The $13 Million Matter of DR3-07201: Allegations of Conflict of Interest at the California Stem Cell Agency

In an unusual move last December, the California stem cell agency removed – with no public explanation – an application for $13 million from consideration by its governing board.

That application is now back before the board on Thursday and is almost certain to be rejected.

What is missing, however, are important specifics about the matter. They are cloaked by the agency's rules that conceal most of the CIRM grant review process, including the names of applicants along with the identities of reviewers and their economic and professional interests. Also shrouded are the details of any complaints about conflicts of interest as well as any other appeals.

Nonetheless, since the proposal was listed on the agenda of a public meeting of a state agency, it is known that it involves application DR3-07201. The unidentified applicant, according to a CIRM summary, sought $13 million for research into a treatment for heart failure, a therapy that is labeled by the applicant in all capital letters as “DYNAMIC.”

The agency's scientific reviewers last year recommended rejection of the request for funding. The agency's review summary said,

“The major serious criticism and flaw stems from the fact that the applicant is currently evaluating the same cellular product in a Phase 1/2 trial in a different subgroup of cardiac patients. Since the objectives of the proposed and currently enrolling trials are similar, reviewers agreed that the proposed Phase 1 trial does not add value and should be re-evaluated after completion and analysis of data from the current trial .”

No scientific score was released for the review but it was last on the list of all applications in this particular round. The agency usually lists the applications in order of their scores.

Following the removal of the application from the board agenda, the California Stem Cell Report in December inquired about the reason. Kevin McCormack, senior director of communications, replied via email,

“We received a last-minute appeal based on an alleged conflict of interest.  In order to allow time to review the claim, we deferred action.  We have done this previously, though I don’t have an exact count.”

When the application popped up on the agenda for this week's meeting, we inquired again, seeking more information. That was seven days ago.

The answer came in the form of a posting yesterday on the CIRM Web site of a one-page memo dated March 7 from Gil Sambrano, CIRM's associate director, review. In the note to the CIRM board, Sambrano said a conflict of interest allegation was raised by the applicant on the morning of Dec. 12, 2013, the day on which the application was to be considered. Sambrano said,

“The applicant alleged that the GWG (grant working group) review of the proposed project may have been 'tainted' by the 'perceived lack of objectivity' of one member of the GWG. There was no specific basis to support a financial, professional or personal conflict as defined in the GWG conflict of interest policy.”

Sambrano said the investigation into the complaint determined there was no violation of the agency's conflict of interest rules. He said,

“We found no evidence that the reviewer had any significant influence on the score or the recommendation. The reviewer was not an assigned reviewer and therefore did not contribute a written critique to the panel. Consistent with the recollection of the review chair and CIRM science officers in attendance, the discussion notes suggest that this reviewer did not provide any comment either in favor or against the proposal. The individual score given by the reviewer was very close to the mean score and thus did not contribute to the broad standard deviation.”

Sambrano continued,

“The applicant also submitted a request for reconsideration based on material new information. Although the applicant provided some information that is new, it did not directly address the main concern of reviewers and therefore did not provide adequate grounds for reconsideration. The request was denied.”

Sambrano said the agency took an additional step of seeking the opinion of two new expert reviewers and the chair of the grant review group. He said they did not find the new information “compelling.”

Reviewer Joyce Frey-Vasconcells was barred from participating in the review of the application, according to its CIRM review summary. Other reviewers in the round who could participate in assessing the application included Joy Cavagnaro, Raj Chopra, Derek J. Hei, Hassan Movahhed and Andrew Balber. Their names were listed on review summaries on other applications in the round where they had conflicts of interest, either professional or economic.

The applicant's appeal does not necessarily end with the CIRM staff decision. The applicant can appear before the board in public on Thursday and seek to overturn the action or ask for further investigation. It can also send material to the agency for delivery to all board members. 

As mentioned previously, the name of the applicant was withheld by the stem cell agency. But it could likely be discerned by a knowledgeable stem cell researcher based on information contained in the review summary. If the applicant would like to send both of its appeals to the California Stem Cell Report, we would be glad to carry their full text and any additional commentary that the applicant would like to make. Other applicants have done so in the past. The agency has no prohibition against such an action and actually has a term for it – self-disclosure.

Our take: The stem cell agency's appeal process ill serves the California public, grant applicants and CIRM itself. The $3 billion agency's reliance on secrecy only raises more questions about cronyism and unfairness, some of which have dogged CIRM since its inception. The recent flap over the $40 million genomics round is only the most recent example. Roughly 90 percent of all the cash handed out by CIRM has gone to institutions that are represented on its governing board, which sets the rules for the grant-making process and determines the nature of the grants. The board's conflicts are built in by Prop. 71, the measure that created the agency in 2004. The only genuine way to ameliorate the issue is with more transparency.

Critiquing the California Stem Cell Story: 'Continuums' vs. Cures

It was a genuine “where's the beef” session for California's nearly 10-year-old, $3 billion state stem cell agency.

A member of the only state body legally delegated to oversee the California Instititute of Regenerative Medicine (CIRM) and its governing board wanted an answer to a simple question: What cures has the agency produced as promised during the 2004 ballot campaign that created the state program?

The occasion was a meeting Jan. 22 in downtown Los Angeles of the Citizens Financial Accountability and Oversight Committee, a group headed by state controller John Chiang. It meets once a year to examine the activities of the agency.

Jim Lott
COPE photo

Jim Lott, a long-time member of the panel and an executive vice president of COPE Health Solutions of Los Angeles, was pressing CIRM Chairman Jonathan Thomas and Ellen Feigal, CIRM's senior vice president for research and development.

According to the transcript, Lott, who described himself as a “big supporter” of CIRM, said, 

“I think when many voted for this, they thought there were going to be some cures coming out of this effort. And my bias is I have a 13-year-old daughter who has a spinal cord injury, partial break. I'd like to go home and tell my wife that this did something to advance the medical therapy that will ultimately provide her with the opportunity to walk again. What can you tell me that we've done that's going to get my daughter out of her wheelchair sooner (rather) than later after all this money has been spent?”

Thomas and Feigal struggled at some length to give him satisfying answers to his question. 

It was a tough series of exchanges with Thomas and Feigal talking about “incremental” work and “continuums” along with unrealistic, high expectations raised by the 2004 campaign. Those expectations burden the agency's current efforts to find new funding for awards beyond 2017, when the cash runs out.

At one point, Lott said it would be a “hard sell” to get voters to back more funding. Thomas acknowledged that and said it is “not stuff that readily translates into good sound bites.”

“You don't have a good message,” Lott said, declaring that he raised the issue two years ago.

“You guys are not speaking to people in ways that they understand the value of what you are doing. And that bothers the heck out of me.”  

Here is an exchange from early in the meeting involving Feigal and Lott, who has spent 23 years in the California hospital industry.

Lott:

“What can we say we've done to advance to a cure or to cures? It's fine that we've got all -- we've contributed to all. What can you say that we've actually done? We don't really have any -- I'm going to just say this because it's a bias and I know it's a bias. We don't have any tangible specific and measurable results that I can point to.”

Ellen Feigal

Feigal:

“Actually –”

Lott:

“Tell me if I'm wrong and demonstrate it to me. I want to understand where the results are.”

Feigal:

“So I'm happy to tell you the results, but I guess the issue is the expectations. And when this was funded, it probably was an expectation that (if we) give them money and within a very, very, very short period of time, and frankly ten years is a relatively short period of time, and, as you may not know, the funding didn't start till 2006, but if you try -- we're trying to do things in a very accelerated way. The funding actually for the disease teams and strategic partnerships just started three years ago. Part of it is advancing....”

Feigal continued in that vein for a few more minutes. Lott then asked about CIRM's return on investment(ROI), which amounts to $6 billion that the state will have to pay to support the agency, including the interest on the money that was borrowed for grants.

Jonathan Thomas
CIRM photo

Thomas, a bond financier from Los Angeles, jumped in,

“The results are, do we have any cures? No, we don't have any cures, but the results are many. They're incremental, but they are all moving along a research continuum that any sort of drug therapy would follow.....”

