A ‘Call to Action’ for change at the FDA

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It’s bad enough to have to battle a debilitating and ultimately deadly disease like Huntington’s disease (HD). But it becomes doubly difficult and frustrating when you feel that the best efforts to develop a therapy for HD are running into a brick wall.

That’s how patients and patient advocates working on HD feel as they see the Food and Drug Administration (FDA) throw up what they feel are unnecessary obstacles in the way of promising research.

So the group Help 4HD International has decided to push back, launching an online campaign to get its supporters to pressure the FDA into taking action. Any action.

Posing the question “Does the FDA understand that time is something we simply don’t have?” Help 4HD is urging people to write to the FDA:

“We have heard the FDA say they feel like our loved ones have quality of life at the end stages of HD. We have heard them say people with HD get to live for 20 years after diagnosis. It seems like the FDA doesn’t understand what we are having to live with generation after generation. We have seen HD research die because the researcher couldn’t get an IND (Investigational New Drug, or approval to put a new drug into clinical trials) from the FDA. We have seen trials that should be happening here in the USA move to other countries because of this. We have seen the FDA continue to put up delays and roadblocks. We are lucky to have amazing research going on for HD/JHD (juvenile HD) right now, but what is that research worth if the FDA doesn’t let it go into clinical trials? Drug development is a business and costs millions of dollars. If the FDA continues to refuse INDs, the fear is that companies will stop investing in HD research. This is a fate that we can’t let happen! We need to write to the FDA and let them know our frustrations and also help them understand our disease better.”

The group has drafted a sample letter for people to use or adapt as they see fit. They’ve even provided them with the address to mail the letter to. In short, they are making it as easy as possible to get as many people as possible to write to the FDA and ask for help.

The HD community is certainly not the only one frustrated at the FDA’s  glacial pace of approval of for clinical trials. That frustration is one of many reasons why Congress passed the 21st Century Cures Act late last year. That’s also the reason why we started our Stem Cell Champions campaign, to get the FDA to create a more efficient, but no less safe, approval process.

Several of our most active Stem Cell Champions – like Frances Saldana, Judy Roberson and Katie Jackson – are members of the HD Community. Last May several members of the CIRM Team attended the HD-Care Conference, held to raise awareness about the unmet medical needs of this community. We blogged about it here.

While this call to action comes from the HD community it may serve as a template for other organizations and communities. Many have the same frustrations at the slow pace of approval of therapies for clinical trials.

We are hoping the 21st Century Cures Act will lead to the desired changes at the FDA. But until we see proof that’s the case we understand and support the sense of urgency that the HD community has. They don’t have the luxury of time.

 

 

‘Right To Try’ laws called ‘Right To Beg’ by Stem Cell Advocates

In recent years, ‘Right to Try’ laws have spread rapidly across the US, getting approved in 32 states, with at least three more states trying to pass their own versions.

The organization behind the laws says they serve a simple purpose:

‘Right To Try’ allows terminally ill Americans to try medicines that have passed Phase 1 of the FDA approval process and remain in clinical trials but are not yet on pharmacy shelves. ‘Right To Try’ expands access to potentially life-saving treatments years before patients would normally be able to access them.”

That certainly sounds like a worthy goal; one most people could get behind. And that’s what is happening. Most ‘Right To Try’ laws are passed with almost unanimous bi-partisan support at the state level.

Beth Roxland

Beth Roxland

But that’s not the view of Beth Roxland, an attorney and health policy advisor with an extensive history in both regenerative medicine and bioethics. At the recent World Stem Cell Summit Roxland said ‘Right To Try’ laws are deceptive:

“These are not patient friendly but are actually patient unfriendly and could do harm to patients. The problem is that they are pretending to do something that isn’t being done. It gives patients a sense that they can get access to a treatment, but they don’t have the rights they think they do. This is a right to ask, not a right to get.”

Roxland says the bills in all 32 states are almost all identical, and use the same cookie-cutter language from the Goldwater Institute – the libertarian organization that is promoting these laws. And she says these laws have one major flaw:

“There is no actual right provided in the bill. The only right is the right to try and save your life, “by requesting” from a manufacturer a chance to try the therapy. The manufacturer doesn’t have to do anything; they aren’t obliged to comply. The bills don’t help; they give people false hopes.”

