Avastin Withdrawal Showed Accelerated Approval Hearing Process No Easy Task For US FDA
Executive Summary
Internal emails show the 2011 hearing on Genentech’s VEGF-inhibitor was taxing for FDA employees, who had to deal with a number of novel issues; the workload is likely to be similarly complex for staff involved in upcoming hearing on Covis’ preterm birth prevention drug Makena.
With the US Food and Drug Administration still strained by the COVID-19 pandemic, the last thing the agency needs is a lengthy administrative proceeding that drains time and resources.
However, that’s the direction in which the agency is headed with the forthcoming public hearing on the Center for Drug Evaluation and Research’s proposal to withdraw accelerated approval of Covis Pharma's preterm birth prevention drug Makena (hydroxyprogesterone caproate).
In October 2020, CDER proposed withdrawing Makena’s approval on the basis that the PROLONG confirmatory trial failed to verify clinical benefit and Makena has not been shown to be effective under its conditions of use. (Also see "Accelerated Approval: US FDA Request For Makena’s Withdrawal Goes Beyond Failed Confirmatory Trial" - Pink Sheet, 5 Oct, 2020.) Covis objected to CDER’s proposal and requested a hearing, which the FDA has granted but not yet scheduled. (Also see "US FDA Chief Scientist Hinton’s Departure Leaves Vacancy Atop Makena Decision Tree" - Pink Sheet, 1 Nov, 2021.)
Ironically, Makena received accelerated approval in February 2011, the same month in which the FDA’s then-commissioner, Margaret Hamburg, granted Genentech, Inc.’s request for a hearing on CDER’s proposal to withdraw accelerated approval of the breast cancer claim for Avastin (bevacizumab). (Also see "FDA Grants Hearing To Appeal Avastin Breast Cancer Withdrawal" - Pink Sheet, 24 Feb, 2011.)
That hearing, which took place over two days in June 2011, was the first withdrawal proceeding under the agency’s accelerated approval regulations. As such, it serves not only as a guidepost for the logistics of the Makena hearing more than 10 years later, but also a harbinger of the work to come for agency staff in gearing up for this proceeding.
The Makena matter is already proceeding at a much slower pace than did the Avastin withdrawal. (See sidebar for comparative timeline.)
After Hamburg ordered the breast cancer claim withdrawn, the Pink Sheet submitted a Freedom of Information Act request for Avastin-related internal communications, emails, memoranda, meeting minutes and calendar entries from 16 December 2010 to 18 November 2011 for individuals in CDER, CBER and the Office of the Commissioner (OC) who played key roles in the proceeding. (Karen Midthun, director of CBER at the time, served as presiding officer for the Avastin hearing.)
The FDA took more than six years to complete fulfillment of the FOIA request, which resulted in more than 2,300 pages of emails and other documents produced by CDER, 126 pages from CBER and 200 pages from OC.
Although many of the internal emails were heavily redacted, it is nevertheless readily apparent that the withdrawal process as a whole, and the hearing specifically, created a huge workload for those agency staff involved.
The emails show the challenges in adhering to the separation of functions between the CDER team that proposed the indication’s withdrawal, and the commissioner’s team that would hear the dispute between the drugs center and Genentech.
The internal emails show the challenges in adhering to the separation of functions between the CDER team that had proposed the indication’s withdrawal, and the commissioner’s team that would hear the dispute between CDER and Genentech.
Internal Avastin-related emails were inadvertently directed to people on the other team, and individuals had to be removed from various distribution lists due to what one email termed the “wall of silence.” There also were questions as to whether and how the separation of functions applied to advisory committee management staff.
The agency also has adopted a separation of functions approach for the Makena matter.
Each CDER submission to the Avastin hearing docket required numerous levels of input, circulation of drafts, fine tuning, clearance and sign-off by multiple parties. There were extensive email chains with changes to the center’s slide presentation for the hearing, as well as concerns about ensuring version control and addressing factual errors resulting from attempts to “dummy down” technical language.
Attorneys on the CDER team weighed how to present the core questions to Midthun, the presiding officer, noting “this is the first time we’ve done this, and we need to make a strategic (and legal) call on how to frame the questions.”
Preparing for the hearing also involved regular in-person meetings weekly, and sometimes more frequently, among the CDER team, with some Sunday sessions at the agency’s White Oak, Md. headquarters.
“It was definitely above and beyond the usual workload that we were having meetings on Saturdays and Sundays and lots of prep sessions to make sure the process is well laid out, the presentations were very clear,” a former senior FDA official with knowledge of the process said in an interview with the Pink Sheet. “It was people working above and beyond their usual work.”
Public Interest
Staff on the CDER and OC teams were keenly aware of attention being paid to the Avastin withdrawal proceeding outside of the agency by breast cancer patients, health care providers and members of Congress, among other stakeholders. FDA staff were on the receiving end of sometimes hostile and profane emails and phone calls from patients and their families.
At one point, Patricia Keegan, who at the time was director of the Division of Biologic Oncology Products, raised concerns about CDER sending “stock responses” to patients and family members who emailed the agency upset about the potential withdrawal, and she urged consideration for how such standard replies would be received.
Keegan suggested assigning a specific person “who is familiar with the sensitivity of this issue” to respond to Avastin commentary from patients.
CDER and OC staff also had to handle requests for information from Congress and proposed appropriations language regarding Avastin.