Lott:

“Here's my problem. As you said earlier, and I agree with it completely, I think it's a question of expectations. I know when I voted for this, and I did vote for it, I had some expectations. And my expectations were (that) we were going to see something in terms of cures at the end of the rainbow after we spend $3 billion, whatever it is that we're spending here.

“So when I asked for an ROI -- and I do understand what you are trying to tell us. I do get it, but it's not translatable. It doesn't translate to the expectations that many of us voters had.”

Lott kept coming back to his essential question

“The point is if we did spend all this money, what did we
get for it?”

Thomas and Feigal, aided by their Power Point presentations, continued to talk about CIRM's partnerships, disease teams and funding mechanisms.

Thomas:

“So if we do go back for a subsequent bond measure, I think we will be able to tell a story that will make California proud of being on the cutting edge and having facilitated the acceleration of the research, which, as Ellen said --”

Lott:

“Not if you don't get beyond the marketing problem you got. I'm telling you, pal, I would have a hard time voting for it again."

Thomas:

“That's fair.”

Our take: The California stem cell agency is virtually unknown to most of the people of California, which is not an unusual situation for most state agencies. Since Thomas was elected chairman in 2011, however, it has vastly improved its communications efforts. Nonetheless, it has not fulfilled the campaign promises of cures and won't be able to do so in the next two years. It does have a story to tell, albeit one that does not fit with the mythology of magical stem cells. Telling that story is hindered by mind-numbing Power Point presentations, which are little more than outlines that would be better replaced by nuanced, written documents. The challenge for the agency is to present not only the dry numbers but package the key figures with information that will connect viscerally and persuade people of the virtues of CIRM. Packaging and sizzle are the watchwords, depending on the audience. Each group has different concerns that need to be researched in advance and then addressed in tailored presentations. Whether CIRM's efforts so far have been worth $6 billion remains to be determined, but it is clear that it has not yet made its best case.

Japanese and California Stem Cell Affairs: An Opportunity to Make a Connection

This baby is a spin-off in Japan from CIRM-financed research.  Kazuhiro Kawamura 

of the St. Mariana School of Medicine delivered the child, which he is holding.

 (Kawamura photo)

Scientists and other stem cell fanciers in Japan will have their first chance this Thursday to take part in a meeting of the governing board of the $3 billion California stem cell agency.

Ken Burtis
UC Davis photo

That's because one of the board members, Ken Burtis of UC Davis, is in Nara, Japan, for a visit on the day of the meeting in Burlingame, Ca. He will be linked to the session via a telephone connection. It will be a two-way hookup that the public can use to participate, a requirement of California state law.

Stem cells are a hot scientific and commercial topic in Japan. According to an article last November in the Japan Times, the country's regenerative medicine market is expected to climb to $15.85 billion in 2030, up from $260 million in 2012. Japan is also the home of the induced pluripotent stem cell, which was first produced there.

Burtis is a professor of genetics and provost at UC Davis. It was not immediately known whether his visit to Japan involved UC Davis, the stem cell agency or was personal.

Burtis' access to the stem cell meeting, which includes a lengthy briefing on the agency's development portfolio, will be from the Hotel Nikko in Nara. Interested parties will be able to participate from the room in which Burtis is monitoring the meeting. However, the meeting agenda does not specify a room number. That will have to be obtained by emailing the stem cell agency at info@cirm.ca.gov. It is best to do that well in advance of the meeting.

This week's meeting has nothing specific on the agenda related to Japanese stem cell affairs, but stem cell research is a global matter. Researchers and others in Japan may well learn something new, particularly from the briefing on the agency's portfolio, and will have an opportunity to pose questions. Additionally, the board will be considering $72 million in "concept" proposals to speed commercialization of stem cell research, which could well be of interest to Japanese stem cell researchers and biotech firms even if they are not eligible for awards.

The California stem cell agency, which is known as CIRM, has also had a collaborative arrangement with Japan Science and Technology Agency since 2008.

Masaya Nakamura
Keio photo

Aileen Anderson
UCI photo

The agreement has resulted in one collaborative funding project involving Aileen Anderson of UC Irvine and Masaya Nakamura of Keio University. Anderson has received $1.3 million from CIRM, which did not announce the amount of funding that Japan provided to Nakamura.

Aaron Hsueh
AFP photo

Aaron Hsueh of Stanford received $2 million from CIRM for work that later led to a novel way of treating some forms of infertility and further work with Japanese researchers. One child has been born in Japan using the techninque. Kazuhiro Kawamura (pictured at the top of this item) and others at St. Mariana University School of Medicine were involved in that effort, which was not funded by CIRM. Another woman was pregnant as of October 2013. No information about the result of that pregnancy was immediately available. (See here and here.)

(Editor's note: This item has been altered slightly from the original version to make it clearer what is on the agenda this Thursday and its relationship to Japan. The headline has been reworded. No information has been dropped.) 

Science and Blogging: A STAP Stem Cell Case Study

It is a story that has to do with high priests, cloistered discussions and the glacial pace of scientific research.

The tale involves George Daley of Harvard, Paul Knoepfler of UC Davis and Japanese and Massachusetts researchers who say they can create STAP cells with an acid bath.

Let's start with the acid bath research, which rocked the stem cell world a few weeks ago. The apparently simple method of generating cells surprised nearly all researchers, some of whom expressed skepticism.

Paul Knoepfler

Paul Knoepfler is one scientist whose analysis of the research was available for the world to see on his blog, ipscell.com. Knoepfler is also one of the few stem cell researchers to blog about their field, a matter that troubles some scientists.

In recent weeks, Knoepfler has carried polls about the STAP research, interviewed two of the researchers involved and encouraged efforts at replicating the findings., among other things. He has even drawn some tentative conclusions. All of which does not necessarily meet with the approval of George Daley. He was quoted in the Boston Globe yesterday by Carolyn Johnson as saying,

“I am concerned about the rush to use blogging and social media to report early experience with a complex biological experiment. Most scientific experiments take time and many replications to work confidently, and early reporting may reflect a negative bias.” 

Within hours Knoepfler, whose blogging on STAP has drawn widespread attention, took a politely different view about the use of the social media and science. He wrote that social media has had a "strongly positive impact" on the discussion of the STAP cell research. He said it has facilitated international communication in a way that the traditional venues could not have done. Knoepfler wrote,

 “Journals are far too slow and frankly just too politically correct.”

He continued,

 “I suspect that in (a) hypothetical social media-less reality there would be no Nature or RIKEN investigations going on to help clarify certain elements of the STAP situation. I’m convinced there would also have been no detailed STAP protocol put out there in the public domain as we saw pop up yesterday. The two STAP Nature papers would also almost certainly still be behind pay walls instead of openly available via my request to Nature to make them that way. 

“Yet at the same time dozens of labs would still be trying STAP-related experiments relatively in the dark and unconnected to each other, wasting time, reagents, and other resources. For a long time, in that hypothetical scenario, only Nature, RIKEN, and the STAP authors themselves would have entirely controlled the flow of information about STAP cells. With all due respect I don’t think that would have benefited the stem cell field.”

Jeanne Loring

As of this writing, Knoepfler's item on the use of social media has drawn six comments. One came from Jeanne Loring, head of the Scripps stem cell program. She said,

“I think this was a successful experiment – a lab meeting without borders. Imagine that a STAP researcher was reporting her results at a lab meeting – you and the hundreds of others in your worldwide lab would be obligated to give critical feedback. The authors shouldn’t feel any more personally attacked than they would if their colleagues in the meeting were criticizing their work. This should be familiar to everyone who works in a lab.”

Our take: Every major enterprise, but perhaps more so in science, contains its high priests, individuals who control discussion and formally or informally lay down rules. Then there are institutions and vested interests that collaborate on setting the standards, such as permitting discussions in only certain cloistered venues, away from the untidiness that might involve the public or those deemed to be ill-informed or whose views are unwelcome. Along with that comes inertia, an unwillingness to change and resistance to new techniques. All of which leads to glacially slow dissemination of information that could speed research and development of therapies that could save lives.