Roxland says there isn’t one substantiated case where a pharmaceutical company has provided access to a therapy solely because of a ‘Right To Try’ law.

However, Starlee Coleman, the Vice President for Communications at the Goldwater Institute, says that’s not true. She says Dr. Ebrahim Delpassand, a cancer specialist in Texas, has testified before Congress that he has treated dozens of patients under his state’s ‘Right To Try’ law. You can see a video of Dr. Delpassand here.

Coleman says ;

“We think the promise of ‘Right To Try’ is self-evident. If one doctor alone can treat 80 patients in one fell swoop, but the FDA can only manage to get 1200 people through its expanded access program each year, we think the potential to help patients is significant.”

Other speakers at the panel presentation at the World Stem Cell Summit said these laws can at the very least play an important role in at least raising the issue of the need for people battling terminal illnesses to have access to experimental therapies. Roxland agreed it was important to have that conversation but she pointed out that what often gets lost in the conversation is that these laws can have hidden costs.

  • 13 states may withdraw hospice eligibility to people who gain access to an early or experimental intervention
  • 4 states may withdraw home care
  • 6 states say patients taking part in these therapies may lose their insurance
  • Several states allow insurers to deny coverage for conditions that may arise from patients getting access to these therapies
  • 30 states say the companies can charge the patients for access to these therapies

Roxland says the motives behind the ‘Right To Try’ laws may be worthy but the effect is misleading, and diverts attention from efforts to create the kind of reforms that would have real benefits for patients.

Here is a blog we wrote on the same topic last year.

Why Goldilocks could provide the answer to changing the way FDA regulates stem cells

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Panel on FDA regulation at World Stem Cell Summit

One of the hottest topics of the past year in regenerative medicine has been the discussion about the need for regulatory reform at the Food and Drug Administration (FDA) so it’s no surprise that topic was the subject of the first main panel discussion at the 2016 World Stem Cell Summit in West Palm Beach, Florida.

The panel, titled ‘FDA Oversight in Regenerative Medicine: What are the Options to Accelerating Translation’, kicked off with Celia Witten, Deputy Director of the Center for Biologics Evaluation and Research at the FDA. She laid out all the new steps that the agency is implementing to try and be more responsive to the needs of researchers and patients.

Perils facing pioneers

Martin McGlynn, the former CEO of StemCells Inc. was up next and he wasted little time listing the companies that had once been considered pioneers in the field only to fail for a variety of reasons. He said one of the big problems is that translational efforts, moving from a good idea to a clinical trial, take too long, saying 15 – 20 years is not unusual and that Big Pharma and strategic investors won’t invest until they see strong Phase 2 study results.

“We need to do great science and design and conduct great clinical trials to advance this field but we also have to come up with a sustainable business model to make this happen.”

A good start

He called the 21st Century Cures Act, which the US Senate approved yesterday, a good start but says many of the challenges won’t be helped by some of the new provisions:

“Many sponsors and companies don’t make it out of open label early studies, so the existence of an accelerated pathway or some of the other enabling tools included in the act will come too late for these groups.”

McGlynn warned that if we don’t take further steps, we risk falling behind the rest of the world where companies are buying up struggling US ventures:

“Many non-USA companies in Japan and China and Australia are quicker to recognize the value of many of the products and approaches that struggle here in the US.”

Too much, too little, just right

Marc Scheineson was the final speaker. He heads the food and drug law practice at Washington, DC law firm Alston & Bird and is a former Associate Commissioner for Legislative Affairs at the FDA. He began his presentation with what he said are the scariest words in the English language: “I‘m a lawyer from Washington D.C. and I’m here to help you.”

Scheineson says part of the problem is that the FDA was created long before cell therapy was possible and so it is struggling to fit its more traditional drug approval framework around stem cell therapies. As a result, this has led to completely separate regulatory processes for the transplantation of human organs and blood vessels, or for the use of whole blood or blood components.