Dealing With ODAC Members
One of the challenges for those organizing the hearing was dealing with the concerns of members of the Oncologic Drugs Advisory Committee who were expected to participate in the hearing.
One ODAC member had previously agreed to take part in the Avastin hearing but, upon receipt of the conflict-of-interesting screening in April 2011, began to have a change of heart. “Arghh. Not sure I want to be at this one. Lots of politics,” the committee member said in an email. This individual had attended one of the two prior ODAC meetings on the Avastin breast cancer indication.
The email prompted a discussion among advisory committee staff as to whether training for new advisory committee members addresses agency expectations for an individual’s participation at meetings.
Michael Ortwerth, who at the time was director of the Advisory Committee Oversight and Management Staff, suggested this individual could be offered the opportunity to resign if he does not believe he is willing to participate in ODAC meetings due to possible controversy surrounding a topic. “As we all know, many of our meetings are controversial,” Ortwerth said in an internal email.
One advisory committee member expressed concern that Genentech would single out ODAC members, publicly delving into their expertise and questioning their competency to judge the product.
In a separate email, Ortwerth said the agency generally expects advisory committee members to participate in meetings unless they have a scheduling conflict or wish to recuse themselves due to potential financial conflicts of interest. “We cannot force a member to participate. However, I believe there is no reason why we could not ask a member if the topics that the committee may discuss would impact their willingness to serve on the committee and if they would wish to resign from the committee.”
Some potential panelists also worried about their professional reputations and how they would be treated by Genentech.
One member expressed concern that Genentech would single out ODAC members, publicly delving into their expertise and questioning their competency to judge the product.
Another ODAC member asked whether committee members could be questioned by attorneys for either CDER or Genentech, and whether committee members are protected from being subpoenaed in any possible future judicial action.
In a response to the latter, advisory committee staff said they did not expect there to be questioning of the ODAC members by attorneys from either CDER or Genentech at the hearing, and no time was allotted for this on the draft agenda. Furthermore, ODAC members would not be involved in any judicial review in the event Genentech brought a court challenge against a final FDA decision ordering the indication withdrawn.
“If as an advisory committee member you are ever contacted by a law firm regarding your participation at an advisory committee meeting, your role as an advisory committee member, etc., we ask that you please do not respond and notify your FDA advisory committee contact … as soon as possible as we at FDA would then forward this information to our Office of Regulatory Affairs that handle all legal notices or documents that are received by advisory committee members in regards to advisory committee matters,” an email from advisory committee staff said.
Not Your Typical Adcomm
In the lead-up to the June 2011 hearing, CDER had to wrangle with logistical issues it normally does not encounter at regular advisory committee meetings. For example, the CDER team had to run its own slides, a task usually handled by advisory committee staff at regular panel meetings.
Both the CDER and Genentech teams did a joint walk-through of the Great Room at the White Oak headquarters one month prior to the hearing. However, CDER’s request for permission to rehearse for the hearing in the Great Room raised concerns among agency staff that doing so would be unfair to Genentech. Instead, the CDER team had multiple rehearsals elsewhere on the White Oak campus, in addition to individual team member prep sessions.
Action items from a 3 June 2011 CDER team meeting ranged from the technical – locating a clinical trials expert to review Genentech’s confirmatory trial proposal and estimate a timeline for recruiting 700 subjects – to the mundane – “find a ‘runner’ for copies etc, and someone that can pick up lunch.”
The hearing was conducted on 28-29 June and involved presentations by CDER and Genentech, as well as a two-hour period for public testimony during which more than 30 people testified, with many patients, family members and physicians urging the FDA to keep the indication on label.
On the first day of the hearing, a patient advocacy group protested on the White Oak campus, an event for which CDER and OC staff were given advance warning.
(See sidebar for reflections from former FDA officials and advisory committee members on the two-day Avastin hearing.)
At the end of the two days, ODAC voted 6-0 in favor of withdrawal, and the final tally sparked disruptions among audience members in the meeting room.
In a 30 June email, Midthun conveyed her thanks to those on the OC team involved in conducting the hearing.
“I want to express my gratitude to each of you for your tireless dedication and hard work leading up to and during this hearing,” she wrote. “I know there was much work that went on behind the scenes and your efforts resulted in a meeting that went very smoothly.”
Decision Day
The OC had intended to announce the final decision on Avastin on Monday, 14 November 2011. However, the Avastin announcement was delayed because the Department of Health and Human Services was planning a big, unrelated announcement involving the Centers for Medicare and Medicaid Services the same day.
In a 17 November email, the commissioner’s office informed counsel for Genentech and CDER that Hamburg’s decision would be posted at 10:30 a.m. the following day and would be available to everyone at the same time.
That timeline for the Avastin decision led Richard Pazdur, who at the time was director of the Office of Hematology and Oncology Products, to ask if OHOP could announce the approval of EUSA Pharma Inc.’s acute lymphoblastic leukemia treatment Erwinaze (asparaginase Erwinia chrysanthemi) at 8:30 a.m. or earlier on 18 November “to avoid the Avastin fiasco.” (Also see "Erwinaze And The Blessings Of A Missed PDUFA Goal" - Pink Sheet, 1 Jan, 2012.)
On the day of the Avastin decision, some members of the CDER team “huddled” in a room on the White Oak campus to await the announcement.
In an internal email to OHOP after the decision was announced, an oncology team leader congratulated “all who worked so hard on this. … It is gratifying to know that there are times when the data actually wins the day. Now everyone get ready for the political and emotional uproar.”