Breaking bad news to stem cell researchers

It’s never easy to tell someone that they are too late, that they missed the deadline. It’s particularly hard when you know that the person you are telling that to has spent years working on a project and now needs money to take it to the next level. But in science, as in life, it’s always better to tell people what they need to know rather than what they would like to hear.

And so, we have posted a notice on our website for researchers thinking about applying for funding that, except in a very few cases, they are too late, that there is no money available for new projects, whether it’s Discovery, Translational or Clinical.

Here’s that notice:

CIRM anticipates that the budget allocation of funds for new awards under the CIRM clinical program (CLIN1, CLIN2 and CLIN3) may be depleted within the next two to three months. CIRM will accept applications for the monthly deadline on June 28, 2019 but will suspend application submissions after that date until further notice. All applicants should note that the review of submitted applications may be halted at any point in the process if funds are depleted prior to completion of the 3-month review cycle. CIRM will notify applicants of such an occurrence. Therefore, submission and acceptance of an application to CIRM does not guarantee the availability of funds or completion of a review cycle.

The submission of applications for the CIRM/NHLBI Cure Sickle Cell Initiative (CLIN1 SCD, CLIN2 SCD) are unaffected and application submissions for this program will remain open.

We do, of course, have enough money set aside to continue funding all the projects our Board has already approved, but we don’t have money for new projects (except for some sickle cell disease projects).

In truth our funding has lasted a lot longer than anyone anticipated. When Proposition 71 was approved the plan was to give CIRM $300 million a year for ten years. That was back in 2004. So what happened?

Well, in the early years stem cell science was still very much in its infancy with most of the work being done at a basic or Discovery level. Those typically don’t require very large sums so we were able to fund many projects without hitting our $300m target. As the field progressed, however, more and more projects were at the clinical trial stage and those need multiple millions of dollars to be completed. So, the money went out faster.

To date we have funded 55 clinical trials and our early support has helped more than a dozen other projects get into clinical trials. This includes everything from cancer and stroke, to vision loss and diabetes. It’s a good start, but we feel there is so much more to do.

Followers of news about CIRM know there is talk about a possible ballot initiative next year that would provide another $5.5 billion in funding for us to help complete the mission we have started.

Over the years we have built a pipeline of promising projects and without continued support many of those projects face a difficult future. Funding at the federal level is under threat and without CIRM there will be a limited number of funding alternatives for them to turn to.

Telling researchers we don’t have any money to support their work is hard. Telling patients we don’t have any money to support work that could lead to new treatments for them, that’s hardest of all.

Budgeting for the future of the stem cell agency

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The CIRM Board discusses the future of the Stem Cell Agency

Budgets are very rarely exciting things; but they are important. For example, it’s useful for a family to know when they go shopping exactly how much money they have so they know how much they can afford to spend. Stem cell agencies face the same constraints; you can’t spend more than you have. Last week the CIRM Board looked at what we have in the bank, and set us on a course to be able to do as many of the things we want to, with the money we have left.

First some context. Last year CIRM spent a shade over $306 million on a wide range of research from Discovery, the earliest stage, through Translational and into Clinical trials. We estimate that is going to leave us with approximately $335 million to spend in the coming years.

A couple of years ago our Board approved a 5 year Strategic Plan that laid out some pretty ambitious goals for us to achieve – such as funding 50 new clinical trials. At the time, that many clinical trials definitely felt like a stretch and we questioned if it would be possible. We’re proving that it is. In just two years we have funded 26 new clinical trials, so we are halfway to our goal, which is terrific. But it also means we are in danger of using up all our money faster than anticipated, and not having the time to meet all our goals.

Doing the math

So, for the last couple of months our Leadership Team has been crunching the numbers and looking for ways to use the money in the most effective and efficient way. Last week they presented their plan to the Board.

It boiled down to a few options.