He says it’s like the fable of Goldilocks and the Three Bears. Some of the regulation is too hard- resulting in a lengthy regulatory process that takes years to complete and costs billions of dollars – and some of the regulation is too soft allowing clinics to open up around the US offering unproven therapies. He says we need a Goldilocks approach that blends the two into regulations that are just right.

Time to take a second step

Scheineson agreed with McGlynn that the 21st Century Cures Act is a good start but it’s not enough.  He says it still relies heavily on the use of traditional criteria to regulate stem cells, and also leaves much of the interpretation of the Act to the discretion of the FDA.

“It’s a first step, an experiment to see if we can break the logjam and see if we can move things to an affordable BLA (The Biologics License Application is needed to be able to market a product once it’s approved by the FDA). But make no mistake, a cell therapy revolution is underway and I believe the FDA should seize the opportunity to promote innovation and not defensively protect the “status quo”.

 

 

Creating a “Pitching Machine” to speed up our delivery of stem cell treatments to patients

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When baseball players are trying to improve their hitting they’ll use a pitching machine to help them fine tune their stroke. Having a device that delivers a ball at a consistent speed can help a batter be more consistent and effective in their swing, and hopefully get more hits.

That’s what we are hoping our new Translating and Accelerating Centers will do. We call these our “Pitching Machine”, because we hope they’ll help researchers be better prepared when they apply to the Food and Drug Administration (FDA) for approval to start a clinical trial, and be more efficient and effective in the way they set up and run that clinical trial once they get approval.

The CIRM Board approved the Accelerating Center earlier this summer. The $15 million award went to QuintilesIMS, a leading integrated information and technology-enabled healthcare service provider.

The Accelerating Center will provide key core services for researchers who have been given approval to run a clinical trial, including:

  • Regulatory support and management services
  • Clinical trial operations and management services
  • Data management, biostatistical and analytical services

The reason why these kinds of service are needed is simple, as Randy Mills, our President and CEO explained at the time:

“Many scientists are brilliant researchers but have little experience or expertise in navigating the regulatory process; this Accelerating Center means they don’t have to develop those skills; we provide them for them.”

The Translating Center is the second part of the “Pitching Machine”. That is due to go to our Board for a vote tomorrow. This is an innovative new center that will support the stem cell research, manufacturing, preclinical safety testing, and other activities needed to successfully apply to the FDA for approval to start a clinical trial.

The Translating Center will:

  • Provide consultation and guidance to researchers about the translational process for their stem cell product.
  • Initiate, plan, track, and coordinate activities necessary for preclinical Investigational New Drug (IND)-enabling development projects.
  • Conduct preclinical research activities, including pivotal pharmacology and toxicology studies.
  • Manufacture stem cell and gene modified stem cell products under the highest quality standards for use in preclinical and clinical studies.

The two centers will work together, helping researchers create a comprehensive development plan for every aspect of their project.

For the researchers this is important in giving them the support they need. For the FDA it could also be useful in ensuring that the applications they get from CIRM-funded projects are consistent, high quality and meet all their requirements.

We want to do everything we can to ensure that when a CIRM-funded therapy is ready to start a clinical trial that its application is more likely to be a hit with the FDA, and not to strike out.

Just as batting practice is crucial to improving performance in baseball, we are hoping our “Pitching Machine” will raise our game to the next level, and enable us to deliver some game-changing treatments to patients with unmet medical needs.

 

Funding stem cell research targeting a rare and life-threatening disease in children

cystinosis

Photo courtesy Cystinosis Research Network

If you have never heard of cystinosis you should consider yourself fortunate. It’s a rare condition caused by an inherited genetic mutation. It hits early and it hits hard. Children with cystinosis are usually diagnosed before age 2 and are in end-stage kidney failure by the time they are 9. If that’s not bad enough they also experience damage to their eyes, liver, muscles, pancreas and brain.

The genetic mutation behind the condition results in an amino acid, cystine, accumulating at toxic levels in the body. There’s no cure. There is one approved treatment but it only delays progression of the disease, has some serious side effects of its own, and doesn’t prevent the need for a  kidney transplant.

