BETHESDA, MD 12 October 2012—As FDA this year reviewed a new drug application for phenylephrine hydrochloride injection, agency personnel were in a quandary. Should the agency approve a decades-old substance that has a pharmacologic effect but for which there is no firm evidence of a clinical benefit?
A group of advisers on September 13 said yes, but only for a narrow indication: neuraxial perioperative hypotension.
The advisers mostly said no—the vote was 2 against 8—regarding the proposed broad indication of "acute hypotensive states such as shock."
If agency personnel agree with those advisers, then phenylephrine hydrochloride injection, an acknowledged vasopressor, will at last have FDA-approved labeling.
FDA’s decision is expected by November 9, the nine-month review deadline under the Prescription Drug User Fee Act.
An unapproved drug. West-Ward Pharmaceutical Corp. admittedly based its new drug application on previously published literature and data the company does not own.
FDA, according to an internal review of the application, told West-Ward in advance that the literature lacked sufficient evidence of phenylephrine’s effectiveness. The studies underlying the literature did not seem adequately designed to show that a clinical outcome improved as a result of phenylephrine treatment, the reviewer wrote.
But, the reviewer continued, FDA told the company "it may be possible to approve phenylephrine to be marketed for increasing BP [blood pressure] in certain hypotensive states."
The company submitted the application in response to FDA’s Unapproved Drugs Initiative, which started in 2006.
As part of the initiative, FDA has been encouraging companies marketing unapproved drug products to comply with the drug approval process. Three companies, including West-Ward, manufacture phenylephrine injection for commercial distribution.
Literature review. Shari Targum, a medical team leader in FDA’s Division of Cardiovascular and Renal Products, said the studies of phenylephrine and the resultant publications raised three unusual issues.
First, the publications inconsistently described the primary endpoint.
Second, the studies sometimes had multiple endpoints but the publications did not describe any statistical adjustment for the multiple comparisons.
Third, the control drug in some of the studies was ephedrine—an unapproved drug.
"That said," Targum told the advisers during the public meeting, "I can say that there is evidence across multiple studies by different investigators that phenylephrine increases systolic and mean arterial blood pressure."
West-Ward’s search of the literature revealed 13 randomized controlled trials of phenylephrine injection in 750 patients.
Six of those studies, accounting for 68% of all the patients, involved women undergoing cesarean section who had received neuraxial anesthesia—an injection of anesthetic in their epidural space or spinal canal. Five studies involved surgery patients who had received general anesthesia. Two studies were of patients with septic shock.
The studies of the drug in patients with septic shock accounted for 11% of all the patients.
Need for vasopressors. John B. Leslie, a consultant to West-Ward and professor of anesthesiology at the Mayo Medical School in Rochester, Minnesota, said anesthesiologists always anticipate hypotension when administering neuraxial anesthesia.
Less so with general anesthesia, he told FDA’s advisers, although "hypotension is not uncommon." That is because patients typically have not eaten or drank anything since the preceding midnight, which predisposes them for mild hypovolemia with resultant hypotension.
The most common time for perioperative phenylephrine administration, Leslie said, is the interval between induction of anesthesia and the surgeon’s first incision. Once the surgeon cuts into the patient, blood pressure increases and the need for a vasopressor is over.
Leslie said phenylephrine’s effectiveness in treating perioperative hypotension is why he insists on having syringes of the vasopressor in his surgery packs at Mayo Clinic Hospital in Phoenix.
Indication. West-Ward proposed that FDA approve the drug for a relatively broad indication: "to increase blood pressure in acute hypotensive states, such as shock and peri-operative hypotension."
FDA’s Targum, in explaining the drug approval process to the advisers at the meeting, said a company needs only "an indication in a specific setting" to get a drug on the market.
Rather than vote on the indication proposed by West-Ward, the advisers decided to vote first on a narrower one that seemed well supported by the literature: neuraxial perioperative hypotension. Then they tackled what remained of the proposed indication.
If the agency were to reject the phenylephrine application, Targum said, clinicians would still be able to use the vasopressors dopamine and norepinephrine, which are FDA-approved drugs.
A lawyer representing other manufacturers of unapproved drugs called on FDA to be consistent in its requirements. He said FDA had told his clients that their new drug applications must present the results of studies conducted expressly to support drug approval.