Michael Eisen

Michael Eisen, a scientist at UC Berkeley, weighs in on this topic regularly. In a blog item September 2012, he noted that most papers that had been submitted 10 months earlier to journals were still languishing on some editor's or reviewer's desk.

“Consider that most papers submitted to journals last November 26th have still not been published. That’s not a random date – it happens to be the day NASA launched an Atlas rocket carrying the Mars Scientific Laboratory from Cape Canaveral.

“While, on Earth, scientific papers were languishing in editorial purgatory and peer review, bouncing back and forth while authors attempted to cater to some reviewer’s whim, maybe went to another journal, and then sat around in production for months while the awaited online publication, an SUV-sized robot made its way to another planet, landed with pinpoint accuracy on the surface and started beaming back pictures. NASA 1. Publishing 0.”

Use of the social media is unsettling to many scientists. Nonetheless, it is a fact of life. Its use will inevitably grow. Like newspapers, the reach and role of the journals are diminishing. The only question is how fast. For researchers to turn their back now on a key information sharing tool such as social media would be like rejecting the microscope because of wariness about new-fangled gizmos and their reliability.

There is another bottom line on all this: Money. One of the reasons for the financial plight of the NIH and research funding is the lack of widespread, public enthusiasm for research. If research funding had the kind of constituency that Social Security and Medicare have, there would be few problems with cash for scientific grants. While research funding is unlikely to ever achieve that sort of support, it can improve its public standing by artful use of social media. Mastering those techniques should be high on the agenda of every researcher in the country.

Craig Venter's "Road to the Cure" Stem Cell Venture

Craig Venter aboard his research yacht in 2004.
Sidney Morning Herald/Dallas Kilponen photo

Craig Venter, the international genomics superstar, is staking out a claim on stem cell turf.

The move comes with the formation of Human Longevity, Inc.(HLI), Venter's new company in the La Jolla, Ca., area.

Venter kicked off the enterprise this week with the announcement that it had $70 million in backing. The company press release said the firm is a “a genomics and cell therapy–based diagnostic and therapeutic company focused on extending the healthy, high performance human life span.''

Most of the news coverage concentrated on genomics. But the firm's press release also said,

“The company will be embarking on an ambitious multi-pronged effort utilizing stem cell therapy advances to enhance and improve the healthy life span. HLI's work is premised on the theory that as the human body ages many biological changes occur, including substantial changes and degradation to the genome of the differentiated, specialized cells found in all body tissues. There is also a depletion and degradation of healthy regenerative stem cell populations in the body over time. HLI will monitor the genomic changes which occur during stem cell differentiation, normal aging, and in association with the onset of disease.

"'The global market for healthy human longevity is enormous with total healthcare expenditures in those 65 and older running well over $7 trillion,' said Dr. (Bob) Hariri. 'We believe that HLI's unique science and technology, along with our business leadership, will positively impact the healthcare market with novel diagnostics and therapeutics.'"

Bob Hariri
HLI photo

Hariri. the former CEO of Celgene Cellular Therapeutics, is vice chairman and co-founder of the new firm, which is located on a street called “Road to the Cure.”

Writing on Biopolitical Times, Pete Shanks of the Center for Genetics and Society in Berkeley picked up part of the conference call earlier this week announcing the company. Shanks said, .

"Asked on this conference call if HLI would be in touch with the new Sanford Stem Cell Clinical Center (at UC San Diego), Venter blandly noted that Larry Goldstein, who heads the center, is on the HLI advisory board. (Peter) Diamandis added:

'Stay tuned for more announcements on the stem cell side.'"

Diamandis is a co-founder of the firm and CEO of the X Prize Foundation. The Sanford stem cell center was funded with $100 million last fall from billionaire Denny Sanford. Goldstein has received $21 million in funding from the California stem cell agency. Three other representatives from UC San Diego are on the HLI scientific advisory board including David Brenner, a longtime member of the governing board of the California stem cell agency.

Venter was a featured speaker at a California stem cell agency governing board meeting in 2012. The J. Craig Venter Institute is a partner in the $40 million genomics stem cell award made by the agency to a team led by Stanford in January during a controversial award process.

Sangamo and the California Stem Cell Agency: Good News for Both

Sangamo Biosciences is one of the California stem cell agency award recipients that is again surfacing in the news in a way that could ultimately burnish the reputation of the $3 billion research enterprise.

Sangamo, a publicly traded company based in Richmond, Ca., popped up in a story in the New York Times dealing with the search for a cure for AIDS involving researchers at the University of Pennsylvania.

Sangamo is also involved in another AIDS research project financed by the stem cell agency at the City of Hope and USC.  The company produces a gene-editing tool and its stock price is soaring. 

The Times story by Denise Grady reported on the phase one clinical trial at the University of Pennsylvania. She wrote,

“The idea of genetically altering people’s cells to make them resist the virus that causes AIDS may seem like a pipe dream, but a new report suggests it can be done.

“The research involves the first use in humans of 'gene editing,' a treatment that zeros in on a particular gene and disables it.”

We asked the stem cell agency how the trial fits with the work financed by CIRM. Kevin McCormack, senior director for communications, replied,

“On first glance it looks as if this works with the CD4 t-cells while the work we are financing focuses on a similar approach but perhaps the best explanation of the difference comes from this section of the original application from John Zaia's team at City of Hope that is partnering with Sangamo. 

“'Recently, ZFNs have been shown to inactivate CCR5 in primary human CD4 T cells, allowing them to preferentially survive and expand in the presence of HIV. A human clinical trial evaluating this approach is on-going, in which patient T cells are re-infused after ZFN-treatment to block CCR5 expression and possibly provide an HIV-resistant reservoir of CD4 T cells (THIS IS THE PIECE IN THE NY TIMES ARTICLE). The CIRM Disease Team proposes an approach to modify a patient’s own HSC to circumvent the need to find matched donors that carry the Δ32 CCR5 mutation and yet provide a renewable and long-lasting source of HIV-resistant cells.'”

Sangamo's stock has climbed dramatically this year. On Jan. 9,  based on news of an investment in the company by Biogen Idec, Sangamo opened at $15.70, rose to $19.12 and closed at $18.88. The volume of shares traded was 10.4 million. The average volume of trading over has been well less than 1 million for most of the last 12 months.

Today the stock closed at $22.96, up from $18.92 at the Tuesday close, the day before the clinical trial news surfaced. Volume hit 11 million shares. Sangamo's 52-week low is $6.86.  

$145 Million Bond Sale Next Month for California Stem Cell Agency

The state of California will offer up $1.6 billion in general obligation bonds next week but none will be for the state stem cell agency.

The next round of bond funding involving the agency is scheduled for April 22 with $145 million slated to go for stem cell financing, Tom Dresslar of the state treasurer's office told the California Stem Cell Report.

The $3 billion agency is financed through state borrowing (bonds), which roughly doubles the cost of its activities because of the interest expense on the bonds. The state currently provides cash to the agency via short-term debt (commercial paper). Then the state sells taxable bonds to repay the short-term debt.

During the 2004 ballot campaign for Prop. 71, the public was led to believe that the agency would be financed with non-taxable bonds, which would have meant lower borrowing costs for the state to the tune of hundreds of millions of dollars.

In 2007, Bernadette Tansey, then of the San Francisco Chronicle, reported that Robert Klein, head of the Prop. 71 campaign and first chairman of the stem cell agency, knew that taxable bonds were likely to be required but did not disclose that fact to the public.

$72 Million for Commercial Stem Cell Therapies?

The $3 billion California stem cell agency next week is likely to move to pump about 12 percent of its remaining, dwindling cash into business-friendly efforts to develop commercial therapies.

Coming before the agency's governing board on March 13 are two “concept” proposals for grant and loan programs totaling $72 million that are in line with CIRM's drive towards the marketplace and fulfillment of the promises of the 2004 ballot campaign that created the agency.

The proposals are coming from the agency's staff and fit with the strategic direction of the board. Such proposals have almost never been rejected in the past. But the board has demonstrated some fiscal concern in recent months as its uncommitted funds have shrunk to roughly $600 million, according an estimate presented by agency Chairman Jonathan Thomas in late January. The agency is scheduled to run out of cash for new awards in 2017.