Researchers at UC San Diego, led by Stephanie Cherqui, think they might have a better approach, one that could offer a single, life-long treatment for the problem. Yesterday the CIRM Board agreed and approved more than $5.2 million for Cherqui and her team to do the pre-clinical testing and work needed to get this potential treatment ready for a clinical trial.

Their goal is to take blood stem cells from people with cystinosis, genetically-modify them and return them to the patient, effectively delivering a healthy, functional gene to the body. The hope is that these genetically-modified blood stem cells will integrate with various body organs and not only replace diseased cells but also rescue them from the disease, making them healthy once again.

In a news release Randy Mills, CIRM’s President and CEO, said orphan diseases like cystinosis may not affect large numbers of people but are no less deserving of research in finding an effective therapy:

“Current treatments are expensive and limited. We want to push beyond and help find a life-long treatment, one that could prevent kidney failure and the need for kidney transplant. In this case, both the need and the science were compelling.”

The beauty of work like this is that, if successful, a one-time treatment could last a lifetime, eliminating or reducing kidney disease and the need for kidney transplantation. But it doesn’t stop there. The lessons learned through research like this might also apply to other inherited multi-organ degenerative disorders.

CIRM’s Randy Mills: New FDA rules for stem cells won’t fix the problem

For the last two days the Food and Drug Administration (FDA) has been holding a hearing in Bethesda, Maryland on new regulations that would tighten control over stem cell treatments. The FDA invited public testimony during the hearing on the regulations that would impact many of the clinics that currently offer unproven therapies

The testimony has been impassioned to say the least. Supporters of the clinics say they offer a valuable service and that patients should be allowed to decide for themselves how they want their own cells to be used. Opponents say the clinics are little more than snake oil sales people, offering bogus, unproven treatments.

One of those presenting was Randy Mills, CIRM’s President and CEO. Randy has been very vocal in the past about the need for the FDA to change the way it regulates stem cell therapies.

In California Healthline Randy explained why he thinks the rules the FDA is proposing will not fix the problem, and may even make it worse:

FDA Must Find A Middle Ground For Sake Of Patients

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Randy Mills

We aren’t happy, as a lot of people aren’t happy, with the proliferation of these stem cell clinics — some of which are probably doing good work. But some are clearly making rather outlandish claims for which there’s no real data. 

There are a couple of conditions coming together to create this storm.

One is that the need is very real. These patients are really struggling. They don’t have alternatives. They’re desperate and they need help. It’s not in the realm of possibility to talk to somebody who is suffering as badly as these patients are and to say, ‘You have to wait a few more decades for the science to catch up.’

On the other hand, we have a regulatory paradigm that only provides two pathways to put a cell therapy onto the market. One pathway is the most intense regulatory requirement anywhere in the world for any product — the biologics license application through the FDA, which takes 10 to 20 years and costs over $1 billion.

The other is through the exemptions the FDA has made, which require absolutely no pre-market approval whatsoever. You can be on the market in days, with no data.

The regulatory burden associated with one is massive and the other is almost nonexistent.

So it’s not at all surprising that we’re seeing a proliferation of these stem cell clinics popping up that are operating under the assumption that they fall under the exemption.

What the FDA is doing now is saying, ‘We’re not happy with this. We’re going to define some terms more narrowly than in the past … and make it more difficult to legally be on the market under the less burdensome regulatory pathway.’

That’s what this meeting is about.

The problem with their strategy is twofold. It doesn’t address the patients, or the need side of the equation. And I don’t think it has a chance of actually working because the FDA will acknowledge that they do not have the resources to enforce these types of regulations at the clinic level.

They would have to be essentially regulating the practice of physicians, which is well beyond their capabilities. Even if they were able to enforce it, it would just drive these patients somewhere else.

We’re advocating for the creation of some middle pathway that would bring essentially unregulated therapies into the regulatory fold, but in a manner which could be complied with.

I would rather know these clinics are being regulated and collecting data than have them operating under the radar screen of the FDA. I would like there to be a formal pre-market review of these therapies before they’re put on the market. I would like there to be safety and efficacy data.

I’m going to try hard to get the FDA to see that just plugging this hole won’t make the problem go away.

Thinking that they’re going to strengthen the regulation and that patients are going to be satisfied that there’s absolutely no chance for help is naive.

