A Rare Event, Scientific Close Calls and a Mishmash from 2004 at the Golden State's Stem Cell Program
Plus "on the fence about people on the fence" -- Ysabel Duron, CIRM director
It is not often that the $12 billion California stem cell agency breaks from its more than 17-year-old, decision-making mold. But it did so this week.
In a rare action on Tuesday, the agency’s directors rejected a $4 million proposal that had been approved by both the agency's grant reviewers and the agency's own staff. Since 2004 -- a period that involves thousands of applications -- the agency's directors have only once or twice turned down an application approved by its reviewers.
On the surface, the action this week amounted to nothing more than a simple 15-0 vote. But it also offered some insights into close calls on science, difficulties with the agency’s new, heavy emphasis on diversity, lack of information for the directors, nuances on scoring an application, muddled ballot initiatives and even a touch of conflicts of interest -- a matter that has plagued the agency since its inception.
At the center of all this is a UCLA-nurtured start-up called ImmunoVec, which sought the $4 million from the California Institute for Regenerative Medicine (CIRM), as the stem cell agency is legally known. The funds would have gone for a stem cell/gene therapy for X-linked chronic granulomatous disease (XCGD), a rare immune disorder that can be fatal.
During their meeting on Tuesday, the directors never mentioned UCLA or ImmunoVec. As usual, the directors had only brief information about the application minus the names of applicants and related institutions, a situation that some directors complained about at their very first award meeting in 2005. Nonetheless, the full application is still deemed to be confidential.
Last month, CIRM’s grant application reviewers, whose names are also withheld, voted, 8-7, in private to give ImmunoVec the $4 million. The application (CLIN1-13315) was additionally scored at 5.5 on a scale of 10 on its diversity, equity and inclusion (DEI) plan, a recent addition to applications. A score of five is described as “not responsive” to CIRM’s DEI requirements. A score of six is described as “responsive.”
The close, 8-7 scientific vote and the middling DEI score gave some CIRM directors pause. “I'm on the fence about people on the fence,” said Ysabel Duron, a patient advocate member of the board who has led the DEI effort.
CIRM Chair Jonathan Thomas said he was in favor of sending the proposal back to the applicant to work on the DEI requirements and to deal with the scientific concerns.
That’s when the board began to look for a way to reject the application without discouraging ImmunoVec. However, a motion had already been made to approve the application in combination with another clinical-stage application, which created a parliamentary muddle.
Torres and a conflict
At one point, Director Art Torres, who had a conflict of interest on the application and should not have spoken to it, suggested that a substitute motion be made. Ultimately the motion to approve the ImmunoVec application was withdrawn. Instead, directors voted, 15-0, to declare that improvement was needed in the proposal but also to encourage the applicant to resubmit it after the deficiencies were addressed.
During the meeting, the back-and-forth, actions and non-actions exposed some of the weaknesses built into CIRM by the ballot initiative that created it. One issue involves the board’s structural conflicts of interests. The initiative, which is now state law, declared that some organizations that benefit from CIRM’s largess must have seats at the table where the money is handed out.
As a result, the original board and now something called the Application Review Subcommittee (ARS) have become principally a rubber stamp for decisions made behind closed doors by reviewers who are not identified and who do not have to publicly disclose their personal or professional conflicts of interest.
The full CIRM board, which must disclose its 35 members' financial interests, does not actually approve grant applications. The formal approval is performed by the ARS, which is composed of 19 members of the full board. The subcommittee was created in 2012 because of the longstanding issues with conflicts of interest among board members.
That said, two members of the ARS, Torres and Karol Watson, were still identified by CIRM as having conflicts of interest on the ImmunoVec application. Torres is a member of the University of California board of regents. Watson is a professor of medicine at UCLA. That means that they could not vote on the application or speak on it because of ImmunoVec’s ties to UCLA.
Eight members of the ARS are also members of the grant review group, which means that they have access to application information that is denied to all the 27 other members of the full CIRM board. Often, the privileged eight carefully offer their perspective in public to other ARS members considering applications.
Inside CIRM Scoring
The measure that created CIRM did not address the specific scoring, the matter that troubled directors Tuesday. But the law requires a large quorum (65 percent) to be present for approval of awards. The actual number is determined by how many board members are eligible to vote. Conflicts have been so rife that many board members have been disqualified. The size of the quorums once dropped to as low as seven persons on a board that then had only 29 members compared to the current 35.
On other occasions, the CIRM board could not conduct business because of a lack of the super quorum. At one meeting in 2008, the board drafted a member of the audience to create a quorum.
The membership of the ARS was crafted in 2012 in such a way to be dominated by CIRM board members that have fewer conflicts. The restructuring reduced the quorum problems but also meant that a substantial number of board members were excluded from the essential purpose of CIRM — awarding research grants. (Here is how the super quorum stifled board members in the past.)
The technicalities of scoring may glaze over the eyes of many. But for applicants and patient advocates, the numbers and definitions can mean that their favored therapy or particular research lives or dies.
Currently, in clinical rounds, reviewers do not have a simple up-or-down choice. They have three possibilities. Number One is to approve the application. That was the action approved by reviewers and the staff on the ImmunoVec proposal. Choice Number Two denies funding and declares that the application “needs improvement…(and can) be resubmitted to address areas for improvement.” Choice Number Three denies funding and declares that the application should not be resubmitted in any form for six months.
Another type of scoring was added this year to rate applications formally on their diversity, equity and inclusion (DEI) plan. The scoring is not done by the scientific reviewers. It is only performed by the eight CIRM board members who are also members of the grant review group. ImmunoVec was given a score of 5.5 on a scale of 10 by the four unidentified CIRM directors who voted. (The agency said today that directors Al Rowlett, Christine Miaskowski, Fred Fisher, Mark Fischer-Colbri and David Higgins attended the review meeting.)
(You can see the scoring, votes, comments and more on the ImmunoVec review summary.)
Even before the ImmunoVec proposal came up Tuesday, questions were raised about the impact of DEI scores on the scientific score and the absence of a DEI template that could be used by applicant.
“The reviewers should be able to look at a template that shows the steps … (that applicants) have to engage in….So that there's no question about what the plan is,” said Duron. She was told by the CIRM staff that work had already begun on such a template.
The initiative that created much of the mishmash this week totaled 10,000 words in 2004. Today, it runs to 17,000 courtesy of Proposition 20 of 2020. Over the last 17 years, the CIRM board has had opportunities to attempt to clean up the initiative’s dubious requirements, minutia, micromanagement and improve CIRM’s charter. But they chose not to.
Over the next decade, CIRM directors will have fresh opportunities to make needed repairs before their cash runs out as it did two years ago. Making reforms will require legislation that has a high bar for passage and that will require compromise. But waiting until the last minute could leave the board holding an unfortunate bag that burdens CIRM and endangers future efforts to secure the funding necessary to sustain the nation's largest state stem cell research effort.
(For more on the longstanding issues created by the CIRM ballot initiatives, see the $700,000 National Academy of Medicine study and the Little Hoover Commission report. A summary of the Hoover recommendations can be found here.)
Labels: cirm future, ballot initiatives, sustainability, grantmaking, dei, conflicts of interest
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