  • Keep funding at the current rate and run out of money by 2019
  • Limit funding just to clinical trials, which would mean we could hit our 50 clinical trial goal by 2020 but would not have enough to fund Discovery and Translational level research
  • Place caps on how much we fund each clinical trial, enabling us to fund more clinical trials while having enough left over for Discovery and Translational awards

The Board went for the third option for some good reasons. The plan is consistent with the goals laid out in our Strategic Plan and it supports Discovery and Translational research, which are important elements in our drive to develop new therapies for patients.

Finding the right size cap

Here’s a look at the size of the caps on clinical trial funding. You’ll see that in the case of late stage pre-clinical work and Phase 1 clinical trials, the caps are still larger than the average amount we funded those stages last year. For Phase 2 the cap is almost the same as the average. For Phase 3 the cap is half the amount from last year, but we think at this stage Phase 3 trials should be better able to attract funding from other sources, such as industry or private investors.

cap awards

Another important reason why the Board chose option three – and here you’ll have to forgive me for being rather selfish – is that it means the Administration Budget (which pays the salaries of the CIRM team, including yours truly) will be enough to cover the cost of running this research plan until 2020.

The bottom line is that for 2018 we’ll be able to spend $130 million on clinical stage research, $30 million for Translational stage, and $10 million for Discovery. The impact the new funding caps will have on clinical stage projects is likely to be small (you can see the whole presentation and details of our plan here) but the freedom it gives us to support the broad range of our work is huge.

And here is where to go if you are interested in seeing the different funding opportunities at CIRM.

Getting faster, working smarter: how changing the way we work is paying big dividends

This blog is part of the Month of CIRM series

Speeding up the way you do things isn’t always a good idea. Just ask someone who got a ticket for going 65mph in a 30mph zone. But at CIRM we have found that doing things at an accelerated pace is paying off in a big way.

When CIRM started back in 2004 we were, in many ways, a unique organization. That meant we pretty much had to build everything from scratch, creating our own ways of asking for applications, reviewing those applications, funding them etc. Fast forward ten years and it was clear that, as good a job as we did in those early days, there was room for improvement in the way we operated.

So we made some changes. Big changes.

We adopted as our mantra the phrase “operational excellence.” It doesn’t exactly trip off the tongue but it does reflect what we were aiming for. The Business Dictionary defines operational excellence as:

 “A philosophy of the workplace where problem-solving, teamwork, and leadership results in the ongoing improvement in an organization.”

We didn’t want to just tinker with the way we worked, we wanted to reinvent every aspect of our operation. To do that we involved everyone in the operation. We held a series of meetings where everyone at CIRM, and I do mean everyone, was invited to join in and offer their ideas on how to improve our operation.

CIRM2.0_Logo

The end result was CIRM 2.0. At the time we described it as “a radical overhaul” of the way we worked. That might have been an understatement. We increased the speed, frequency and volume of the programs we offered, making it easier and more predictable for researchers to apply to us for funding, and faster for them to get that funding if they were approved.

For example, before 2.0 it took almost two years to go from applying for funding for a clinical trial to actually getting that funding. Today it takes around 120 days.

But it’s not just about speed. It’s also about working smarter. In the past if a researcher’s application for funding for a clinical trial failed it could be another 12 months before they got a chance to apply again. With many diseases 12 months could be a death sentence. So we changed the rules. Now if you have a project ready for a clinical trial you can apply any time. And instead of recommending or not recommending a project, basically voting it up or down, our independent panel of expert reviewers now give researchers with good but not great applications constructive feedback, enabling the researchers to make the changes needed to improve their project, and reapply for funding within 30 days.

This has not only increased the number of applications for clinical trials, it has also increased the quality of those applications.

We made similar changes in our Discovery and Translation programs. Increasing the frequency of each award, making it easier for researchers to know when the next round of funding was coming up. And we added incentives to encourage researchers to move successful projects on to the next level. We wanted to create a pipeline of the most promising projects steadily moving towards the clinic.

The motivation to do this comes from our patients. At CIRM we are in the time business. Many of the patients who are looking to stem cells to help them don’t have the luxury of time; they are rapidly running out of it. So we have a responsibility to do all we can to reduce the amount of time it takes to get the most promising therapies to them, without in any way compromising safety and jeopardizing their health.