The largest new proposal before the board would provide up to $40 million for four or five preclinical development awards. They would be aimed at development activities prior to a phase one clinical trial and at helping to attract future funding. Businesses and non-profits would eligible with businesses possibly taking a forgivable loan.

The second proposal would provide up to $32 million for possibly three awards in the agency's strategic partnership program ranging from $10 million to $12 million. The objective would be completion of a phase one or phase two clinical trial within three years. Matching funding would be required. Both businesses and non-profits would be eligible with forgivable loans a possibility for businesses.

If potential competitors for the awards are interested in shaping the direction of the proposals, next week's meeting in Burlingame is the time to appear before the board. The next step is posting a request for applications, scheduled for April and May. Board action on applications would come early next year.

$40 Million California Genomics Award: Missing Names of Conflicted Reviewers Disclosed

When the governing board of the California stem cell agency last month considered proposals for a $40 million genomics stem cell center, it failed to disclose the names of the grant reviewers who were barred from reviewing the applications because of conflicts of interest.

Normally, the names are reported to the public when the $3 billion agency posts summaries of the reviews of applications – prior to consideration of the proposals by the agency's board.

The departure from the agency's normal grant-making procedures is not the first in the genomics round, which is the subject of an internal examination by the agency that includes the board's outside counsel, James Harrison of Remcho Johansen and Purcell of San Leandro, Ca. Allegations of conflicts of interest and complaints about the role of CIRM President Alan Trounson, score manipulation, irregularities and unfairness have been raised.

It is unlikely that the normal disclosure of conflicted reviewers' names would have affected the outcome of the genomic awards at the governing board meeting Jan. 29. However, if questions had been raised at the public board meeting about the absence of the names, concerns about the closed-door review process may well have been elevated, given the earlier conflict-of-interest violation involving reviewer Lee Hood.  

The names of the reviewers with conflicts were added to the review summaries this week following an inquiry Monday by the California Stem Cell Report, which sought to double-check the apparent fact that no reviewers were in conflict since none were listed as recused.

Kevin McCormack, senior director for communications for the agency, replied,

“There were some conflicts of interest with the genomics review but apparently there is a bug in our data system, which is why they aren't showing up. We're going to fix that so thanks for bringing it to our attention.”

Here are the names of the reviewers now listed on the CIRM review summaries as being recused and the four applications involved. The four were recommended for funding by reviewers.

Stanford-Salk's winning application, Richard Gibbs, Maynard Olson; UCLA, Bradley Bernstein, Richard Gibbs, Aarno Palotie, Barry Rosen; Scripps-Illumina, Maynard Olson, Martin Pera, Jared Roach; UC San Francisco–UC Berkeley, none.

Robert Klein, the California Stem Cell Agency and a $5 Billion Proposal

The California stem cell agency last week put a little distance between it and its former chairman, Robert Klein, who is currently touting a new, $5 billion bond measure to rescue the agency from its financial demise.

The agency's comments came in response to a news story about comments that Klein, a Palo Alto real estate investment banker, made at a symposium at UC San Diego's Moores Cancer Center.

Bradley Fikes of the San Diego U-T wrote a story on Feb. 20 about the appearance that was headlined “$5B initiative proposed for stem cell research.” Fikes said,

“Supporters of California’s multibillion-dollar stem cell program plan to ask for $5 billion more to bring the fruits of research to patients.”

Fikes reported that Klein said “he’s going to be talking with California voters about the proposal. If the public seems receptive, backers will work to get an initiative on the 2016 ballot to extend funding for the California Institute for Regenerative Medicine(CIRM).”

Klein, who left the agency nearly three years ago, has talked for several years about another bond measure on top of the $3 billion, 10-year borrowing effort approved by voters for CIRM in 2004. His latest statements are the first in which he has publicly specified a figure.

In the wake of Fikes' story, the California Stem Cell Report asked the agency for a comment on Klein's remarks and his current role at the agency. Kevin McCormack, senior director for communications, replied Friday,

“Bob has been talking about a new bond initiative for a couple of years now so this is not altogether surprising. However, our focus remains where it always is, on our mission and the progress that is being made by CIRM-funded researchers to find new treatments and cures for patients, and we are continuing to explore avenues to sustain that progress.”

Currently the agency is looking into some sort of public-private arrangement that could finance its operations beyond 2017, when funds will run out for new awards. The 2004 initiative limited the agency's $3 billion bond authorization to only 10 years. CIRM is counting the 10 years as beginning from the date the first bonds were sold.

So far, the assumed public contribution for CIRM's future is a fraction of what Klein is touting – only $200 million.

Klein's public appearances around the state talking up another bond measure raise questions about how his efforts fit with the planning of the agency itself and the financial explorations of the current chairman, Jonathan Thomas, a Los Angeles bond financier, and other members of the CIRM board. California policy makers, potential wealthy donors, foundations and corporations may well be confused about whether Klein is speaking for the agency either directly or indirectly.

Given McCormack's carefully worded statement, it is reasonable to assume that CIRM is not entirely enthusiastic about Klein's bond measure pronouncements.

Additionally, premature discussion of more state borrowing, which has been criticized by Gov. Jerry Brown, could lead to a hardening of positions at an early stage. In 2011, when Klein initially broached another bond issue, the San Jose Mercury News said in an editorial,

“What planet are these guys from?....Going back for more would make no sense regardless of the economy....”

Board Counsel at California Stem Cell Agency Engaged in Examination of $40 Million Genomics Award

The California stem cell agency yesterday confirmed that the counsel to its governing board, James Harrison, is involved in the examination of its $40 million genomics round, which has been criticized for irregularities, unfairness,score manipulation and the role of its president, Alan Trounson.

Harrison has been with the board since its inception and wrote parts of Proposition 71, the ballot initiative that created the $3 billion research effort in 2004. Harrison, who is a partner in the Remcho Johansen & Purcell law firm of San Leandro, Ca., also has expertise in conflicts of interest and ethics. He is on contract with the agency and is not an employee.

In response to a question Feb. 8, asking whether Harrison was looking into the grant review process in the genomics round, Kevin McCormack, senior director for communications, confirmed that the agency was examining how the applications were handled. However, he did not reply directly to the question of whether Harrison was involved in the inquiry.

After being asked again yesterday, McCormack said,

“As you know after every review we go back to see what we could have done better and that usually involves several staff members at the agency, including James, who look at what happened and try to identify ways to improve next time.”  

Stem Cell Blog Hits High Seas

This blog will go dark for a week or so while we make a passage north from Huatulco to Zihuatanejo in Mexico. For those who don't know, the publisher of this enterprise and his wife live fulltime on a sailboat in Mexico, moving from place to place from time to time. For those who are interested in that sort of business, you can read about it on hopalongchronicles.com.

California Stem Cell Agency Shies Away from a $200 Million Possibility

The California stem cell agency has backed far, far away from a tobacco tax initiative that would provide it with more than $200 million a year – funds that could save it from an untimely demise in a few short years.

The leadership of the $3 billion enterprise fears that the tobacco industry would tar the entire stem cell research field in a no-holds-barred ballot campaign financed with $50 million or more.

CIRM Chairman Jonathan Thomas said that the tobacco industry would paint “a very negative, and unnecessarily so, picture of stem cell research and would very likely result in a measure that would go down and create a chilling effect on the view of all the good we've done.”

In a reference to the tobacco industry, he said,

“These guys, they play for keeps, and they say things in their ads...that are misleading or inaccurate, but there's nothing you can do about it.”

Thomas said that initially the ballot proposal sounded “great” but after agency officials talked to political consultants and pollsters, their perspective changed.

He said that he understood that the agency is being written out of the proposed initiative which is aimed at funding a wide range of brain research.

Thomas made his comments at a meeting of the only state body charged with overseeing the finances of the stem cell agency – the Citizens Financial Accountability and Oversight Committee, which is chaired by State Controller John Chiang. Thomas was commenting in connection with the fact that the agency will run out of funds for new grants in the latter part of 2017.

