FDA – Cooperative Agreement to Support an Evidence-Based Clinical Practice Guideline for the Safe Tapering of Benzodiazepines (U01) Clinical Trials Not Allowed

June 13, 2022 by dld5dt@virginia.edu


The U.S. Food and Drug Administration (FDA) seeks applications to develop, disseminate, implement, and evaluate an evidence-based Clinical Practice Guideline (CPG) for the safe tapering of benzodiazepines. Applicants must propose a comprehensive evidence-based plan that advances safe tapering of benzodiazepines.


Benzodiazepines are a class of drugs widely used to treat many conditions, including anxiety, insomnia, seizures, social phobia, and panic disorder. Benzodiazepines are also used as premedication before some medical procedures. However, it is important for prescribers to consider the risks of benzodiazepine misuse, abuse, addiction, physical dependence, and withdrawal, and monitor patients on therapy, even when patients take the medication as prescribed. Ensuring the availability of evidence-based, indication-specific prescribing information has always been part of FDA’s approach to ensuring the safe use of the products it regulates, including benzodiazepine products.

Recognizing the critical role that health care providers play in addressing this public health priority, FDA continues to assess the evidence on the use of benzodiazepines with a goal of improving benzodiazepine prescribing. While benzodiazepine prescribing has been trending down since 2013,[1] treatment with benzodiazepines is still widespread; in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient retail and mail-order pharmacies, according to a September 2020 FDA Drug Safety Communication (DSC).[2] Further, this DSC noted that patients are often treated for a long time; in 2018, around half of patients who were dispensed oral benzodiazepines received them for two months or longer. This duration of therapy is noteworthy because patients can experience withdrawal symptoms after discontinuation or dose reduction even when the patient uses the benzodiazepine as directed. Additionally, in 2020, almost 5 million people in the U.S. used benzodiazepines in a manner other than as directed by a physician.[3]

One particular area of need is information on the long-term use and safe tapering of benzodiazepines. Although clinical trials of three months’ duration are typically used to establish long-term efficacy in the context of drug development, the efficacy of benzodiazepines beyond three months has not been systematically evaluated. Continued use of benzodiazepines at therapeutic doses for a prolonged period may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after long-term use may precipitate acute withdrawal reactions, which can be life-threatening. Other risks associated with abrupt discontinuation or rapid dosage reduction of benzodiazepines include rebound and relapse of psychiatric symptoms or increased seizure frequency and status epilepticus in patients prescribed benzodiazepines for seizure indications. To reduce the risk of withdrawal reactions, rebound and relapse of psychiatric symptoms, or increased seizure frequency, a gradual taper to discontinue benzodiazepines or to reduce the dosage is generally recommended. However, an optimal benzodiazepine tapering schedule has not been systemically evaluated in patients on long-term benzodiazepine therapy.

Addressing the safe use of benzodiazepines is particularly important as FDA continues working to confront the staggering toll of the evolving drug overdose crisis. While the number of prescription opioids dispensed has steadily declined since 2012, opioid overdose deaths continue to rise. Over 107,000 Americans died of drug overdoses in 2021, according to the Centers for Disease Control and Prevention’s provisional estimates.[4] Other controlled substances, including benzodiazepines and stimulants, are frequently co-involved with opioids in overdose deaths. The highest number of overdose deaths involving benzodiazepines occurred in 2020, of which a small proportion occurred without any opioid.[5] Complicating overdose prevention efforts are falsified pills, widely available for sale on the street and the internet, that are made to look like prescription benzodiazepine products but may contain illicitly manufactured, unapproved benzodiazepine compounds, fentanyl, and other substances.[6],[7]

FDA’s work to address the safe use of benzodiazepines supports the Department of Health and Human Services (HHS) Overdose Prevention Strategy’s focus on primary prevention, as it is a key opportunity to reduce clinically inappropriate prescribing of medications with misuse potential.[8] The high volume of benzodiazepine prescribing, lack of systematic evaluation of patients on long-term benzodiazepine therapy, and lack of optimal benzodiazepine tapering schedule(s), among other factors, suggest that guidelines may be beneficial for health care providers, their patients, and public health. One approach to setting such standards would be to establish evidence-based clinical practice guidelines (CPGs) for the safe tapering of benzodiazepines.

Key Dates:

Open Date (Earliest Submission Date): June 3, 2022
Letter of Intent Due Date(s): June 23, 2022
Application Due Date(s): August 3, 2022, by 11:59 PM Eastern Time.

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Filed Under: Funding Opportunities