate the outcomes of citizen petitions that address public health concerns. We found that most petitions were filed by manufacturers against other manufacturers. Only 346 (18%) of all petitions were submitted by individuals and non-profit organizations, and 178 (87.3%) of these petitions with a final response were denied. On average, these petitions required 2.85 years for a final agency decision, and many decisions remain pending 10–13 years after their initial submission. The great majority of the approved requests included some form of risk communication, such as labeling changes, boxed warnings or placement of a drug into a Risk Evaluation and Mitigation Strategy. As a policy instrument to improve the safety of medical and food products, the citizen petition process requires sophisticated legal and scientific expertise, and may not represent a viable route for ordinary citizens to petition the FDA to “redress grievances.”
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Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizen petition filed to address these thalidomide safety issues. Case study. The AG petitioned the FDA requesting thalidomide-related safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved. New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon.
Brand-name drug companies have been filing citizen petitions with the Food and Drug Administration expressing concerns about generic drugs under review, in last-ditch efforts to hold off competition. A promising solution lies in erecting procedural blocks.
The First Amendment to the US Constitution guarantees “the right of the petition the Government for a redress of grievances.” When it comes to the regulation of drugs and protection of public health, individuals have the right to address their concerns by directly petitioning the US Food and Drug Administration (FDA). Any person (including a non-US citizen) can request that the FDA “issue, amend, or revoke a regulation or order or take or refrain from taking any other form of administrative action.” Although healthcare professionals rarely submit such petitions, they can exert a powerful impact on the labeling requirements for drugs. Metformin is one such example. Metformin is widely accepted as the first-line drug for the treatment of type 2 diabetes mellitus. It effectively lowers hemoglobin A1c levels by 1% to 2% and is weight neutral, safe, and inexpensive. Moreover, one trial demonstrated that it reduces cardiovascular disease complications in patients with newly diagnosed type 2 diabetes mellitus. When metformin was first approved in 1994, it was contraindicated in patients with heart failure and in those with elevated creatinine levels because of concerns about lactic acidosis. This restriction on drug use usually necessitated a switch from metformin to a glucose-lowering agent in a different category, one that frequently carried other risks (such as hypoglycemia), appreciably increased cost, or both. In 2006, the FDA eliminated the heart failure contraindication in response to 2 observational studies.1 These studies suggested that metformin is safe and may actually confer mortality benefits in patients with heart failure.1 However, the contraindication in patients with elevated creatinine levels remained unchanged. Since then, concerns over lactic acidosis have been examined and found to be largely unfounded unless kidney disease is advanced. On the basis of the available data, metformin can be used safely …
Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100,000 person-years to 10 per 100,000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus--use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.
In recent years, brand-name drug companies have engaged in an array of conduct that has delayed generic competition. While some of the activity — such as settlements between brand and generic firms and “product hopping” from one drug version to another — has received attention, another behavior has, until now, flown under the radar. This Article examines the activity of “citizen petitions.” A citizen petition is a request for the U.S. Food and Drug Administration (FDA) to take an action such as evaluating a drug’s safety or effectiveness. When used appropriately, it could raise awareness of legitimate concerns with a drug. But when used inappropriately, it could extend the brand firm’s monopoly by delaying FDA approval of generic drugs. This delay could result in literally millions of dollars a day being transferred from consumers to drug companies. Despite their delaying potential, citizen petitions have not been examined in significant detail. This Article offers the first empirical study of citizen petitions, reviewing every petition filed with the FDA between 2001 and 2010. It finds that petitions have increased in the past decade and that 68% of petitions are filed by brand companies, with more than 75% of brand petitions targeting generic drugs. The study concludes that the FDA has granted 19% of citizen petitions and has denied 81%. It finds that generics’ petitions are more successful, with 28% granted and 72% denied, as compared to brands’ petitions, of which 19% are granted and 81% denied. To reduce delays from petitions, Congress enacted legislation in 2007 that required the FDA to rule on certain petitions within 180 days. This study finds that this legislation has not been successful in reducing the number of petitions. After passage of the legislation, the average number of filings per year increased from 27 to 34. Brand petitions against generics increased from 9 to 16 per year. And the grant rate for brands’ petitions against generics declined from 20% to 19%. Building on the empirical study, the Article highlights the incentives brand firms have to file petitions, along with the role petitions play in the toolbox of delaying conduct. It also introduces examples that demonstrate the problem, such as the petitions delaying (1) depression drug Wellbutrin for 133 days at a cost to consumers of $600 million and (2) insomnia drug Ambien for 1225 days at a cost of $3.1 billion. The landscape in the pharmaceutical industry today is ripe for petitions, with an impending “patent cliff,” declining drug-company profits, and increased use of related conduct such as brand-generic settlements and product hopping. As a tool that is being used more frequently and that has evaded attempts to limit its abusive potential, citizen petitions warrant scrutiny.