There isn’t a lot of evidence to suggest these types of procedures are overly risky. It’s not that they don’t have risk, but everything in medicine does. If you’re a patient who has absolutely no alternative, you’re probably willing to take the chance.

New approach could help turn back the clock and reverse damage for stroke patients

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Stroke: courtesy WebMD

Stroke is the leading cause of serious, long-term disability in the US. Every year almost 800,000 people suffer from a stroke. The impact on their lives, and the lives of those around them can be devastating.

Right now the only treatment approved by the US Food and Drug Administration (FDA) is tissue plasminogen activator or tPA. This helps dissolve the blood clot causing most strokes and restores blood flow to the brain. However, to be fully effective this has to be administered within about 3-4 hours after the stroke. Many people are unable to get to the hospital in time and as a result suffer long-term damage, damage that for most people has been permanent.

But now a new study in Nature Medicine shows that might not be the case, and that this damage could even be reversible.

The research, done by a team at the University of Southern California (USC) uses a one-two punch combination of stem cells and a protein that helps those cells turn into neurons, the cells in the brain damaged by a stroke.

First, the researchers induced a stroke in mice and then transplanted human neural stem cells alongside the damaged brain tissue. They then added in a dose of the protein 3K3A-APC or a placebo.

hey found that mice treated with 3K3A-APC had 16 times more human stem-cell derived neurons than the mice treated with the placebo. Those neurons weren’t just sitting around doing nothing. USC’s Berislav Zlokovic, senior author of the paper, says they were actively repairing the stroke-induced damage.

“We showed that 3K3A-APC helps the grafted stem cells convert into neurons and make structural and functional connections with the host’s nervous system. No one in the stroke field has ever shown this, so I believe this is going to be the gold standard for future studies. Functional deficits after five weeks of stroke were minimized, and the mice were almost back to normal in terms of motor and sensorimotor functions. Synapses formed between transplanted cells and host cells, so there is functional activation and cooperation of transplanted cells in the host circuitry.”

The researchers wanted to make sure the transplanted cell-3K3A-ACP combination was really the cause of the improvement in the mice so they then used what’s called an “assassin toxin” to kill the neurons they had created. That reversed the improvements in the treated mice, leaving them comparable to the untreated mice. All this suggests the neurons had become an integral part of the mouse’s brain.

So how might this benefit people? You may remember that earlier this summer Stanford researchers produced a paper showing they had helped some 18 stroke patients, by injecting stem cells from donor bone marrow into their brain. The improvements were significant, including in at least one case regaining the ability to walk. We blogged about that work here

In that study, however, the cells did not become neurons nor did they seem to remain in the brain for an extended period. It’s hoped this new work can build on that by giving researchers an additional tool, the 3K3A-ACP protein, to help the transplanted cells convert to neurons and become integrated into the brain.

One of the other advantages of using this protein is that it has already been approved by the FDA for use in people who have experienced an ischemic stroke, which accounts for about 87 percent of all strokes.

The USC team now hope to get approval from the FDA to see if they can replicate their experiences in mice in people, through a Phase 2 clinical trial.

 

 

 

 

 

 

 

Finally a possible use for your excess fat; using it to fix your arthritic knee

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One of the most common questions we get asked at CIRM, almost every other day to be honest, is “are there any stem cell treatments for people with arthritis in their knees?” It’s not surprising. This is a problem that plagues millions of Americans and is one of the leading causes of disability in the US.

Sadly, we have to tell people that there are no stem cell treatments for osteoarthritis (OA) in the knee that have been approved by the Food and Drug Administration (FDA). There’s also a lack of solid evidence from clinical trials that the various approaches are effective.

But that could be changing. There’s a growing number of clinical trials underway looking at different approaches to treating OA in the knee using various forms of stem cells. Sixteen of those are listed at clinicaltrials.gov. And one new study suggests that just one injection of stem cells may be able to help reduce pain and inflammation in arthritic knees, at least for six months. The operative word here being may.

The study, published in the journal Stem Cells Translational Medicine,  used adipose-derived stromal cells, a kind of stem cell taken from the patient’s own fat. Previous studies have shown that these cells can have immune boosting and anti-scarring properties.