Our take: Thomas is correct that it would be a bloody campaign. Stem cell research is a big target. However, the tobacco industry is even bigger. It needed to spend $50 million to very narrowly defeat a similar tax measure in 2012 by only 30,000 votes out of 5 million cast.

A successful campaign for the stem cell agency would be about life (stem cells) versus death (tobacco). Indeed, a truly vicious campaign by the tobacco industry could well backfire on the industry, creating even more antipathy and animosity than now exists. A winning ballot measure also needs a good villain to help rally support. In 2004, when the stem cell agency was created, the campaign had that villain -- former President George Bush and his restrictions on human embryonic stem cell research. 

A ballot proposal could win but it would take a united front, an early start and a willingness to take some fire.

Important policy issues, however, would arise involving dedication of tax revenues for a specific purpose, one of the reasons the state of California has had financial difficulties.

All of which is moot since the agency has made it clear that it is not game for the battle.

Amid Allegations of Unfairness, California's Stem Cell Agency Begins Examination of $40 Million Genomics Award Round

The California stem cell agency today said it has begun an examination of the grant review process in its $40 million genomics round, which has been criticized for irregularities, unfairness, score manipulation and the role of its president, Alan Trounson.

The agency confirmed the inquiry after the California Stem Cell Report asked last Thursday asked whether the board's counsel, James Harrison, was looking into the matter.

Kevin McCormack, senior director for CIRM communications, replied today in an email,

“There are always ways in which we can improve our performance, and we regularly review our processes to try and ensure we do a better job with each round of funding. We have been looking into the genomics award to identify areas where we can improve the process for future awards.” 

McCormack did not specifically respond to the question of Harrison's involvement. We have queried McCormack again about whether Harrison is involved. (McCormack subsequently confirmed Harrison's participation.)

Harrison, who is with Remcho Johansen and Purcell of San Leandro, Ca., has been outside counsel to the board since its inception. He drafted portions of Proposition 71, which created the $3 billion research effort in 2004. Harrison has expertise in conflict of interest and ethics issues as well as other related public policy matters.

Harrison's role at the agency exceeds that of a simple attorney. His length of service, knowledge and skills give him much wider influence.

CIRM's examination of the genomics round review followed complaints from rejected applicants and others about the process, which has been covered extensively by the California Stem Cell Report.

Trounson has come in for criticism in connection with the review and his subsequent recommendation in favor of the successful Stanford-led bid. One of the critics is Jeanne Loring, head of the stem cell program at the Scripps Research Institute and whose genomic application was rejected by Trounson and the CIRM staff. Her application and two others were recommended for funding by reviewers. Loring has contradicted Trounson's assertion that all applicants were given information that matching funds were part of the review criteria. Her application contained none. Stanford said it had $7 million.

Loring said that Trounson has interfered in CIRM's review processes in favor of Stanford. Trounson has been a guest at a Montana ranch owned by Irv Weissman, head of the Stanford stem cell program. Trounson did recuse himself in an earlier round involving an application linked to Weissman, but did not recuse himself in the genomics round.

Weissman was not listed in the latest Stanford application, but was in its original version. The associate director of Weissman's Stanford stem cell institute, Michael Clarke, was included in the final CIRM-approved version. Trounson lauded Clarke at the governing board's meeting last month in support of the Stanford project.

Correction

The “genomics award” item on Feb. 9 erroneously identified Stanford researcher Michael Clarke as William Clarke.  

California's $40 Million Stem Cell Genomics Award: Irregularities, Complaints and Integrity

A number of firsts were recorded last month as the California stem cell agency gave $40 million to a Stanford-led consortium to put California in the global forefront of stem cell genomics.

Not all of those firsts necessarily enhanced the reputation of the California Institute of Regenerative Medicine (CIRM), as the $3 billion agency is formally known.

The unusual events and irregularities surrounding the award, CIRM's largest research grant, merit additional attention, given their implications about the integrity of the agency's grant review process and how the agency does its business.

The California Stem Cell Report recently asked a number of persons connected with the round and other knowledgeable individuals about the process. Their comments included a judgment that the agency staff “took a lot of liberties behind closed doors.” One of the rejected applicants "unequivocally" disputed assertions by CIRM President Alan Trounson that all applicants were informed by him about the need for matching funds, a key criteria for grant reviewers. The request for applications did not contain such a requirement.

The comments came in addition to earlier complaints by rejected applicants that scores had been manipulated in an “appalling” fashion and that scientific merit was not the first order of business in assessing the top four applications.

Also surfacing was a problem generated by Proposition 71, the ballot initiative that created the stem cell agency in 2004. The measure set up a 29-member governing board, including deans of medical schools and others with ties to research organizations. The board was supposed to exercise its expertise on funding decisions. However, only seven members of the board actually voted in the genomics round. Most of the rest had legal conflicts of interest and were not allowed to even participate in the discussion. It is not unusual for that sort of situation to arise during funding decisions by the board.

The CIRM stem cell genomics story began publicly in a scientifically big way with an article in the journal Nature Biotechnology in January 2012  by Trounson and two members of his staff. In it, Trounson said his proposal was needed so that the agency could take a "firm and lasting grip" on stem cell leadership.

Later that month, the governing board of the agency approved the concept for one or two genomics award. In February 2013, grant reviewers for CIRM, whose identities are withheld by the agency, took a crack at the applications. However, they declined to send any applications forward to the board for final action. It was the first time in the agency's nine-year history that has occurred. The reviewers offered no public explanation for the move.

The closed-door review session was marked by a conflict-of-interest violation by Lee Hood of Seattle, Wash., an internationally known genomics specialist, who was recruited by Trounson to be a reviewer in the round. Hood is a close friend of Irv Weissman, who heads Stanford University's stem cell institute. Weissman was named in Stanford's then $24 million application. Hood and Weissman also own a ranch together in Montana.

Trounson has been a guest at the ranch. In 2012, he recused himself during CIRM board discussions of two applications involving Weissman. The applications were from StemCells, Inc., of Newark, Ca., for $20 million each. StemCells, Inc., was founded by Weissman, who still holds a large amount of stock in the firm and serves on its board of directors.

Following the unsuccessful genomics review in February 2013, the applications were sent back to researchers with reviewer comments. The proposals could be retooled for a re-review in the fall, they were told.

After the fall review, the reviewers – minus Hood -- sent the applications to the board with recommendations to fund all four despite the fact that they would cost $146 million, well above the $40 million budgeted for the round. It was the first time that reviewers had made such a decision. Normally they stay within the budget, but they offered no public explanation for their actions in the genomics round.

At that point the CIRM staff, headed by Trounson, became more involved. Under new procedures, the staff may make recommendations concerning applications. In this case, they recommended that only the Stanford application be funded, but only after restoring a provision eliminated by reviewers. Trounson also recommended no funding for the three other top applications in the round. It was the first such major intervention by Trounson and the most aggressive staff move on grant applications.

Trounson offered only a 23-word phrase for recommending the Stanford application and no explanation for rejecting the other three. Stripped from the public review summaries for the three competing applications were the dollar amounts that they had requested. It has been the longstanding practice of the agency to include those figures. The amounts ultimately were made available to the board at its Jan. 29 meeting.

At that meeting, Trounson strongly backed retention of funding in the Stanford application for a project led by Michael Clarke, associate director of Weissman's stem cell institute at Stanford. Following the 2013 conflict violation involving Hood and Weissman, Weissman was removed from Stanford's application. Clarke was included, however. No questions were raised at last month's board meeting about whether Clarke could be regarded as a surrogate for Weissman's interests and whether that would involve a conflict of interest for Trounson.

Late in the meeting, Trounson also said that he had personally told all the applicants, with the exception of Stanford, that matching funds were expected as part of the applications, an assertion disputed following the meeting by Jeanne Loring of the Scripps Research Institute, whose rejected proposal contained no matching funds.

She said in an email,

"During the ICOC (governing board) meeting, Alan Trounson said that he had told us during his visit to all of the first round grantees that it would be important provide money for 'matching' funds. I state unequivocally that he did not tell me or anyone in my lab about this."   (Loring's boldface)

Stanford said its application contained $7 million in matching funds. The agency withheld the figures when they were requested by the California Stem Cell Report prior to the Jan. 29 board meeting, although it has released the figures in at least one other grant round.

