3 CIRM challenges: search for new prez, funding, & clinical POW!

The idea of CIRM as a dedicated state stem cell agency was one of the things that got me excited about starting my time as a professor doing research on stem cells in California way back in 2005-2006 on the job hunt. Fast forwarding to today now 11 years later, CIRM is still on the cutting edge, but some major things have changed for California’s stem cell agency and as it looks to its future, the questions and challenges are different too.CIRM 2.0

By analogy, the original CIRM was at first like a stem cell itself navigating its differentiation branches as it went. The new CIRM of 2017, what some call CIRM 2.0, is in contrast more like a developing tissue. It has matured and has a history to build upon as it continues. Today CIRM and its staff aren’t newbies. They were newbies by necessity when I came to California in 2006 because they were literally inventing themselves with no past example to use as a model. Now they are stem cell veterans and CIRM is trying to sort out its fresh path ahead relative to its current path rather than strike a path from scratch.

Three key areas need tackling to navigate the new path for maximum positive impact.

Funding. Does CIRM 2.0 and its backers go for a “Prop 71 2.0” to get another round of California state funding? If so, how much and how to approach the voters? If not (or if “yes”, but the effort isn’t successful), where does CIRM get its funding to continue? Of course, in theory a third option is that CIRM simply ends when its current funding runs out, but to me that’s not a real option. CIRM cannot end because it has so much more to do and it is in some ways just getting to the most exciting part: the bedside part of the bench-to-bedside path. Update: over at California Stem Cell Report, David Jensen has the scoop on an industry-centric stem cell bond proposal idea.

New Prez. CIRM 2.0 President and CEO Randy Mills announced the surprising news recently that he’s moving on from CIRM after a relatively short, but impactful tenure. Who will be the new CIRM President? It’s anybody’s guess at this point, but I’d say that CIRM needs to achieve two things at once here: move very quickly to get a new leader and make that leader be a fantastic choice for CIRM. What exactly do I mean by the latter? The new CIRM President ideally should have impeccable stem cell credentials and also big picture clinical vision as well as strong leadership skills. I asked CIRM where things stand on the President search today and CIRM Sr. Director Public Communications & Patient Advocate Outreach, Kevin McCormack, provided this quote:

“the Presidential Search subcommittee is going to be meeting on July 17th to evaluate the options regarding appointing a permanent President and CEO to replace Randy. They’ll then make their recommendations to the full Board.”

I’m planning a future post to throw some names out on the table for discussion of people who might be considered for the position by CIRM.

Clinical POW! CIRM’s mission is focused on having transformative clinical impact so the agency needs some snap, crackle, and POW! on that front moving forward. It already has provided key support for a number of ongoing clinical trials and the goal moving forward is final approved products that are proven safe and effective. I would call that some stem cell POW! Not everything is going to be a success, but I predict that some will.

I believe that CIRM has the potential to achieve all this. That doesn’t mean it’ll be easy, but what great things have ever been easy?

President Mills Leaving, CIRM Needs New Leader to Navigate Future Challenges

Randy MillsCIRM announced today that its President and CEO, Randy Mills, is soon leaving for a new job as President of the National Marrow Donor Program/Be The Match in Minnesota. Update: Dr. Maria Millan, the CIRM Vice President of Therapeutics, will be its leader starting July 1 until a new leader is chosen.

For this kind of position three years is a relatively short tenure so CIRM will need to scramble a bit to keep continuity and momentum as it searches for and ultimately puts in place a new leader. It’s a critical time for CIRM as it and its allies consider big picture strategy for the future, approaches to future funding such as a possible new proposition for state funding (Prop 71 2.0), and how to continue all those exciting clinical trials and research beyond the current period of its funding.

In general, Mills had a big positive impact on CIRM and helped it go to the next level. About the only thing I wasn’t a fan of in terms of his leadership was my perception of his negativity toward the FDA and toward FDA oversight of stem cells, and how that manifested at CIRM during his time there. But good people can strongly disagree on policy. We’ll have to wait and see how the regulatory experiment of stem cell provisions in the 21st Century Cures Act, which Mills may have helped to make possible, will impact regenerative medicine in terms of changes in FDA oversight. It could also impact CIRM too.