The cells were removed by liposuction, so not only did the patient’s get a boost for their knees they also got a little fat reduction. A nice bonus if desired.

The study was quite small. It involved 18 patients, between the ages of 50 and 75, all of whom had suffered from osteoarthritis (OA) in the knee for at least a year before the treatment. This condition is caused by the cartilage in the knee breaking down, allowing bones to rub against each other, leading to pain, stiffness and swelling.

One group of patients were given a low dose of the cells (23,000) injected directly into the knee, one a medium dose (103,000) and one a high dose (503,000).

Over the next six months, the patients were closely followed to see if there were any side effects and, of course, any improvement in their condition. In a news release, Christian Jorgensen, of University Hospital of Montpellier, the director of the study, said the results were encouraging:

“Although this phase I study included a limited number of patients without a placebo arm we were able to show that this innovative treatment was well tolerated in patients with knee OA and it provided encouraging preliminary evidence of efficacy. Interestingly, patients treated with low-dose ASCs significantly improved in pain and function compared with the baseline.”

The researchers caution that the treatment doesn’t halt the progression of OA and does not restore the damaged cartilage, instead it seems to help patients by reducing inflammation.

In a news article about the study Tony Atala, director of the Wake Forest Institute for Regenerative Medicine, in Winston-Salem, N.C. and the editor of Stem Cells Translational Medicine said the study offered the patients involved another benefit:

“In fact, most of the patients (in the study group) who had previously scheduled total knee replacement surgery decided to cancel the surgery. It will be interesting to see if these improvements are seen in larger groups of study participants.”

Interesting is an understatement.

But while this is encouraging it’s important to remember it was done in a small group of patients and needs to be replicated in a much larger group before we can draw any solid conclusions. It will also be important to see if the benefits last longer than six months.

We might not have to wait too long for some answers. The researchers are already running a 2-year trial involving 150 people in Europe.

We’ll let you know what they find.

 

Why is a cell therapy that restores sight to the blind against the law?

FDA

A lot of people are frustrated with the US Food and Drug Administration (FDA) and its woefully slow process for approving stem cell therapies. That’s one of the reasons why we started the CIRM Stem Cell Champions campaign, to gather as many like-minded supporters of stem cell research as possible and help to change the way the FDA works, to create a more efficient approval process.

You can read more about that campaign and watch a short video on what being a Stem Cell Champion involves (hint: not very much).

Now Randy Mills, our President and CEO, has teamed up with former US Senator Bill Frist to explain precisely why the FDA needs to change the way it regulates stem cells, and to offer a simple way to create the system that will best serve the needs of patients.

This Op Ed appeared on Fox News’ online Opinion section on Friday, May 20th.


Cell therapy reversed blindness for 47,000 patients in 2015. So why is it against the law?

By C. Randal Mills Ph.D., Sen. Bill Frist M.D.

As medical miracles go, restoring sight to the blind is right up there. A mother seeing her baby for the first time, or a child being able to count the stars is a beautiful gift, and its value cannot be overstated. Last year 47,000 Americans received that gift and had their blindness reversed through the transplantation of cells from a corneal donor’s final selfless act.

It is safe, it is effective, and because it is curative, it is a relatively cost effective procedure. It is medicine at its most beautiful. And according to FDA regulations, the distribution of this cell therapy is in violation of federal law.

That’s right. The regulation says that no matter how competent the surgeon, the FDA must first approve cells from donated corneas as if they were a drug—a process that takes over a decade and can costs billions of dollars — all for a practice that has been successfully restoring sight for more than 50 years. And this is only one example.

The good news: the FDA doesn’t always adhere to its regulations and has not in this case.

The bad news: inconsistent enforcement creates uncertainty, deterring innovation for other unmet medical needs such as arthritis, back pain, and diabetic ulcers.

How did a country known for pioneering medical breakthroughs get here?

Appropriate regulation of living cells that treat disease is inherently complex. Some therapies, like corneal cell transplants, are well-understood. Others are far more sophisticated and can involve forcing cells to change from one type to another, cutting out defective genes, and growing cells in culture to expand their numbers into the billions. Although this may sound like science fiction, it’s the type of very real science that will revolutionize the practice of medicine. And it is a challenging spectrum to regulate.

