Maggie Jeffries, M.D. / Avanti Anesthesiology, LLC

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site between July 19 and August 5, 2021. Investigator Andrea A. Branche, representing FDA, reviewed your conduct of the following clinical investigations:

Protocol ANES001, “Effects of Various PO Medication Combinations on Patient Satisfaction after Cataract Surgery,” of the investigational drugs diazepam, tramadol, ondansetron, and midazolam/ketamine HCl/ondansetron (MKO Melt®), which you performed as a sponsor-investigator

Protocol ANES002, “Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Midazolam and Ketamine following Administration of a Sublingual Formulation Containing Midazolam and Ketamine for Conscious Sedation,” of the investigational drug midazolam/ketamine HCl (MK Melt™), performed for Imprimis Pharmaceuticals

This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected.

At the conclusion of the inspection, Investigator Branche presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your August 12, 2021, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated August 12, 2021, it appears that you did not adhere to the applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in Title 21 of the Code of Federal Regulations, part 312 (21 CFR 312) governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:

FDA regulations require a sponsor to submit, and to have in effect, an investigational new drug application (IND) before initiating a clinical investigation of a drug subject to 21 CFR 312.2(a) (see 21 CFR 312.20 and 312.40(a)) in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2. You failed to comply with these requirements. You initiated and conducted a clinical investigation of investigational drugs subject to section 505 of the FD&C Act without submitting and having in effect an IND1. Specifically, you initiated and conducted the clinical investigation of the investigational drugs diazepam, tramadol, ondansetron, and MKO Melt® under Protocol ANES001, without having in effect an IND.

In your August 12, 2021, written response to the Form FDA 483, you stated that an IND was not needed. First, you claimed that MKO Melt® is not an investigational drug. You stated that MKO Melt® has been on the market for many years and is commonly used for sedation during cataract surgery, and that the drugs in MKO Melt® (midazolam, ketamine, and ondansetron) are well-known and commonly used in the practice of anesthesia. Second, you stated that the clinical investigation met the criteria in 21 CFR 312.2(b)(1) for exemption from the requirements of part 312.

We address both of your arguments below.

1. Protocol ANES001 was a clinical investigation of drugs subject to 21 CFR Part 312.

A clinical investigation is defined in 21 CFR 312.3(b) as “any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.”

The clinical investigation conducted under Protocol ANES001 involved the administration of diazepam, tramadol, ondansetron, and MKO Melt®, or some combination thereof, to human subjects. Based on the information collected on inspection, Protocol ANES001 was designed to study and compare the efficacy of these drugs for anesthesia. The protocol specified the drug intervention to be administered to subjects scheduled for cataract surgery according to a randomization schedule. As such, the clinical investigation limited clinical judgment and limited the interventions available for administration to each subject. FDA has long held that when an investigator limits his choices, his patients’ choices, and the choices of the people working for him in the treatment of those patients, he is conducting a clinical investigation. A clinical investigation differs from the practice of medicine because in the latter, the primary intent is to treat an individual patient.2 Therefore, the use of these drugs in Protocol ANES001 was not “in the course of medical practice.”

Your statement in your written response that MKO Melt® studied in Protocol ANES001 is not an investigational drug is not persuasive because it is inconsistent with the design and conduct of the clinical investigation. Specifically, Protocol ANES001 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. Finally, the fact that the drugs individually can be part of a standard of care does not render these drugs noninterventions in a study setting, as was the case here, where the protocols prespecified the drug intervention to be administered to subjects.

Consequently, the investigation conducted under Protocol ANES001 was a clinical investigation of the investigational drugs diazepam, tramadol, ondansetron, and MKO Melt®.

2. The clinical investigation conducted under Protocol ANES001 does not meet the exemption criteria in 21 CFR 312.2(b)(1) and is subject to the IND requirements under 21 CFR 312.

As noted above, FDA regulations require a sponsor to submit an IND before conducting a clinical investigation of a drug in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2(b). Under 21 CFR 312.2(b)(1), the clinical investigation of a lawfully marketed drug product in the United States is exempt from the IND regulations for a clinical investigation if all of the following exemption criteria are met:

1. The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use, and there is no intent to use the investigation to support any other significant change in the labeling of the drug.

2. In the case of a lawfully marketed prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.

3. The investigation does not involve a route of administration, dosage level, use in a patient population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.

4. The investigation is conducted in compliance with the requirements for institutional review set forth in 21 CFR part 56, and with the requirements for informed consent set forth in 21 CFR part 50.

5. The investigation is conducted in compliance with the requirements of 21 CFR 312.7.

The clinical investigation of the investigational drugs (diazepam, tramadol, ondansetron, and MKO Melt®) conducted under Protocol ANES001 did not meet the criteria listed at 21 CFR 312.2(b)(1).

Specifically, the investigation did not satisfy the third and fourth exemption criteria above.

With respect to the third criterion above, the clinical investigation conducted under Protocol ANES001 involved administering investigational drugs in a population, at a dosage level, and in a combination, that significantly increased the risks (or decreased the acceptability of the risks) associated with the use of the drugs.3

The clinical investigation conducted under Protocol ANES001 involved the administration of investigational drugs in subjects undergoing cataract surgery, a population that significantly increased the risks (or decreased the acceptability of the risks) associated with the use of the drug product tramadol, either alone or in combination with the drug product diazepam.