By the end of 2016 those changes were very clearly paying dividends as we increased the frequency of reviews and the number of projects we reviewed but at the same time decreased the amount of time it took us to do all that.

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But we are not done yet. We have done a good job of improving the way we work. But there is always room to be even better, to go even faster and be more efficient.

We are not done accelerating. Not by a long shot.

Translating great stem cell ideas into effective therapies

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CIRM funds research trying to solve the Alzheimer’s puzzle

In science, there are a lot of terms that could easily mystify people without a research background; “translational” is not one of them. Translational research simply means to take findings from basic research and advance them into something that is ready to be tested in people in a clinical trial.

Yesterday our Governing Board approved $15 million in funding for four projects as part of our Translational Awards program, giving them the funding and support that we hope will ultimately result in them being tested in people.

Those projects use a variety of different approaches in tackling some very different diseases. For example, researchers at the Gladstone Institutes in San Francisco received $5.9 million to develop a new way to help the more than five million Americans battling Alzheimer’s disease. They want to generate brain cells to replace those damaged by Alzheimer’s, using induced pluripotent stem cells (iPSCs) – an adult cell that has been changed or reprogrammed so that it can then be changed into virtually any other cell in the body.

CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and Alzheimer’s – which has no cure and no effective long-term treatments – clearly represents an unmet medical need.

Another project approved by the Board is run by a team at Children’s Hospital Oakland Research Institute (CHORI). They got almost $4.5 million for their research helping people with sickle cell anemia, an inherited blood disorder that causes intense pain, and can result in strokes and organ damage. Sickle cell affects around 100,000 people in the US, mostly African Americans.

The CHORI team wants to use a new gene-editing tool called CRISPR-Cas9 to develop a method of editing the defective gene that causes Sickle Cell, creating a healthy, sickle-free blood supply for patients.

Right now, the only effective long-term treatment for sickle cell disease is a bone marrow transplant, but that requires a patient to have a matched donor – something that is hard to find. Even with a perfect donor the procedure can be risky, carrying with it potentially life-threatening complications. Using the patient’s own blood stem cells to create a therapy would remove those complications and even make it possible to talk about curing the disease.

While damaged cartilage isn’t life-threatening it does have huge quality of life implications for millions of people. Untreated cartilage damage can, over time lead to the degeneration of the joint, arthritis and chronic pain. Researchers at the University of Southern California (USC) were awarded $2.5 million to develop an off-the-shelf stem cell product that could be used to repair the damage.

The fourth and final award ($2.09 million) went to Ankasa Regenerative Therapeutics, which hopes to create a stem cell therapy for osteonecrosis. This is a painful, progressive disease caused by insufficient blood flow to the bones. Eventually the bones start to rot and die.

As Jonathan Thomas, Chair of the CIRM Board, said in a news release, we are hoping this is just the next step for these programs on their way to helping patients:

“These Translational Awards highlight our goal of creating a pipeline of projects, moving through different stages of research with an ultimate goal of a successful treatment. We are hopeful these projects will be able to use our newly created Stem Cell Center to speed up their progress and pave the way for approval by the FDA for a clinical trial in the next few years.”

The Spanish Inquisition and a tale of two stem cell agencies

Monty

Monty Python’s Spanish Inquisition sketch: Photo courtesy Daily Mail UK

It’s not often an article on stem cell research brings the old, but still much loved, British comedy series Monty Python into the discussion but a new study in the journal Cell Stem Cell does just that, comparing the impact of CIRM and the UK’s Regenerative Medicine Platform (UKRMP).

The article, written by Fiona Watt of King’s College London and Stanford’s Irv Weissman (a CIRM grantee – you can see his impressive research record here) looks at CIRM and UKRMP’s success in translating stem cell research into clinical applications in people.

It begins by saying that in research, as in real estate, location is key:

“One thing that is heavily influenced by location, however, is our source of funding. This in turn depends on the political climate of the country in which we work, as exemplified by research on stem cells.”