Unfortunately, what we have today amounts to a regulatory light switch for cell therapy; one that is either OFF or ON. For some cell therapies there is essentially no pre-market regulation. But at some point of added complexity, often arbitrarily decided by the FDA, the switch flips to ON and the cell becomes a drug in the minds of the Agency. And the consequences could not be more profound.

A product can be introduced through the OFF pathway in days with no FDA review and at very little cost. The ON pathway on the other hand, takes 10-20 years and can cost over a billion dollars. For cell therapy, there is no in between.

It is not possible to regulate the continuum of cell therapies fairly and effectively by using this binary approach. The system is broken and is impeding the hunt for safe and effective treatments for suffering patients.

Why? Because sensible people don’t invest significant capital gambling that the FDA will give them a pass out of its rules. They evaluate the time and cost of development assuming they will be forced down the ON pathway. They also assume that this arbitrary approach to regulation will (and often does) work against them by allowing a competitor to enter the market through the OFF pathway, placing them at a prohibitive disadvantage. The results speak for themselves. After 15 years under this paradigm we have had only a few cell therapies approved, all commercial disasters.

This is because the ON-OFF approach fails to adequately account for the difference in cell therapy complexity. To better understand, imagine this methodology applied to the regulation of automobiles. The government might permit low tech cars, say the Model T, to be sold without pre-market regulation. But if a manufacturer wanted to improve the vehicle by adding air conditioning, a radio or other such feature, the car would be subject to massive pre-market regulation. And not just on the new feature. Instead, the addition of the new feature would trigger a bumper-to-bumper evaluation of the entire car, increasing its development cost from basically nothing to that of a Lamborghini. The result would be streets full of hot, radio-less go-karts, except for a few ultra-high-end sports cars whose manufacturers are now defunct because they were never able to recoup the disproportionate costs of satisfying the regulatory system. This is what we see with cell therapies today: progress that is sluggish at best.

How can we move forward?

Ironically, the FDA identified a solution to the problem. In order to account for the broad spectrum inherent to cell therapy, in the late 90’s the FDA proposed a progressive, risk-based approach. The higher the risk, the greater the regulation. This guards against under regulation that might put patients at risk and prevents overregulation that can disincentivize the development of new or improved products.

In the FDA’s own words, the regulation they proposed would abide by a few basic principles:

  • “Under this tiered, risk-based approach, we propose to exert only the type of government regulation necessary to protect the public health.”
  • “The regulation of different types of human cells… will be commensurate with the public health risks…”
  • “These planned improvements will increase the safety of human cells… while encouraging the development of new products.”

It was a remarkably common sense approach that would have balanced safety with the need for innovation over an exceptionally broad range of technological complexity and risk.

It would have.

Unfortunately, the regulatory framework that was promised was never delivered, and it is time to resuscitate it. The burden placed on the development of cell therapies must accurately reflect the risks; must be balanced against the very real consequences of doing nothing (patients continuing to suffer); and must be consistently and fairly applied. In short, the FDA had it right and we need to give them the tools to deliver the regulatory paradigm they originally envisioned.

If we fix this highly fixable problem, we can create a system that will drive new innovations and better outcomes. Europe and Japan have already acted and are seeing the benefits. People with great ideas are coming off the bench, and game changing therapies are entering practice. While challenging the status quo does not sit well with some, particularly those who stand to prosper from the built-in barriers to entry the current structure provides, in the United States we have a responsibility to do better for patients and fix this broken system.

Randal Mills, Ph.D., is the President and CEO of the California Institute for Regenerative Medicine

William “Bill” H. Frist, M.D. is a nationally-acclaimed heart and lung transplant surgeon, former U.S. Senate Majority Leader, and chairman of the Executive Board of the health service private equity firm Cressey & Company.

Timing is everything: could CRISPR gene editing push CIRM to change its rules on funding stem cell research?

