MGI Pharma’s Aquavan(R) (fospropofol) is a phosphate prodrug of the anesthetic propofol. Propofol must be administered by an anesthesiologist because of its rapid onset.
A slow onset of sedation would reduce the likelihood of sudden and unexpected general anesthesia. MGI hoped that this delay would allow it to obtain an indication that would lift the restriction on use only by anesthesiologists, vastly increasing the value. Additionally, while propofol’s low aqueous solubility requires a lipid emulsion, fospropofol is water soluble. Alas, the advisory committee voted 8-2 against the broadened indication, meaning it will compete head-to-head with propofol.
The news and company press release headlines indicated the advisory committee approved fospropofol, 6-3. True – for the same labeling as propofol. Comment: Why do news wires always reuse the headline of press releases without thinking them through?
Predictably, the American Society of Anesthesiologists were against the expanded use by non-trained doctors.
Due to pk differences, MGI conducted a Phase 2 dose-ranging study. Once dose was selected, they conducted 2 Phase 3 studies with an arm of midazolam, a drug of choice for non-anesthesiologists. The Phase 3 studies were performed by non-anesthesiologists. Yet, the advisory committee noted that the protocol for these studies wasn’t real-world. They worried that AE’s would be like propofol and thus truly require an anesthesiologist. Hence, the final result.
Prodrugs are submitted under 505(b)(2). The advisory committee said the safety and efficacy were similar to propofol, only dosing and product form differed. The phase 3 studies were conducted to get labeling that differed from the RLD. It would appear that MGI failed to get this labeling.