Complaints about manipulation of the scores were raised prior to the board meeting by Pui-Yan Kwok,  leader for an application from UC San Francisco and UC Berkeley. He said that the scores of the top to applications were “based on the reviewers removing from consideration the poorest performing center-initiated projects.” He described the situation as appalling.

The agency defended its practices at the board meeting and in response to questions. It said the scoring procedures were permitted under the RFA. It said that while the procedures may be different than those of the NIH so is the stem cell agency. It said that all persons involved had been screened for conflicts of interest under CIRM rules and state law. 

In response to a query by the California Stem Cell Report concerning the process and the questions that needed to be addressed, Loring replied,

“I am concerned about the interference of the CIRM president in influencing the ICOC decisions. He has de facto power to promote or defeat specific applications, and he often wins by promoting one applicant over another. Stanford and Stanford faculty-founded companies such as Stem Cells. Inc., should not be so blatantly promoted over others. The relationship between the president and the head of the stem cell program at Stanford involves personal favors which make him conflicted and he should at the very least recuse himself from any discussion or recommendation of Stanford faculty's applications.”

Loring continued,

“The 29-member board is difficult enough to deal with, but now that most of the members are considered to be conflicted and are not allowed to even discuss the applications, we are left with a small number of non-scientists making decisions about scientific merit.

“I know that at least 5 members of the ICOC were very upset that they were unable to voice their opinions about what should be their mission- to guide CIRM's policies and choices for funding so that they are in the best interest of the voters.”

(For the full text of Loring's remarks see here.)

Other critical comments came from a longtime observer of the agency, who asked not to be identified, and who said,

“It appears that CIRM staff took a lot of liberties behind closed doors in driving this initiative to its final outcome. For example, what happened to require a resubmission and re-review etc. Did they change anything about this initiative in the process?  Were certain criteria shared with some but not all applicants?

“It also appears that the board was taken by surprise and not prepared to deal with the complexities in this initiative.  Clearly staff has not kept them in the loop and they had little access to the details of the process and how reviewers were managed.  They have always funded the vast majority of what the reviewers scored highly, and still did not break the bank.  This is a brand new situation where the reviewers recommended more grants than they could afford to fund.  This happens a lot in the NIH (especially today with severe budget cuts), so NIH has developed many processes to deal with this.  CIRM has not seen anything like this before.”

During the board meeting, some board members questioned parts of the grant review process. The anonymous observer said, 

“The questions (all legitimate) raised by the certain members of the board were by and large not understood or picked up by the other voting members, so they went nowhere. 

“Too many thoughtful board members were conflicted out, leaving the decision-making to a handful who are not prepared to deal with this complex situation.  I blame the IOM (Institute of Medicine) report in giving too much power, without the appropriate process, to staff.  Staff can recommend, but if the board has no information other than what staff provides, then they are acting in the dark.”

(For the full text of those remarks see here.)

In response to the same query, Michael Snyder of Stanford and Joe Ecker of the Salk Institute in La Jolla, co-leaders of the Stanford-led effort, did not raise any questions about the CIRM review process. They said,

“The net result (of their proposal) is that this center will help bring cutting edge technologies to all stem cell researchers in California and along with the funded projects will help keep California at the leading edge of two important fields: stem cell research and genomics, and thereby help accelerate both the science and therapeutics treatments possible in this field, and spur industry and economic development. questions.”

(For the full text of their remarks see here.)

(Editor's note: An earlier version of this item incorrectly said the first name of Michael Clark was William.)

California's Stem Cell Genomics Award: Text of Remarks by Jeanne Loring of Scripps

Here is the text of comments from Jeanne Loring, director of the Center for Regenerative Medicine at the Scripps Research Institute, in response to questions from the California Stem Cell Report concerning the review process for applications in the $40 million stem cell genomics round.

Boldface within Loring's response is hers. Parenthetical identifications of terms or individuals have been inserted in Loring's remarks by the California Stem Cell Report.

California Stem Cell Report: What questions do you think need to be addressed considering the events surrounding the award?

Loring:

 "1. What instructions were given to first round applicants about merging applications?

"Alan (Trounson, CIRM's president) visited all of the first round applicants. On his visit to San Diego, Alan met separately with me and my Illumina partners, Larry Goldstein of UCSD and Craig Venter of the Venter Institute. Alan told me that Larry had taken him to a mens' club and Craig had taken him to a motorcycle dealership. I took him for a tour of Illumina's new facilities, which I thought was appropriate for a scientific site visit. 

"At his visit to all of the first round applicants, Alan Trounson suggested that we merge our applications if we could. My interpretation of that suggestion was that we actually merge our center proposals- UCSF's with ours, for example. I was not told that addition of subcontracts from other institutions could be interpreted as a merger with those institutions. The Stanford group's claim that Scripps and Illumina were consortium members of theirs was disingenuous, since our Scripps/ Illumina consortium was a competing genome center application, and we did not merge any part of our application with Stanford's. 

"To make the claim that they had 'merged' with Scripps and Illumina, Stanford added one project from a junior faculty member at Scripps, and contracted Illumina to do sequencing for them- they have had long-standing contracts with Illumina for services.

"The difference between Stanford's relationship with Illumina and my relationship with Illumina is analogous to Stanford paying a Tesla dealer to repair a car and me teaming up with Tesla to design a new type of car.

"We were not told who the other applicants were, which made it a challenge to determine who we might merge with. We chose to contact Pui Kwok, through my collaborator Susan Fisher at UCSF, Joe Ecker at Salk, Mike Snyder at Stanford, and Josh Stuart at UCSC about potential partnering.

"When I spoke with one of the people we contacted, he said that I could get a place in the consortium put together by Stanford if I were to get my institution to contribute $2 million in matching funds. This was not entirely a surprise; I had heard from colleagues at UCSD that UCSD's vice chancellor, David Brenner, had initiated the collection of matching funds by pledging $2 million to the consortium.

"2. At the Grants Working Group(GWG, the grant review group): what differences were there between the stated requirements in the RFA and what the reviewers were told to do during the meeting?

"Matching funds

"The RFA did NOT require contributions from grantees, and certainly did not suggest that such contributions would be considered to be items for the GWG to judge, since they were tasked with only on the quality of the science, the 'scientific merit.' To quote from the message sent to me from Gil Sambrano(the CIRM staffer who handles most of the review process), announcing my score and the GWG report, 'Applications were reviewed using the criteria detailed in the RFA and scored on scientific merit.'

"That makes me wonder if the reviewers told at the GWG meeting to include monetary contributions from the potential grantees positively in their scoring, in spite of the fact that their scoring is stated by CIRM as being solely on the basis of scientific merit?

"During the ICOC (the agency's governing board) meeting, Alan Trounson said that he had told us during his visit to all of the first round grantees that it would be important provide money for 'matching' funds. I state unequivocally that he did not tell me or anyone in my lab about this. 

"Scoring applications after removal of projects that the GWG scored poorly.

"We learned when the reviews were posted that the GWG scored two of the Stanford center projects very poorly. We do not know the actual scores they gave those projects, nor do we know what scores were given to our own projects. We do know that CIRM instructed the GWG to score the entire Stanford grant after removing the two low scoring projects. All three of our projects scored high enough to be included in the overall review of our application.

"The Stanford project received a range of scores from 70 to 95 after the two projects were removed. Our application received a range of scores from 70 to 88 with all projects left in place. It is not much of a stretch to imagine that if the low-scoring Stanford projects had been kept in, there would not have been scores of 95 by any of the reviewers. It is not too speculative to suggest that their scores would have been lower, perhaps lower than ours, if the low-scoring projects had not been removed.
We were not told of the practice of the GWG altering grants in order to improve the scores of those grants. I am also appalled that this was done, since it is not allowed in NIH review of multi project U and P awards, the closest equivalent to the CIRM genome center award. 'P' awards are Program Project Grants, in which several investigators write sub-proposals to be done in concert with each other. I review these grants, and we are instructed that we cannot remove subprojects in order to change the scores. Similarly, 'U' awards are for consortia that are to be coordinately managed. I also review these applications, and again, it is forbidden for us to alter the applications as written. The goal of the reviewers for these NIH awards is to 'review the grant we are given'.
CIRM staff indicated at the ICOC meeting that the GWG had recommended funding of the Stanford project. 

