The FDA has issued a warning letter to a Houston, Texas-based anesthesiologist for failing to submit an investigational new drug application (IND) and obtain informed consent as required in an anesthesia trial.

The warning letter cites Maggie Jeffries, owner of Avanti Anesthesiology and a specialist in ophthalmic anesthesia, for a lack of regulatory compliance during a trial involving oral drug combinations for anesthesia that she led as sponsor-investigator. Specifically, the FDA determined that the protocol had no IND in effect despite requiring one. An IND was necessary, the agency said, because the protocol involved administering diazepam, tramadol, ondansetron and MKO Melt (midazolam, ketamine and ondansetron) to assess and compare their efficacy for anesthesia in patients having cataract surgery.

Jeffries’ August 2021 response to the prior Form 483 issued contended that an IND wasn’t needed for several reasons: first, that MKO Melt has been in use for years, is not an investigational drug and is often used for sedation during cataract surgery; second, that the drugs in MKO Melt are well-known and frequently used in anesthesia practice; and lastly, that the study met the criteria for IND exemption.

The FDA, however, disagreed on these points, explaining its reasoning in the warning letter.

“[The protocol] required administration of specific drugs, depending on a randomization schedule; assessment and documentation of subjects’ answers to questions before discharge and the following day; and comparison of treatment arms to see how many subjects did not need extra medications during surgery,” the agency said. “The fact that the drugs individually can be part of a standard of care does not render these drugs non-interventions in a study setting, as was the case here, where the protocols prespecified the drug intervention to be administered.”

The protocol also failed to meet all criteria needed to be exempt from an IND, the agency determined, specifically that the investigation meets all informed consent/institutional review requirements and doesn’t involve a route of administration, dosage level, use in a population or other factor that significantly increases the risks, or decreases acceptability of risks, associated with use of the trial drugs.

The trial’s population — patients undergoing cataract surgery — significantly increased the risks associated with using tramadol alone and with diazepam. Despite this, safety measures, such as safety monitoring before, during and after surgery, adverse event monitoring, study stopping criteria and exclusion criteria, were not established, the FDA found.

In addition, the tramadol dosage level significantly increased the risks of its use, and the use of diazepam and tramadol together created the risk of profound sedation, respiratory depression, coma and death, as tramadol is an opioid agonist and diazepam is a benzodiazepine, the agency said.

With all this in mind, the FDA found that Jeffries also neglected to properly obtain informed consent by failing to identify experimental procedures and describe reasonably foreseeable risks to patients. According to the agency, the informed consent form read: “There are no additional risks or side effects associated with participation in the study. The risks of anesthesia are in the anesthesia consent and do not differ from what you would experience should you not participate in the study.”

In addition, a laminated copy of the consent form was given to patients while they waited for surgery, with personal copies only provided upon request.

Avanti Anesthesiology did not respond to a request for comment by deadline.

Read the full warning letter here: https://bit.ly/3Ft8GcJ.