FDA issues guidance on developing long-acting local anesthetics

The US Food and Drug Administration (FDA) has issued draft guidance on the development of local anesthetic products with a prolonged duration of effect that can last for days.
 
The guidance, published on 16 March 2023, is part of a larger effort to reduce the use of opioid analgesic drugs, according to FDA. “Although different local anesthetic drug products have different pharmacokinetic (PK) profiles, in general their effects last a few hours. However, the increasing interest in reducing or eliminating the use of opioid analgesic drug products is leading to development of dosage forms of local anesthetic drug products that prolong the duration of action of the drug product to a period of days rather than hours,” the agency wrote.
 
The guidance focuses on the development of local anesthetic drug products that produce postoperative analgesia and which require a new drug application (NDA) under section 505(b) of the Federal Food, Drug, and Cosmetic Act.
 
Development plans
 
FDA recommends that sponsors discuss their development plans early on with Division of Anesthesiology, Addiction Medicine, and Pain Medicine in FDA’s Center for Drug Evaluation and Research. That discussion should include any planned comparative bioavailability studies and efficacy and safety studies.
 
Additionally, development programs should be conducted in a sequential matter, starting with in vitro studies to characterize the drug release profile. Following that, sponsors should conduct initial PK studies to identify doses and dosing regimens. With that initial work done, sponsors should then conduct safety and efficacy studies that are designed to support the proposed indication. The number, type and design of the safety and efficacy studies will depend on several factors, including whether the product is the first modified-release formulation for an existing immediate-released local anesthetic product and if there are significant differences compared to the listed drug.
 
In some cases, clinical efficacy and safety studies may not be necessary to support approval, but sponsors will need to submit data to characterize local drug exposure as well as systemic drug exposure. “Because of the unique product-specific characteristics of local anesthetic drug products with prolonged duration of effect, if a sponsor decides to conduct only relative bioavailability PK studies to support its local anesthetic drug product, or is considering exploring a modeling approach with available in vitro and in vivo data, the sponsor should discuss the plans with the Division early in the drug product development program,” the agency wrote.
 
Efficacy and safety
 
For new local anesthetic drug products, at least two adequate and well-controlled studies are necessary to support a surgery-specific or anatomical site-specific indication. In the case of a modified-release formulation of a previously approved local anesthetic product, at least one adequate and well-controlled trial is needed for a surgery-specific or anatomical site-specific indication.
 
The recommended primary efficacy endpoint for evaluating postoperative analgesic effect is the area under the curve (AUC) of pain scores. FDA noted that the clinical pain score used should be validated in the patient population being studied.
 
FDA advised that the safety evaluation should address the general safety implications of extending the duration of action of the product, the safety of any novel inactive ingredients, the risks of site of administration wounds and infections, risks of systemic exposure, risks of neurologic deficits or sensory/motor deficits, the safety of repeated dosing, and the compatibility with coadministration of other anesthetic products.
 
Comments on the draft guidance can be submitted to regulations.gov and labeled as Docket No. FDA-2023-D-0608. The public comment period closes on 14 June 2023.
 
Local anesthetic drug product guidance