This is simply untrue. As the message from Gil Sambrano states: 'The GWG understood that this initiative will support only one or two centers and only a single data coordination and management component within a total budget of $40M.  However, as the GWG's scores and recommendations were based solely on scientific merit, the group did not select which center(s) should ultimately be funded as this is a programmatic assessment.'

The GWG was tasked with scoring based on 'scientific merit' (which CIRM instructed them would include monetary contributions). Programmatic assessment is required to choose an application, and CIRM is not part of the Programmatic committee, according to the following quote from the message from Sambrano:
'ICOC/Application Review Subcommittee MeetingFunding decisions will be made by the Application Review Subcommittee of CIRM’s governing board, the Independent Citizens Oversight Committee (ICOC), at a public meeting that will be held in Berkeley, CA on January 29, 2014.  The Subcommittee, which meets concurrently with the Board, is composed of 16 voting members (the Patient Advocate and Industry members of the Board, along with the Chair and statutory Vice Chair of the Board) and 13 non-voting members (the 13 members of the Board who are appointed from institutions that are eligible to receive CIRM funding).
'The Applications Review Subcommittee will conduct a programmatic assessment of applications reviewed by the GWG. The Subcommittee may consider any factors (such as availability of funds, overall grant portfolio, RFA priorities, strategic considerations) that might impact on their decision to fund or not fund applications. The Subcommittee aims to fund applications that are both scientifically meritorious and that bring programmatic value to the CIRM portfolio.'

In the meeting, CIRM did not present information about any application except Stanford's, giving the strong impression that this application was the only one of merit. The ICOC members of the Application Review Subcommittee were not provided with the applications in order to assess the factors they were charged to assess.

California Stem Cell Report: Are there structural issues created by Proposition 71, the measure that created the agency, that made things more or less difficult?

Loring: 

"The 29-member board (ICOC) is difficult enough to deal with, but now that most of the members are considered to be conflicted and are not allowed to even discuss the applications, we are left with a small number of non-scientists making decisions about scientific merit.

"I know that many members of the ICOC were very upset that they were unable to voice their opinions about what should be their mission- to guide CIRM's policies and choices for funding so that they are in the best interest of the voters."

California Stem Cell Report: Are there processes at CIRM that show weaknesses or need to be re-examined? Do you have any specific recommendations for changes?

Loring: 

"The ICOC members should be provided with all of the grant applications as well as the reviews. They can choose to ignore them, but if they find that certain grant apps or disease-specific areas require more high level consideration, they should have the tools to provide that guidance.

"I am concerned about the interference of the CIRM president in influencing the ICOC decisions. He has de facto power to promote or defeat specific applications, and he often wins by promoting one applicant over another. Stanford and Stanford faculty-founded companies such as Stem Cells Inc, are blatantly promoted over others. The relationship between the president and the head of the stem cell program at Stanford involves personal favors which make him conflicted and he should at the very least recuse himself from any discussion or recommendation of Stanford faculty's applications."

Loring also included the following:

Text of message from Gil Sambrano on Friday, January 10, 11:06 am
"Dear Dr. Loring:

Thank you for submitting your application under the California Institute for Regenerative Medicine’s (CIRM) Stem Cell Genomics Centers of Excellence Awards RFA 12-06. We are providing you this report as the Program Director (PD) and designated point of contact on the application, but it is your responsibility to share this information as appropriate with members of your team.

The applications underwent peer review at a meeting held on November 7-8, 2013 by the members of CIRM’s Grants Working Group (GWG). Applications were reviewed using the criteria detailed in the RFA and scored on scientific merit.

Review ReportBelow, please find the Review Report of your application.  This report includes the average scientific score and the funding recommendation of the GWG. Applications are scored on a scale that ranges from 1 – 100, with 100 being the highest achievable score.

Applications are separated into three funding tiers.  An application’s average score determines the funding tier as follows:

75-100 = Tier 1 - recommended for funding
65-74 = Tier 2 - moderate scientific quality or consensus on scientific merit cannot be reached, and may be suitable for programmatic consideration by the ICOC
1-64 = Tier 3 - not recommended for funding

The Review Report provides only a brief summary of the evaluation of your application by the GWG. The report is not an exhaustive critique and does not cover all of the factors that may have contributed to the final score or the final recommendation. The report highlights key points relevant to the review criteria that were captured from reviewers’ written comments and from the discussion of your proposal by the GWG during the review meeting.

ICOC/Application Review Subcommittee MeetingFunding decisions will be made by the Application Review Subcommittee of CIRM’s governing board, the Independent Citizens Oversight Committee (ICOC), at a public meeting that will be held in Berkeley, CA on January 29, 2014.  The Subcommittee, which meets concurrently with the Board, is composed of 16 voting members (the Patient Advocate and Industry members of the Board, along with the Chair and statutory Vice Chair of the Board) and 13 non-voting members (the 13 members of the Board who are appointed from institutions that are eligible to receive CIRM funding).

The Applications Review Subcommittee will conduct a programmatic assessment of applications reviewed by the GWG. The Subcommittee may consider any factors (such as availability of funds, overall grant portfolio, RFA priorities, strategic considerations) that might impact on their decision to fund or not fund applications. The Subcommittee aims to fund applications that are both scientifically meritorious and that bring programmatic value to the CIRM portfolio.

Under California’s open meeting laws, members of the public, including applicants for CIRM funding, may provide written and oral comments to the ICOC regarding items on the Board’s agenda. Applicants may attend and observe the ICOC meeting. Applicants may contribute oral comments for not more than three (3) minutes during the public comment periods. The ICOC Chairman will announce the public comment period, which typically occurs prior to the Board’s voting on any motion. Applicants may also provide written comments to the ICOC. All correspondence to the ICOC must be submitted to the Executive Director of the ICOC, Maria Bonneville, at mbonneville@cirm.ca.gov. Please do not send correspondence to the ICOC that relates to an appeal of a funding recommendation by the GWG as it will be redirected to the CIRM Review Office (see “Response to Review” below).

In preparation for the ICOC meeting, the Review Report (with PI and institution identities removed) will be posted no later than Friday, January 17, 2014 on our website at http://www.cirm.ca.gov/ReviewReports. Additional information for CIRM’s public meetings can also be found on our website.

Award NotificationCIRM will notify you by email of the ICOC’s funding decisions following the ICOC meeting.

Response to ReviewThe GWG conducts the scientific evaluation of proposals submitted to CIRM. If the applicant (PI/PD) wishes to appeal the scientific review by the GWG (or seek reconsideration of the recommendation), the PI/PD must first consult with the CIRM Review Office. All appeal requests must be made through the CIRM Review Office within 10 days of CIRM making this report available (i.e., deadline is January 21, 2014). Grounds for an appeal are limited to the circumstances described in “Guidance for Appeal of Scientific Review and Reconsideration Policy” available via this link: http://www.cirm.ca.gov/board-and-meetings/guidance-appeals-and-requests-reconsideration-grants-working-group-funding
--
Gilberto R. Sambrano, Ph.D.
Associate Director, Review
California Institute for Regenerative Medicine
210 King Street
San Francisco, CA 94107
(415) 396-9103
To:  jloring@scripps.edu; wynne@scripps.edu
REVIEW REPORT FOR CIRM RFA 12-06R GENOMICS CENTERS OF EXCELLENCE AWARDS (R)
Application: Center for Advanced Stem Cell Genomics

PI: Jeanne Loring
Institution: Scripps Research Institute

Recommendation Overview: The GWG provided two final scores for each application as follows: 1) an overall center score (covering the center-initiated projects, collaborative research activities, and center organization and operations plan) and 2) a data coordination and management component score.
The overall scientific merit and quality of the proposals submitted under this RFA were viewed by the GWG to be deserving of high scores. Overall center scores placed four proposals in Tier 1, one proposal in Tier 2 and none in Tier3. The separate data management and coordination component scores placed two proposals in Tier 1, two in Tier 2 and one in Tier 3.
The GWG understood that this initiative will support only one or two centers and only a single data coordination and management component within a total budget of $40M.  However, as the GWG's scores and recommendations were based solely on scientific merit, the group did not select which center(s) should ultimately be funded as this is a programmatic assessment. CIRM staff is recommending that the ICOC fund only the highest scoring genomics center and the corresponding highest data coordination and management center which together will fulfill the goals of this initiative.
The scores, GWG Tier recommendation and CIRM staff recommendation are as follows:

GWG Overall Center Recommendation: Tier 1GWG Overall Final Score: 76

GWG Data Center Recommendation: Tier 2GWG Data Center Final Score: 72
CIRM Staff Recommendation: Do not fund
EXECUTIVE SUMMARYThis Genomics Center will be led by a program director (PD) from an academic institution and a co-PD from an industry organization. Three Center-Initiated Projects (CIPs) are proposed, and, as required by the RFA, a plan for inclusion of Collaborative Research Projects and a Data Coordination and Management Center are described.