Now CIRM’s Board has an exciting, difficult task ahead. Who do they want as their new leader to tackle CIRM’s challenge? What kind of background and future vision? The priorities, leadership skills, and vision of the new leader are likely to together be a major factor in CIRM’s future success. Who are the top possible candidates out there right now? I’m going to do a follow-up, future post on these questions and CIRM’s future.

Radical, Supercharged Vision for Future of CIRM: Interview with New Prez Mills

Randy MillsChange is in the air for the California stem cell agency, CIRM. It has a new President, Randy Mills, and CIRM is soon going to be like a new agency too.

I recently did an interview with Mills that illuminates some of the big changes that are imminent. I also asked him what his favorite type of stem cell is and his view of the regenerative medicine regulatory changes in Japan relative to those here with the FDA.

Paul: Going from the biotech industry to lead CIRM is a big change. What inspired you to make the change?

Mills:  It was actually a two step process. After 20 years in regenerative medicine, the last 10 as the CEO of a publically traded company, I had actually intended to take some time off from work so I could spend more with my wife and children. Perhaps not to permanently retire, but at least take a step back and do more selective things, like sitting on Boards and such.

As my wife says though, I really stunk at that, and quickly became bored.

So when I received a call from CIRM asking if I were interested in the CEO position I gave it serious consideration. Having spent the past 5 years as a grant reviewer for CIRM, I was already quite familiar with the Agency. If you believe in the potential of regenerative medicine and cell therapy as I do, there is no place in the world you could go to have a bigger impact. No company, no other state, not even a country can have the impact California can have in bringing these treatments to patients.

My interest at CIRM isn’t to “stay the course” – it is to be as innovative as possible to make the agency radically more effective and efficient. And so with that, I accepted the challenge.

Paul: You’ve had some time to get settled in at CIRM. What has surprised you most?

Mills: To the upside – without question, the team at CIRM.  They are really a remarkable group of capable and dedicated professionals. They’re not just good at their job, they really care about the work they do and its ability to impact people’s lives. It is such a gift for a new leader to be able to come into an organization and have such talent to work with.  I have challenged the team to rethink the way we do business at CIRM in a really big way and they have responded to the call, producing CIRM 2.0. I am excited that with the rollout of 2.0, people will be able to see just how talented the team is that I get to work with everyday.

Paul: I’ve heard that you plan to extend CIRM funding of new grant proposals to 2020 based on existing funding. Will this mean less funding per year and will that in turn mean focusing more on fewer priorities? For example, one of the questions I’m most asked about CIRM lately by colleagues: will there be another Basic Bio RFA or are those history now given a more translational/clinical focus moving forward?

Mills: It’s funny, I was able to extend the funding life of CIRM until at least 2020 by using a little trick I once learned called “math.” Not to put to fine of a point on it, but I basically looked at how much money we actually had left to spend (approximately $1 billion) and divided it by how much money we actually awarded each year – about $190 million. And there you have it, 2020.

Now what really made the difference in the projection was correcting some of our previous spending assumptions. For example, if a $100 million concept plan was approved by the Board, we would assume all $100 million was spent, when in actuality we typically only spend a fraction of it.

Also built into the previous projections was an assumption that all money we awarded would be spent. However, CIRM awards are milestone driven – meaning that if the project isn’t working as agreed upon by both parties up front, the program is cancelled. Since this is biotech, we know that not all projects are going to work, and thus we will not actually spend all of the money we award.

As for Basic Biology, we fully intend to continue a modified version of the program. The name will be changed to “Discovery” to reflect the new, more active and driven culture at CIRM. We also may go about it in a different manner. We want to have a much more targeted approach, one that asks people to focus on particular problems that are important and partner with us overcome specific obstacles that are holding back the development of treatments.

Paul: What are your top priorities for the near-term future for CIRM?

Mills: Accelerating stem cell treatments to patients in need – that is our primary goal. Everything else we do is subordinate. We have developed a four-part test that the team and I use as a compass.

First, will what we are doing speed up the development of stem cell treatments for patients? Will it increase the likelihood of a successful treatment reaching patients? Is it for an unmet medical need? And lastly is it efficient?

To accomplish this we are implementing CIRM 2.0, the faster, more responsive version of CIRM that will hopefully give us more high quality stem cell programs.

