Pink Sheet: 世界の薬事規制と承認審査に関するニュース
By John Davis 31 Mar 2020
This is an update of recommendations from the European Medicines Agency's Committee for Medicinal Products for Human Use on the...
US FDA advisory committee members say if SA4Ag is efficacious in ongoing trial of spinal surgery patients, efficacy data could support a broader claim encompassing limited number of other orthopedic procedures with similar pathophysiology and infection risk, such as hip and knee replacement surgeries.
Efficacy data for Pfizer Inc.'s Staphylococcus aureus vaccine SA4Ag in spinal surgery patients potentially could support approval in other types of orthopedic surgery patients, but not as many as the sponsor has proposed, US FDA advisory committee members concluded Nov. 7.
The majority of FDA's Vaccines and Related Biological Products Advisory Committee said that the S. aureus vaccine's efficacy could be generalized to patients undergoing elective orthopedic surgeries that are similar in scope, duration or infection risk to the spinal surgeries in Pifzer's ongoing Phase IIb STRIVE trial. For example, the efficacy data could support a broader claim for use in patients undergoing total hip and knee replacement surgeries.
However, committee members balked at the notion that STRIVE would support approval for prophylactic use ahead of other types of orthopedic surgical procedures for which the infection risk differs, such as patients undergoing tendon repairs and carpal tunnel surgery.
"If the vaccine is efficacious it could be generalized to other procedures with similar attack rates and similar risk factors, like the length of the surgery or the type of incision or the use of foreign materials in the surgery," said Karin Bok, senior vaccine science advisor at the National Vaccine Program Office.
And while most panelists were willing to accept some degree of extrapolation with the efficacy data to a broader population than that studied in STRIVE, several said they would nevertheless like to see some safety data in these other orthopedic surgical populations prior to approval.
FDA convened the meeting to discuss Pfizer's proposal to use safety and efficacy results from STRIVE (Study B3451002) as the primary data supporting a proposed indication in adults undergoing any elective orthopedic surgery. (Also see "Pfizer's Staph Vaccine: Can Narrow Trial Population Support Broader Claim?" - Pink Sheet, 3 Nov, 2017.)
STRIVE is a randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of a single intramuscular dose of the four-antigen vaccine in preventing postoperative invasive S. aureus disease in adults ages 18-85 years of age scheduled to undergo elective open, posterior approach, multilevel, instrumented, spinal fusion surgery. The trial began in July 2015; to date, approximately 1,900 subjects have been randomized from approximately 100 clinical sites.
Although STRIVE is currently a Phase IIb study, Pfizer is in talks with FDA to convert it to a Phase III study that would enroll a total of 6,000 subjects.
Although STRIVE is currently a Phase IIb study, Pfizer is in talks with FDA about converting it to a Phase III study that would enroll a total of 6,000 subjects (3,000 each in the vaccine and placebo arms).
William Gruber, Pfizer senior vice present of vaccine clinical research and development, said the company is committed to moving forward with expanding the trial to secure a broad indication for use. However, if FDA concludes a broader claim could not be supported by STRIVE beyond the spinal surgical setting, the company would need to reassess the resources needed to expand the study and could consider terminating it, he said.
Gruber highlighted challenges in conducting efficacy clinical trials in hip and knee replacement surgeries given the lower incidence rate of infections in those procedures relative to spinal surgeries.
For example, an efficacy trial in hip arthroplasty patients would require approximately 25,000 subjects for more than 10 years, while a study in knee arthroplasty patients would entail approximately 40,0000 subjects over 15 years, he said. In comparison, the Phase IIb/III STRIVE trial with 6,000 patients is anticipated to take six years to complete.
Gruber asserted the STRIVE population is representative of elective orthopedic surgery patients because the pathogenesis is similar across surgery types, patient demographics and risk factors for developing S. aureas surgical site infections are similar, and there are commonalities in procedural risk factors of orthopedic surgical site infections.
In Pfizer's view, the proposed indication would encompass various types of orthopedic procedures where the musculoskeletal system is the target of, and not incidental to, the surgery. (See box.)
"Our goal really is to have a broad indication and empower recommending bodies then to make judgments about the risk benefit profile," Gruber said.
However, panelist John Kirkpatrick, chief of orthopedic surgery at the Veterans Administration Medical Center in Orlando, Fla., pointed to differences in the pathophysiology and incidence of infections across the list of proposed surgical procedures.
Hip arthroplasty, knee arthroplasty and spinal fusion could all be encompassed within the same indication because they are similar from a pathophysiology perspective and involve implants, Kirkpatick said, whereas some other procedures on the list do not involve implants or do not currently require antimicrobial prophylaxis.
"I disagree with the opinion of Dr. Gruber that you should license everything and then let the medical team figure out what it is, because unfortunately the medical team doesn't police itself enough to stop using things that are approved that don't work," Kirkpatrick said. "I would much rather side on the FDA taking a stance and saying the things that have a valid scientific rationale, that pass the reasonable assurance of safety and efficacy, are reasonable to consider for this."
Melinda Wharton, director of the Centers for Disease Control and Prevention's Immunization Services Division, said the STRIVE trial seemed to be a reasonably stringent and pragmatic assessment of efficacy in an orthopedic surgical population.
"It is hard for me to believe that if the vaccine is effective in preventing staph infections in what are these relatively high-risk procedures that it would not also confer protection for procedures where the infection risks were not quite so high, so I am comfortable with generalizing," Wharton said.
"That does not mean of course that the vaccine should be used for all orthopedic procedures," she continued. "One would expect that clinical groups that make recommendations for vaccine use could address some of the nuances that might not be addressed in product labeling."
Janet Englund, director of pediatric transplant infectious diseases at Seattle Children's Hospital, said she would not go so far as to say the STRIVE data could be generalized to "other" elective orthopedic surgical populations.
"I could deal with replacing 'other' with 'similar,'" she said, distinguishing tendon surgery and other more minor procedures that carry less risk of infection and are shorter in duration than the spinal surgeries studied in STRIVE. "The company should be hearing it from us that we don't consider them all the same."
In addition, Englund said she would like to see more safety data, particularly for patients undergoing procedures that were not studied in STRIVE.
"I really think we need more safety data and I feel strongly that that could be separated … into another study in some of the knee replacement or some of the other [populations] where we don't really need to have a positive Staph aureus culture as an endpoint," she said.
Several other committee members echoed the call for a larger safety population that encompasses other types of surgical patients. However, this view was not uniformly shared by all committee members, with some saying they believed that safety data in the spinal surgery patients would be generalizable to other patients undergoing elective orthopedic procedures.
Pink Sheet: 世界の薬事規制と承認審査に関するニュース
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