CRISPR

Talk about timely. When we decided, several months ago, to hold a Standards Working Group (SWG) meeting to talk about the impact of CRISPR, a tool that is transforming the field of human gene editing, we had no idea that our meeting would fall smack in the midst of a flurry of news stories about the potential, but also the controversy, surrounding this approach.

Within a few days of our meeting lawmakers in the UK had approved the use of CRISPR for gene editing in human embryos for fertility research —a controversial first step toward what some see as a future of designer babies. And a U.S. Food and Drug Advisory report said conducting mitochondrial therapy research on human embryos is “ethically permissible”, under very limited conditions.

So it was clear from the outset that the SWG meeting was going to be touching on some fascinating and fast moving science that was loaded with ethical, social and moral questions.

Reviewing the rules

The goal of the meeting was to see if, in the light of advances with tools like CRISPR, we at CIRM needed to make any changes to our rules and regulations regarding the funding of this kind of work. We already have some strong guidelines in place to help us determine if we should fund work that involves editing human embryos, but are they strong enough?

There were some terrific speakers – including Nobel Prize winner Dr. David Baltimore; Alta Charo, a professor of Law and Bioethics at the University of Wisconsin-Madison  ; and Charis Thompson, chair of the Center for the Science, Technology, and Medicine in Society at the University of California, Berkeley – who gave some thought-provoking presentations. And there was also a truly engaged audience who offered some equally thought provoking questions.

CIRM Board member Jeff Sheehy highlighted how complex and broad ranging the issues are when he posed this question:

“Do we need to think about the rights of the embryo donor? If they have a severe inheritable disease and the embryo they donated for research has been edited, with CRISPR or other tools, to remove that potential do they have a right to know about that or even access to that technology for their own use?”

Alta Charo said this is not just a question for scientists, but something that could potentially affect everyone and so there is a real need to engage as many groups as possible in discussing it:

“How and to what extent do you involve patient advocates, members of the disability rights community and social justice community – racial or economic or geographic.  This is why we need these broader conversations, so we include all perspectives as we attempt to draw up guidelines and rules and regulations.”

It quickly became clear that the discussion was going to be even more robust than we imagined, and the issues raised were too many and too complex for us to hope to reach any conclusions or produce any recommendations in one day.

As Bernie Lo, President of the Greenwall Foundation in New York, who chaired the meeting said:

“We are not going to resolve these issues today, in fact what we have done is uncover a lot more issues and complexity.”

Time to ask tough questions

In the end it was decided that the most productive use of the day was not to limit the discussion at the workshop but to get those present to highlight the issues and questions that were most important and leave it to the SWG to then work through those and develop a series of recommendations that would eventually be presented to the CIRM Board.

The questions to be answered included but were not limited to:

1) Do we need to reconsider the language used in getting informed consent from donors in light of the ability of CRISPR and other technologies to do things that we previously couldn’t easily do?

2) Can we use CRISPR on previously donated materials/samples where general consent was given without knowing that these technologies could be available or can we only use it on biomaterials to be collected going forward?

3) Clarify whether the language we use about genetic modification should also include mitochondrial DNA as well as nuclear DNA.

4) What is the possibility that somatic or adult cell gene editing may lead to inadvertent germ line editing (altering the genomes of eggs and sperm will pass on these genetic modifications to the next generation).

5) How do we engage with patient advocates and other community groups such as the social justice and equity movements to get their input on these topics? Do we need to do more outreach and education among the public or specific groups and try to get more input from them (after all we are a taxpayer created and funded organization so we clearly have some responsibility to the wider California community and not just to researchers and patients)?

6) As CIRM already funds human embryo research should we now consider funding the use of CRISPR and other technologies that can modify the human embryo provided those embryos are not going to be implanted in a human uterus, as is the case with the recently approved research in the UK.

Stay tuned, more to come!

This was a really detailed dive into a subject that is clearly getting a lot of scientific attention around the world, and is no longer an abstract idea but is rapidly becoming a scientific reality. The next step is for a subgroup of the SWG to put together the key issues at stake here and place them in a framework for another discussion with the full SWG at some future date.

Once the SWG has reached consensus their recommendations will then go to the CIRM Board for its consideration.

We will be sure to update you on this as things progress.