CIRM 2.0 is actually a term I know you first coined Paul. I really liked the symbolism of it. The 2.0 version of something doesn’t imply that the first version was flawed – like the Ford Pinto. Instead it takes a good product and makes it better – like the iPhone! That is what we are doing with CIRM 2.0. Looking at everything in the process and asking ourselves, “how can we make this better?” We plan to launch the first wave of CIRM 2.0 January 1st, and I think stakeholders are really going to like it.

From there, it is on to CIRM 3.0. For me, it is critical that we never stop thinking of ways to get better.

Paul: What about longer term plans for beyond 2020? Will there be a new California Proposition (e.g. essentially Prop 71 2.0)?

Mills: JT (Jon Thomas, Chairman of CIRM) and I are working on some exciting concepts for how to make CIRM the most effective over the long-term. They are still in the early stages of development, so look for more on this later. In the meantime, it is all hands on deck getting ready for the launch of CIRM 2.0.

Paul: We saw just now that ViaCyte got FDA approval for their IND for Type I Diabetes, which is extremely exciting. Are there other similar companies/products funded by CIRM that seem in the pipeline to achieve similar major milestones in the next 1-2 years?

Mills: Oh sure. By the end of this year alone we expect to have ten programs that are approved for clinical trials. This includes research in cancer, leukemia, heart disease, sickle cell disease, HIV/AIDS and blindness. (You can read about those here http://blog.cirm.ca.gov/2014/11/20/10-years10-therapies-10-years-after-its-founding-cirm-will-have-10-therapies-approved-for-clinical-trials/ )

We have many more promising projects in the pipeline that we hope will get approval for a clinical trial within the next year and, of course, we hope that with CIRM 2.0 that will be able to significantly increase this trend.

Paul: Are there ways that CIRM can become even more collaborative with, supportive of, and synergistic with industry? For example, might there be more building of ties to ARM? 

Mills: Absolutely. The first thing we need to do is improve our product. The second thing we need to do is market it. And this goes for academia as well as industry. If we want to attract the best prospects, we need to have a system that is responsive to their needs.

Under our current process it can take around two years for a successful applicant to actually get funded. No company with a promising therapeutic candidate can afford to wait around for two years, they need to get it into clinical trials now. That’s why we are launching CIRM 2.0, so that we have an opened ended application program, one that is available for the researchers as soon as the product candidate is ready.

As for marketing the program, we think the more the word gets out about this and all of the other great features of CIRM 2.0, the more high quality interest we will see from industry and academia alike.

Paul: One of my pet projects yet to get fully moving, but still quite important I think is formal academic training programs (fellowship/subspecialty; http://www.ncbi.nlm.nih.gov/pubmed/23477401) for physicians in cellular and regenerative medicine.  What do see as CIRM’s role in these kinds of educational initiatives? Would you support academic training of MDs of the specific kind I mentioned?

Mills: If it meets the four-part test, sure, we would consider it. But at this time we don’t currently have an approved concept plan for something like that.

Paul: Do you have a favorite kind of stem cell and why?

Mills: It’s a toss up between mesenchymal mint chip and pluripotent pasticcio – they are both delicious!

In reality, no. I am agnostic as to stem cell type. My favorites are the ones that help patients.

Paul: Looking more broadly, what do you see as the top opportunities and also challenges for the regenerative medicine field today and in the near future?

Mills: This single most important thing for us to do in cell therapy is to generate clear and convincing evidence of efficacy in humans. All of the other major issues surrounding regenerative medicine, such as high product cost and scalability can and will be solved once there is obvious and compelling proof of concept data for a product. Looking ahead, I am really excited about some of the things coming down the CIRM pipeline that have the potential to reach this high standard.

Paul: Can you comment on the draft plan for accelerating the process of review and funding applications?

Mills: CIRM 2.0 is a new, streamlined process making it easier and faster to apply for funding from the stem cell agency designed to attract high quality projects ready to make progress quickly.

In the past it could take up to two years to go from us requesting applications for funding to getting the money out the door as part of an approved contract. CIRM 2.0 simplifies and accelerates the process, cutting that two years down to just four months. And if you miss that deadline you only have to wait one month for the next application deadline to come around.

Every application will be reviewed by an expert budget review group to make sure the proposed budget is appropriate for the scope of the work. If not, the budget reviewers will recommend changes. Then it goes to our independent expert scientific review group which can also recommend changes if they feel those would strengthen the application. Only after we have an application that we are really enthusiastic about, do we forward it to the CIRM Board with a recommendation to fund. Remarkably, we can do all of that in just 81 days.