And, as Weissman and Watt note, political climate can have a big impact on that funding. CIRM was created by the voters of California in 2004, largely in response to President George W. Bush’s restrictions on the use of federal funds for embryonic stem cell research. UKRMP, in contrast was created by the UK government in 2013 and designed to help strengthen the UK’s translational research sector. CIRM was given $3 billion to do its work. UKRMP has approximately $38 million.

Inevitably the two agencies took very different approaches to funding, shaped in part by the circumstances of their birth – one as a largely independent state agency, the other created as a tool of national government.

CIRM, by virtue of its much larger funding was able to create world-class research facilities, attract top scientists to California and train a whole new generation of scientists. It has also been able to help some of the most promising projects get into clinical trials. UKRMP has used its more limited funding to create research hubs, focusing on areas such as cell behavior, differentiation and manufacturing, and safety and effectiveness. Those hubs are encouraged to work collaboratively, sharing their expertise and best practices.

Weissman and Watt touch on the problems both agencies ran into, including the difficulty of moving even the best research out of the lab and into clinical trials:

“Although CIRM has moved over 20 projects into clinical trials most are a long way from becoming standard therapies. This is not unexpected, as the interval between discovery and FDA approved therapeutic via clinical trials is in excess of 10 years minimum.”

 

And here is where Monty Python enters the picture. The authors quote one of the most famous lines from the series: “Nobody expects the Spanish Inquisition – because our chief weapon is surprise.”

They use that to highlight the surprises and uncertainty that stem cell research has gone through in the more than ten years since CIRM was created. They point out that a whole category of cells, induced pluripotent stem (iPS) cells, didn’t exist until 2006; and that few would have predicted the use of gene/stem cell therapy combinations. The recent development of the CRISPR/Cas9 gene-editing technology shows the field is progressing at a rate and in directions that are hard to predict; a reminder that that researchers and funding agencies should continue to expect the unexpected.

With two such different agencies the authors wisely resist the temptation to make any direct comparisons as to their success but instead conclude:

“…both CIRM and UKRMP have similar goals but different routes (and funding) to achieving them. Connecting people to work together to move regenerative medicine into the clinic is an over-arching objective and one that, we hope, will benefit patients regardless of where they live.”

Rare disease underdogs come out on top at CIRM Board meeting

 

It seems like an oxymoron but one in ten Americans has a rare disease. With more than 7,000 known rare diseases it’s easy to see how each one could affect thousands of individuals and still be considered a rare or orphan condition.

Only 5% of rare diseases have FDA approved therapies

rare disease

(Source: Sermo)

People with rare diseases, and their families, consider themselves the underdogs of the medical world because they often have difficulty getting a proper diagnosis (most physicians have never come across many of these diseases and so don’t know how to identify them), and even when they do get a diagnosis they have limited treatment options, and those options they do have are often very expensive.  It’s no wonder these patients and their families feel isolated and alone.

Rare diseases affect more people than HIV and Cancer combined

Hopefully some will feel less isolated after yesterday’s CIRM Board meeting when several rare diseases were among the big winners, getting funding to tackle conditions such as ALS or Lou Gehrig’s disease, Severe Combined Immunodeficiency or SCID, Canavan disease, Tay-Sachs and Sandhoff disease. These all won awards under our Translation Research Program except for the SCID program which is a pre-clinical stage project.

As CIRM Board Chair Jonathan Thomas said in our news release, these awards have one purpose:

“The goal of our Translation program is to support the most promising stem cell-based projects and to help them accelerate that research out of the lab and into the real world, such as a clinical trial where they can be tested in people. The projects that our Board approved today are a great example of work that takes innovative approaches to developing new therapies for a wide variety of diseases.”

These awards are all for early-stage research projects, ones we hope will be successful and eventually move into clinical trials. One project approved yesterday is already in a clinical trial. Capricor Therapeutics was awarded $3.4 million to complete a combined Phase 1/2 clinical trial treating heart failure associated with Duchenne muscular dystrophy with its cardiosphere stem cell technology.  This same Capricor technology is being used in an ongoing CIRM-funded trial which aims to heal the scarring that occurs after a heart attack.