Administration of oral tramadol and oral diazepam in the cataract surgery population significantly increased the risks associated with the use of the drug products. According to the FDA-approved labeling for tramadol and diazepam, the terminal elimination half-lives of oral tramadol, tramadol’s active metabolite M1, diazepam, and diazepam’s active metabolite N-desmethyldiazepam are significantly longer (6, 7, up to 48, and up to 100 hours, respectively) than the average recovery time for cataract surgery (30 to 60 minutes). As such, the half-lives (the period of time required for the concentration or amount of drug in the body to be reduced by one-half) of the drugs will exceed the average recovery time, thus increasing subjects’ risk of adverse events.

The mean peak plasma concentration (the highest drug concentration after administration) of tramadol and its active metabolite M1 occur at 2 and 3 hours, respectively, which is significantly longer than the approximate duration of cataract surgery (15 to 60 minutes). Peak plasma concentration of tramadol and its active metabolite M1 would occur well after the end of cataract surgery, making tramadol unsuitable for use during cataract surgery because its maximum effect would not occur until after the end of cataract surgery, increasing the duration the subject may experience adverse events and the subject’s chance of experiencing adverse events after surgery. Thus, the administration of oral tramadol in the cataract surgery population significantly decreased the acceptability of risks associated with the use of the drug product.

In addition, the protocol involved a drug dosage level that significantly increased the risks (or decreased the acceptability of the risks) associated with the use of the drug product tramadol. Specifically, the study involved a tramadol dose of 100 mg regardless of hepatic function. However, the metabolism of tramadol and its active metabolite M1 are reduced in patients with hepatic impairment, resulting in longer elimination half-lives. A lower dose of tramadol is therefore recommended in this patient population. Thus, by using a tramadol dose of 100 mg regardless of the patient’s hepatic function, the study significantly increased the risks and/or decreased the acceptability of the risks associated with the use of the drug product.

Lastly, the protocol involved investigational drugs in combination that significantly increased the risks (or decreased the acceptability of the risks) associated with the use of the drug products diazepam and tramadol. The study involved concurrent administration of oral tramadol, an opioid agonist, and oral diazepam, a benzodiazepine. Concomitant use of opioids and benzodiazepines such as diazepam and tramadol may result in profound sedation, respiratory depression, coma, and death. Thus, the study significantly increased the risks and/or decreased the acceptability of the risks associated with the use of the drug products.

In your August 12, 2021, response, you stated that the drug doses used are in accordance with what is usual and customary in the administration of anesthesia. Your statement is factually incorrect, because the labeling of the respective drugs shows that neither oral tramadol nor oral diazepam are indicated for anesthesia. Your response did not address that the studies significantly increased the risks and/or decreased the acceptability of the risks to subjects associated with the use of these drug products, because you did not have measures in place to sufficiently guarantee the safety of study participants in the cataract surgery setting or in the setting of concomitant diazepam and tramadol use. For example, Study ANES001 did not provide suitable safety monitoring before, during, and after the surgery; adverse event (AE) monitoring; study stopping criteria; or exclusion criteria.

With respect to the fourth criterion above, you failed to conduct the investigation in compliance with informed consent requirements set forth in 21 CFR part 50. Specifically, you failed to give any subjects enrolled in your study under Protocol ANES001 a copy of the informed consent form, as required under 21 CFR 50.27(a). In your August 12, 2021, written response, you state that you had a laminated copy of the consent form that you gave to all subjects while they were waiting for surgery, and that you provided the subjects with a copy of the consent form only if they requested it.

In addition, you failed to obtain informed consent that identifies any procedures which are experimental and that describes reasonably foreseeable risks, as required under 50.25(a)(1) and (2). The informed consent form used in your clinical investigation does not identify any procedures which are experimental. The informed consent form states: “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.”

We acknowledge that the finding discussed above was not included on the Form FDA 483 you received, and therefore your written response does not address this specific issue. As a clinical investigator, you are responsible for compliance with all applicable FDA regulations governing the conduct of clinical investigations and the protection of human subjects, including the obtaining of informed consent in compliance with 21 CFR part 50. Failure to obtain informed consent in accordance with 21 CFR part 50 involving subjects in research jeopardizes the safety and welfare of subjects by denying them an opportunity to fully assess the risks and benefits of their participation in the clinical investigation.

As noted above, the investigation conducted under Protocol ANES001 was a clinical investigation as defined by 21 CFR 312.3 and is subject to the requirement that an IND must be in effect before initiation unless all the exemption criteria in 21 CFR 312.2(b)(1) are met. Because the administration of the investigational drugs (diazepam, tramadol, ondansetron, and MKO Melt®) in this clinical investigation significantly increased the risks and/or decreased the acceptability of the risks associated with the use of these drug products, and because you failed to conduct the investigation in compliance with the informed consent requirements set forth in 21 CFR part 50, the exemption criteria at 21 CFR 312.2(b)(1)(iii) and (iv) were not met, and under 21 CFR 312.20 and 312.40, you were required to submit and to have in effect an IND before initiating this clinical investigation.

Your written response did not provide any assurances of corrective actions or a corrective action plan explaining how you would comply with IND regulations moving forward. As a result, your response is inadequate. Without this information, we are unable to determine whether you will comply with IND regulations in the future.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address these deficiencies and establish procedures to ensure that any ongoing or future studies comply with FDA regulations.

This letter notifies you of our findings and provides you with an opportunity to address the deficiencies noted above. Within 15 business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to address this matter adequately may lead to regulatory action. If you believe that you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.

If you have any questions, please contact Miah Jung, Pharm.D., M.S., at 240-402-3728 or CDER-OSI-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:

Miah Jung, Pharm.D., M.S. Branch Chief Compliance Enforcement Branch Division of Enforcement and Postmarketing Safety Office of Scientific Investigations Office of Compliance Center for Drug Evaluation and Research U.S. Food and Drug Administration Building 51, Room 5219 10903 New Hampshire Avenue Silver Spring, MD 20993