Also, under CIRM 2.0 you only apply when you have a project that is ready to start within 45 days of it being approved for funding by our Board.

Paul: We recently saw the first patient in history administered an IPSC-based therapy in Japan in a clinical study there. Remarkably this occurred just 7 years after the first published report of human IPSCs. Could you comment on the different regulatory framework in place in Japan that made such an acceleration of bench-bedside possible. Do you favor such an approach in the US?

Mills: The approach in Japan has evolved over the past decade. The PMDA (the Japanese version of FDA) was not always so friendly to stem cell therapy. Having been directly involved for the past decade in the development of the first allogeneic stem cell product submitted for approval in Japan, I can tell you that the PMDA has moved a long way in their thinking.

It gives me hope that the FDA might reconsider its approach on certain issues relating to stem cell development.

Loring Open Letter to CIRM: Continuing Shared Labs Will Keep California’s Stem Cell Edge

Jeanne LoringBy Jeanne Loring

As the California Institute for Regenerative Medicine (CIRM) celebrates its successes on its 10th anniversary, there is coincidentally a less happy CIRM-related event. One of CIRM’s first investments in stem cell research was a network of dedicated stem cell laboratories throughout California. This program, called “shared labs” has been cancelled.

The shared lab idea originated as a means for California researchers to work on human embryonic stem cells without compromising their funding from the NIH. CIRM invested a million dollars for each of 17 institutions to purchase equipment for a laboratory that would have the sole purpose of supporting human stem cell research, development, and training. They provided a modest stipend for support staff and instructors.

As with every bold idea, there were unexpected consequences. In this case, CIRM did not anticipate that the shared labs would have such an enormous impact beyond their original intention. Over the last 6 years they have existed, the labs have provided the infrastructure upon which California’s reputation as the center of the stem cell universe was built.

Unwittingly, CIRM’s shared lab program jump-started human stem cell research in California, sending it on a trajectory that has led to stem cell clinical trials in just 6 years. Far beyond being havens for embryonic stem cell research, the labs became the places where new technologies were developed and shared, where clinical projects were born, and where scientists carried out the necessary lab work for bringing a stem cell therapy to the clinic.

CIRM did not expect that there would be interaction among the labs that would make the whole greater than the sum of the parts. The network of shared labs became our means to communicate and share ideas. It sparked new partnerships between institutions throughout the state, and became a conduit for trainees to move from CIRM’s Bridges internships to graduate school. One scientist described the shared labs as “the beating heart of California’s stem cell program”.

Why would CIRM discontinue such a remarkably successful program with so many unexpected benefits?

The decision was made in 2013, and predates “CIRM 2.0”, the optimistic restructuring that recently breathed new life into the institute. It is being implemented by Randy Mills, who became CIRM’s president just a few months ago.

A year ago, CIRM’s future looked bleak. In December 2013, Alan Trounson was CIRM’s president, and he expected that CIRM would run out of money by 2017, if not sooner. At that month’s meeting of CIRM’s governing committee, called the ICOC (Independent Citizens Oversight Committee), all of the discussion was focused on the end game- how they would spend the last hundreds of millions left in their coffers.

Anticipating an attack on the shared lab program, scientists from 11 of the dedicated CIRM-supported stem cell labs traveled to that ICOC meeting in LA to plead the case for continued support of stem cell infrastructure. We were asking for a chance to reapply for stipend funds for the labs, which would cost CIRM about $350,000 per year for each lab. The transcript of that ICOC meeting is here (jump to page 205) and the blog I wrote about the meeting is here.

Some of the ICOC members found the scientists’ requests compelling, and understood the scientists’ concern that loss of the infrastructure would have negative impact on all aspects of CIRM’s mission, from training young scientists to supporting development of clinical applications for stem cells.

But, money was the main concern, and the decision came down to this: did CIRM want to retain the laboratory infrastructure or did it want to dismantle it and disperse the money to other projects?

The answer was clear to the researchers in the audience and the fact that we were all there was living proof that the shared laboratories had made us into a cohesive group throughout California. In addition, CIRM had already invested nearly $20 million just in the equipment for the labs, and millions more in training the personnel who run them.

One irony is that the NIH now funds a broader range of human embryonic stem cell research, so the original purpose of the labs no longer applies. But the NIH and other funders don’t pay for maintaining labs like these. That idea belongs to CIRM, which remains the only agency that fortuitously created a network of stem cell scientists.