Duchenne muscular dystrophy (DMD) is a genetic disorder that is marked by progressive muscle degeneration and weakness. The symptoms usually start in early childhood, between ages 3 and 5, and the vast majority of cases are in boys. As the disease progresses it leads to heart failure, which typically leads to death before age 40.

The Capricor clinical trial hopes to treat that aspect of DMD, one that currently has no effective treatment.

As our President and CEO Randy Mills said in our news release:

Randy Mills, Stem Cell Agency President & CEO

Randy Mills, Stem Cell Agency President & CEO

“There can be nothing worse than for a parent to watch their child slowly lose a fight against a deadly disease. Many of the programs we are funding today are focused on helping find treatments for diseases that affect children, often in infancy. Because many of these diseases are rare there are limited treatment options for them, which makes it all the more important for CIRM to focus on targeting these unmet medical needs.”

Speaking on Rare Disease Day (you can read our blog about that here) Massachusetts Senator Karen Spilka said that “Rare diseases impact over 30 Million patients and caregivers in the United States alone.”

Hopefully the steps that the CIRM Board took yesterday will ultimately help ease the struggles of some of those families.

If you want to accelerate stem cell therapies then create an Accelerating Center

Buckle up

Buckle up, we’re about to Accelerate

“You can’t teach fish to fly,” is one of the phrases that our CIRM President & CEO, Randy Mills, likes to throw out when asked why we needed to create new centers to help researchers move their most promising therapies out of the lab and into clinical trials.

His point is that many researchers are terrific at research but not so great at the form filling and other process-oriented skills needed to get approval from the Food and Drug Administration (FDA) for a clinical trial.

So instead of asking them to learn how to do all those things, why don’t we, CIRM, create a system that will do it for them? And that’s where we came up with the idea for the Accelerating Center (we’re also creating a Translating Center – that’s a topic for a future blog but if you can’t wait to find out the juicy details you can find them here.)

The Accelerating Center will be a clinical research organization that provides regulatory, operational and other support services to researchers and companies hoping to get their stem cell therapies into a clinical trial. The goal is to match the scientific skills of researchers with the regulatory and procedural skills of the Accelerating Center to move these projects through the review process as quickly as possible.

But it doesn’t end there. Once a project has been given the green light by the FDA, the Accelerating Center will help with actually setting up and running their clinical trial, and helping them with data management to ensure they get high quality data from the trial. Again these skills are essential to run a good clinical trial but things researchers may not have learned about when getting a PhD.

We just issued what we call an RFA (Request for Applications)  for people interested in partnering with us to help create the Accelerating Center. To kick-start the process we are awarding up to $15 million for five years to create the Center, which will be based in California.

To begin with, the Accelerating Center will focus on supporting CIRM-funded stem cell projects. But the goal is to eventually extend that support to other stem cell programs.

Now, to be honest, there’s an element of self-interest in all this. We have a goal under our new Strategic Plan of funding 50 new clinical trials over the next five years. Right now, getting a stem cell-related project approved is a slow and challenging process. We think the Accelerating Center is one tool to help us change that and give the most promising projects the support they need to get out of the lab and into people.

There’s a lot more we want to do to help speed up the approval process as well, including working with the FDA to create a new, streamlined regulatory process, one that is faster and easier to navigate. But that may take some time. So in the meantime, the Accelerating Center will help “fish” to do what they do best, swim, and we’ll take care of the flying for them.

 

 

 

Board gives stem cell institute marching orders, and a road map

The poet T. S. Eliot once wrote: “If you aren’t in over your head, how do you know how tall you are?” Well, everyone at CIRM, California’s stem cell institute, is about to find out how tall we are.