Center Organization and Operational Plan - The organization of the proposed Genomics Center is well conceived as a collaboration between highly qualified investigators from an academic institution and an industry partner, representing a diversity of competencies. The balance between expertise in stem cell biology and genomics technologies is a particular strength.

- The PD has extensive research experience at the interface of stem cell biology and genomics and is committed to serving the stem cell community; he/she is well suited to lead this program.

- The industry partner institution, and especially the co-PD, is well positioned to develop novel cutting edge genomics technologies and make them accessible to customers.
- The teams from the two applicant institutions have a well-established, strong working relationship; reviewers considered this an important attribute of this proposal.

- All elements necessary for the establishment and operation of a successful Genomics Center are in place; the structure and composition of the proposed administrative and oversight committees are appropriate and should ensure both delivery of projects and high standards of work.

- The three CIPs are designed to support the service aspects of this Genomics Center by focusing on the development of tools that can be generally used to explore genomics data. Reviewers considered it a strength that, if successful, these projects will both create novel tools and technologies and validate them. There was some concern that some of the tools may not be made easily and widely available.

- Although a letter from leadership indicates enthusiastic institutional support from the academic institution, no additional funds or specific dedicated space have been designated. Reviewers expressed serious concern about this lack of material commitment.

- Some reviewers expressed concern that both the PD and co-PD are already heavily committed individuals and questioned whether they would have the capacity to fully provide a strong commitment to this project.


Center Organization and Operational Plan - The proposed Genomics Center appears well designed to support collaborative research projects and to make relevant state-of-the-art genomics technologies readily accessible to investigators with primary expertise in stem cell biology or translational research.

- The proposed application process is appropriate, review procedures and criteria are well thought out.

- The offer to culture cells for external collaborators in the Genomics Center's core lab is especially appealing, as that would remove a variable from the experiments and thus help with standardization of conditions for genomics assays.

- Concern was expressed about whether potential collaborators who have limited experience in genomics would receive adequate assistance in designing their proposed studies.


CIP-1The applicants propose to develop an updated and expanded version of an existing genomics tool. They plan to make available global gene expression and epigenomic data, obtained through a series of systematic analyses of human pluripotent stem cells and their derivatives, to serve as reference for future experiments. They also propose to analyze the heterogeneity of stem cell populations and to develop genomic tools for the assessment of stem cell quality. Finally, they intend to use disease-specific induced pluripotent stem cells (iPSC) to study the molecular basis of two neurodevelopmental diseases and identify disease-modifying compounds.

- This project adopts a broad approach toward developing pragmatic, accessible tools for basic research on stem cells in vitro, and to lay the groundwork for more effective clinical translation. This would represent a valuable resource to the stem cell community.

- Enthusiasm was diminished by the notion that most of the activities are applications of existing tools or extensions of existing work. While important goals, the activities were not viewed as particularly innovative.

- The goals of this project are overly ambitious, raising doubt that all aims can be achieved. Given the tremendous track record of the principal investigator (PI), though, it is expected that substantial progress will be made.

- Reviewers' opinions about the utility of an already existing analytical tool, to be further developed under this award, were divided. Some judged it positively as an important tool that has been made freely available in its current form and were enthusiastic about the plan for dissemination of the updated version. Conceptually, they considered the proposed approach to be very valuable, as it has the potential to provide objective standards for assessing cell fate and for quality control of cell populations. Other reviewers expressed concern that the current tool has not been widely adopted in the stem cell community, calling into question its usefulness.
- The proposed work on neurodevelopmental diseases is disconnected from the central focus of this project and might have been better developed as a separate project.
- Reviewers criticized the general lack of experimental detail, particularly in aims 4 and 5, which impeded assessment of feasibility.
- The project plays to the strengths of the PI as a well-established leader in the stem cell field with a strong record of productivity and innovation.

- The broad scope of the project is matched by the experience and expertise of the team involved.

CIP-2This project addresses the integrity of stem cells for clinical transplantations and their utility in translational and clinical research. The goals are to establish informatics tools for determining the functional significance of genome wide molecular variations in therapeutic stem cell populations and to develop and validate methods for assessing the prevalence of deleterious alterations in stem cell populations. The applicants also plan to develop and validate a workflow for integrating genomics information with identification of potential therapeutic compounds and their effects on patient-derived induced pluripotent stem cells and on patient treatment outcomes. Finally, the plan is to disseminate all developed tools and protocols to the stem cell community.

- The utility of the proposed tools and protocols for translational genomics-based research would be high.
- The first goal is straightforward and feasible. Reviewers emphasized that input data must be high quality, as noted by the applicants, and suggested that applicants consider that the cellular differentiation state may affect functional significance of specific genomics variation.

- Other goals are more risky, but if successfully developed, they should be widely applicable and help stimulate the use of stem cell-based systems to explore both disease mechanisms and potential therapies.
- Toward assessing prevalence of deleterious alterations in stem cell populations, reviewers recommended that a variety of additional stem cell datasets, especially some originating outside the team, be included in the project.

- The feasibility of a key component of the study, linking genomic information from patients to potential therapeutics and individualized treatments, was difficult to assess, since the applicants did not specify the types of diseases to be studied.
- Reviewers observed that parts of this proposal are vague and hard to follow, and it was unclear what some of the deliverables would be.

- There is a clear plan for dissemination of the acquired expertise and knowledge.

- The PI is well qualified for this work and has assembled a powerful leadership team that possesses the necessary expertise.


CIP-3This project is led by the industry partner organization and is focused on the development of several single cell genomic technologies and tools for large-scale epigenetic analyses.

- Reviewers noted that only one of the technologies under development is truly stem cell-specific, but the proposed work would nevertheless deliver technologies extremely valuable to the stem cell community.

- The tools to be improved or developed are at the forefront of technical advances.

- Reviewers geatly appreciated the novelty of one of the proposed technologies.
- Some reviewers were concerned that the project essentially constitutes commercial development of genomic products and questioned whether it was appropriate for CIRM to support this activity.  Others felt that the developed technologies would provide valuable research tools and could have great potential impact on stem cell science.
- Concern was expressed about whether the new technologies would be specifically disseminated to California investigators and whether their cost might be prohibitive to many researchers.

- The basic technologies underlying this proposal have already been developed and it should therefore be feasible to complete the proposed developments in the proposed time scale.

- The PI and team are exceptionally well qualified to deliver on this project.


Data Coordination and Management - The DCM team is led by two individuals. One has a track record of developing a highly successful, adaptable, user-friendly platform. The other is an expert in medical informatics, although reviewers expressed concern that a biosketch for this individual was not included in the proposal.

-The proposed DCM structure and leadership would likely ensure solid database structure, data access and visualization capabilities.
- Reviewers considered the details provided on the data management plan to be inadequate; there was little description of how the DCM Center will participate in data integration and analysis or interact with various projects.

- Reviewers acknowledged the importance of patient privacy protection but felt the focus on this issue in the application was overemphasized and distracting.

- The descriptions of data visualization tools are reasonable but not particularly innovative or tailored to the specific needs of the stem cell community."