The U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS), familiarly known as "MedWatch," is the nation's primary tool for postmarket pharmaceutical safety surveillance. This system relies on adverse events voluntarily reported by health care providers and consumers either directly to the FDA or to drug manufacturers, which are required to prepare and forward the information to the agency. Little is known about how frequently adverse events are reported. Previous estimates range from 1 to 31% depending on the event, drug, and time period. We used published incidence studies to calculate reporting rates for hemorrhage, emergency hospitalization, and venous thromboembolism (VTE) associated with four drugs. We estimated annual reporting rates of 1.07% for 33,171 emergency hospitalizations of patients older than 65 years associated with warfarin, 0.9% for 13,363 hospitalizations of clopidogrel and ticlopidine, and 1.02% for an estimated 67,200 hemorrhage cases associated with warfarin. We also estimated a 9-year reporting rate of 2.3% for VTE associated with thalidomide. The incidence of these hematologic adverse drug events is high and reporting rates are low, and near the lower boundary of the 1 to 15% range seen for other events.
To the Editor: The immunomodulatory drugs thalidomide and lenalidomide recently received US Food and Drug Administration approval for the treatment of multiple myeloma.¹- 4 Venous thromboembolism (VTE) is a potentially serious complication associated with their use.⁵- 8 We conducted a systematic review of thromboembolism occurring with immunomodulatory drug treatment of cancer.
Epoetin therapy for dialysis-related anemia is the single largest Medicare drug expenditure. The type of facility (profit, chain, and affiliation status) at which a patient receives dialysis might affect epoetin dosing patterns and has implications for future epoetin policies. To examine the association between dialysis facility ownership and the dose of epoetin administered. Data from the US Renal Data System were used to identify 159,522 adult Medicare-eligible, end-stage renal disease patients receiving in-center hemodialysis during November and December 2004. Regression models were used to estimate the mean epoetin dose and dose adjustment by profit, chain, and affiliation status. Weekly mean epoetin dose administered in December 2004 and the adjustment in dose between November and December 2004. Compared with patients in nonprofit dialysis facilities (n = 28,199), patients in large for-profit dialysis chain facilities (n = 106,116) were consistently administered the highest doses of epoetin regardless of anemia status. Compared with nonprofit facilities, for-profit facilities administered, on average, an additional 3306 U/wk of epoetin. Among the 6 large chain facilities with a similar patient case-mix, the average dose of epoetin ranged from 17,832 U/wk at chain 5 (nonprofit facilities with a mean hematocrit level of 34.6%) to 24,986 U/wk at chain 2 (for-profit facilities with a mean hematocrit level of 36.5%). Dosing adjustments also differed by type of facility. On average, compared with nonprofit facilities, for-profit facilities increased epoetin doses 3-fold for patients with hematocrit levels of less 33% and also increased the doses among patients with hematocrit levels in the recommended target of 33% to 36%, especially in the largest for-profit chain facilities. The greatest difference in dosing practice patterns between facilities was found among patients with hematocrit levels of less than 33%. Dialysis facility organizational status and ownership are associated with variation in epoetin dosing in the United States. Different epoetin dosing patterns suggest that large for-profit chain facilities used larger dose adjustments and targeted higher hematocrit levels.
FDA Center for drug evaluation and research. Response to Citizen Petition FDA-2009-P-0246 for Label Change for Epogen®
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  • Director
Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer
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  • C Angelotta
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University of Pennsylvania and Cornell University Petition. Citizen Petition to revise the label of Metformin Google Scholar
  • Regulations
  • Gov
Letter to Dr. Charles L. Bennett (re FDA-P-2014-1611). University of South Carolina
  • J Woodcock