Strategic Plan coverYesterday our governing Board approved a new Strategic Plan. To call it ambitious might be considered an understatement. Among the goals it commits us to achieving are:

  • Funding 50 new clinical trials in 5 years including 10 for rare or orphan disorders and 5 in conditions affecting children
  • Fostering enactment of a new, more efficient federal regulatory approval process for stem cell treatments
  • Introducing 50 new therapeutic candidates or devices into the development pipeline
  • Reducing the time it takes to move a stem cell treatment from the earliest Discovery stage into a clinical trial by 50%
  • Increasing the number of projects moving to the next stage of development by 50%

No easy task

Each goal by itself might be considered challenging. Taken together they are likely to stretch us all. And yet that’s why we joined CIRM, why we feel fortunate to be part of this mission. We have a chance to be part of a movement that could change the face of medicine as we know it. We knew it wouldn’t be easy. But now we know what we have to do to help achieve that.

As Randy Mills, our President and CEO, said in a news release, the goal in developing this Strategic Plan was to create a clear vision for the next five years of the Institute:

”We have around $900 million left to work with and we wanted a plan that used that money to the best possible effect, maximizing our chances of pushing as many new treatments to patients as possible. We didn’t want something ‘good enough’, we wanted something ‘great’. This plan is extremely ambitious, but also realistic in the goals it sets out and the way those goals can be met.”

The Strategic Plan – you can read it in full here – doesn’t just lay out goals, it also creates a road map on how to meet those goals. They include engaging industry more, being more creative in how we move the most promising projects from one stage of research to the next, and finding ways to change the regulatory approval process to help remove obstacles and speed up the progress of these therapies into clinical trials.

Aiming high

We know we may not achieve all our goals. As Randy Mills said at our Board meeting: “This is a difficult plan. These goals are not easy to achieve.” There are always risks in pursuing something so big and ambitious but no one ever achieved anything truly worthwhile by playing it safe. We are not interested in playing it safe.

We may start out by being, as T. S. Eliot put it “in over our heads”. But we’re confident we’ll be able to grow tall enough to make this plan work.

As Randy Mills told the Board: “If we are all in this together then the probability of success is high, and if we are successful then all this would have been worthwhile.”

Call to Action by FDA at World Stem Cell Summit

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FDA Deputy Commissioner Dr. Robert Califf talking at the World Stem Cell Summit

The World Stem Cell Summit annual conference in Atlanta kicked off today with a clarion call from Dr. Robert Califf, the Deputy Commissioner for the Food and Drug Administration. He told the audience:

“We want you to accelerate translation to produce safe and effective therapies that can be delivered reliably”

It was a message that everyone in the room, scientists and patient advocates, would love to be able to comply with. The question of course is how do you do that in a way that puts the emphasis on both speed, to get the therapies to patients who need them, and safety, so you don’t put those patients at risk.

That’s quite a challenge considering that, as panel moderator Julie Allickson of Wake Forest Institute for Regenerative Medicine said:

“the estimate now is it costs $2.4 billion and up to ten years to take something to the clinic.”

Even if that dollar amount is higher than many think it would take to bring a stem cell therapy to a clinical trial it is an indication of the challenge the field faces.

Califf, who has only been at the FDA for 8 months, says that regenerative medicine is:

“not the only field exploding with scientific knowledge and seeing a future that’s very different from what we see today so it’s exciting but also an enormous challenge for the FDA. One of the real eye openers for me is to be at the FDA and hear about drugs that have been on the market for 45 years and we’re still learning about them.”

He says the first goal of the FDA has to be to protect the public, and that it’s hard to balance safety and innovation. “That’s an issue we struggle with every day.”

Califf was optimistic that the balance can be struck and progress can be made, but said that this can only truly be done if the patient is at the table as an active participant.

“Our national clinical research system is well intention but flawed. We need to have a new system that shares information right across the system and where patients are at the center. Patients should be driving the national research infrastructure. They are an essential part of change. It’s happening in Congress because they are hearing from constituents that this is what they want, a voice in the research being done that affects them.”

For the patients and patient advocates in the audience it was a welcome message. For years they have been calling for a louder voice in the research that affects them and their loved ones. Knowing they have a sympathetic ear in the FDA could be an encouraging sign that their voices are finally being heard.

We will be writing more as the conference unfolds so stay tuned!