A second irony is that having existing stem cell labs has been a boon for California. Institutions were able to attract an estimated $240 million from granting agencies and philanthropy for research based on the existence of the dedicated stem cell labs. This represents a tenfold return on CIRM’s investment.

In spite of our testimony, we lost. Alan Trounson didn’t pay attention to anything we said, and instead told us that the labs were a luxury that CIRM couldn’t afford, and that we should find other sources of money to pay our staff, perhaps turning the labs into for-profit service centers. We explained that we all had been trying to raise alternative funds for our laboratories for years, but there is concrete evidence that facilities like these just don’t exist in the US without subsidies from a granting agency.

Because of potential conflicts of interest, only 6 members of the 29-member ICOC could vote. Two of them (Art Torres and Diane Winoker) abstained; the other 4 voted to close the program.

What will happen now? One or two labs will be able to support their staff with other grant money and be able to keep their labs, although they will no longer be shared. Some will lose everything: the lab space, the highly trained personnel, and CIRM’s equipment.

The third irony in this story is that the ICOC voted in October 2014 to continue the Bridges internship program for another year, unaware, apparently, that closing the shared labs means there will be no labs in which to teach the interns and no trained personnel to teach them.

I know I speak for the majority of my colleagues when I say that the dedicated stem cell laboratory program was the key to establishing the rapid pace of stem cell research in California. Loss of the labs and their trained personnel will lose us the edge that made California uniquely qualified for stem cell success.

What can we do? We have a very specific request. We ask that CIRM consider one of the ideas raised by an ICOC member at the fateful December meeting: open a new request for applications to allow the shared lab directors to reapply for a competitive award. Since CIRM has already paid for the equipment, we need only to pay for upkeep and for our personnel who run the labs and teach courses to Bridges interns.

I’ve shared this letter with other lab directors; those listed below express their support for this letter.

Dennis Clegg

Peter Donovan

Susan Fisher

Linda Giudice

Arnold Kriegstein

Andrew McMahon

David Schaffer

Evan Snyder

Alice Tarantal

David Warburton

Karl Willert

Welcome CIRM 2.0 and President Mills

The future is now.

Or so goes the expression.

For CIRM, it rings true today.

CIRM 2.0

Last year I blogged about what we might expect from the new CIRM that would evolve and take form in the future.

I was particularly thinking about this coming incarnation of CIRM, which I called CIRM 2.0, as it related to post-2017 when existing Prop. 71 state funding will run out and I was making the case for additional state funding for beyond 2017 for CIRM.

However, the stem cell field often changes rapidly, even overnight.

In that spirit, from my view for all intents and purposes CIRM 2.0 started yesterday. A big change came years early.

CIRM announced yesterday that C. Randal “Randy” Mills will be its new President taking the place of departing President Alan Trounson.

C. Randal Mills

Biotech leader Mills (formerly of Osiris) serving as the new CIRM President ushers in a fundamentally new era for CIRM and so it immediately kicks off CIRM 2.0.

A warm welcome to President Mills.

What does this all mean for CIRM from a broad perspective?

At and even before its inception, CIRM was all about human pluripotent stem cells, especially embryonic stem cells. The same was true for the first few years.

The production of iPS cells in mouse and human forms in 2006 and 2007 set in motion an ensuing shift for CIRM to include a great deal of iPS cell research in its portfolio.

The election of US President Obama in 2008 eventually released pressure on human ES cell research along with the resolution of the Sherley v. Sebelius Case. Sure, there were some painful moments such as during that time when all NIH hESC research was halted, but they were resolved. And CIRM’s focus continued to shift just a bit further.

Even with these changes, CIRM was still primarily focused on pluripotent stem cells. The notion of a leader with a primarily for-profit mesenchymal stem cell-centered focus at the helm of CIRM would have seemed impossible even just a few years ago. However, a tidal shift just happened. Okay, so it didn’t happen all at once overnight and observers of CIRM could see this trend begin a few years ago, but the appointment of Mills as the new CIRM Prez crystallizes this change.

It bears repeating. The future is now at CIRM.

What’s the bottom line?

The CIRM of today and the future is primarily going to be about focused stem cell clinical product development (the main goal of Prop. 71) and raising capital to support that development beyond 2017.

Let’s see what develops.