Important, endangered species in stem cell medicine: the phase III trial

Traditional clinical trials have four phases. Each phase plays an important, unique role in testing whether new drug products are safe and effective as well as how they compare to the standard of care.

stem cell clinical trial system

Today in the stem cell field across the globe, the Phase III is under fire including what some might call friendly fire from some academics even.

For instance in Japan and now in the US, there has been pressure to drop the requirement for Phase III in certain cases.

Japan has raced ahead on implementing this change.

The idea behind this move is to accelerate getting new treatments such as regenerative medicine therapies to patients. However, there is a point to having Phase III trials so reducing the requirement for them could pose risks in addition to the potential benefit of speeding up the process. Stem cell clinics have generally not even bothered to do real clinical trials at all. See diagram from Figure 1 of my recent paper.

Bypassing Phase III may be appropriate in rare compassionate use cases and that is now permitted via discussion with the FDA here in the US, but what I’m talking about in this post is the broader idea of not requiring Phase III even in non-compassionate use cases.

The NIH summarizes the four clinical trial phases this way:

  • Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
  • Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
  • Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
  • Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug’s effect in various populations and any side effects associated with long-term use.

The Pancreatic Cancer Network has a nice summary of why Phase III trials are important:

“Q: What is the importance or significance of Phase III trials?
A: Phase III trials are the best way to find a new standard for treatment. Once a Phase III study is completed, the groups of patients can be directly compared to one another to evaluate outcomes. (In other words, researchers can see if one group did better than the other group.) If the patients on the new treatment did better, a new standard of care may be established.

Therefore, this type of trial may result in drugs gaining approval by the FDA and changing the way doctors treat patients. Promising treatments may emerge in other phases, but those trials are not definitive enough to change standards of care or the way we treat patients.”

In other words, based solely on Phase I and II data, no one can be sure the new drug in question is safe, effective, or better than the standard of care. While this example is regarding cancer, the general points here are applicable to stem cell therapies too.

The idea being floated around of eliminating Phase III trials for stem cell products here in America would be a big change and bring new risks into play.

Is that worth the potential benefit of increased speed of getting stem cells to the bedside?

Poll: What’s now most exciting in stem cell & regenerative medicine field?

New Interview With Masayo Takahashi (高橋 政代) on IPSC Trial: Guest Piece by Michael Cea

By Michael Cea
Stem Cell Analyst & Advocate
(editor’s note: piece was originally posted on Michael’s blog here; follow Michael on Twitter @msemporda)

 

Having followed closely the developments in programs using pluripotent based therapeutics I was fortunate during ISSCR2015 to have the opportunity to sit down with Dr Masayo Takahashi to discuss her pioneering efforts to translate Shinya Yamanaka’s groundbreaking iPS technology for debilitating retinal conditions.Masayo Takahashi

As most everyone is aware, the first iteration of the program, for advanced Wet AMD, has entered the clinic and been safely administered to the first patient – a milestone achievement for the field, which has been widely covered by the media, especially in Japan. However, as I learned first hand, this first step is but a part of a comprehensive strategy to address most retinal diseases by way of various cultured cell transplantation methods, depending on the patient condition – including suspension therapies and multi-layered organoid developed tissue. This was best described by Masayo “what I have said to the Japanese regulators is that ideally we need all cell types – sheets, suspensions, auto, allo – and the surgeons will choose which to use for each patient.”

Monkey stem cell RPEsBefore relaying the key segments of the interview, I wanted to express some thoughts of how practical and committed to the patient Masayo is. Her clinical practice is at the very heart of her professional vision – to bring relief to those that come to her for help. Disappointment again and again in not being able to help drives her passion for new therapies. She is both confident and open to the process that has already taken more than a decade and a half of her research. The goal being, in time, to have all the tools necessary to deliver on the promise to her patients and fulfill on that hope, that is very real and apparent today – something she couldn’t point to just a few short years ago. Her new message is very clear now “visual impairment is not as bad as they think and you can change that world – so there is hope – yes.”

Cheers

Interview:

Q: There is a lot of hype in the field how have you addressed that?

MT: When I started to do the regenerative medicine work the media broadcast our efforts and many patients came and they expected I could help them. But 10 years ago I was very nervous because after hearing the news they were disappointed in front of me so I started to talk to the media and educate. Every month we worked with media so gradually within this period they learned and suppressed their expectations so in Japan the hype isn’t so high anymore.

Q: Does the Internet makes things easier for patients to understand?

MT: People who can connect with the Internet can understand but the older people still don’t have access to the Internet and rely on the newspaper and TV but sometimes they’re informed wrongly as a result so I still struggle.

Q: Is that due to the technical language and complexity of the science?

MT: Common sense is different from the medical reality but the regenerative medicine area is very focused so we can use the media to inform the public correctly. Regenerative medicine won’t cure everything but if you think in a different way you can do many things. The “hope” should be the correct one. People need to learn the way of thinking of the scientists – in Japan people are very clever and gradually they have understood. So if you teach correctly they can understand gradually. It’s important to relay the correct information. Media sometimes tries to simplify as a need or belief in the communication method yet they lose the true message. Stem cells are a specific area with many unknowns – yes – it’s like a “black box.”

Q: You started using ES neuronal cells then moved to iPS and retinal cells

MT: Yes, a little background. I started in 2000 with ES cells and proved in mid-2000 using primate ES cells that we could treat some retinal diseases but we hesitated to move to the clinical stage because the risk of immune rejection. By that time iPS cells came out and I was very happy as I knew the last hurdle would be solved w/ iPS cells so we immediately started research using those cells and after 5 to 6 years of translational research in preclinical studies we started the 1st patient clinical application last September and we will judge the safety and effect 1 year later this September. We announced mid-term results in March and so far we don’t observe any immune rejection without any immunosuppression, which we expected as a result of using autologous iPS cells.

There was a famous paper in the journal Nature that the autologous iPS cells invoked immune rejection in a mouse model but I think the research design wasn’t very good. They transplanted kind of a tumor which would be rejected – not the iPS cells but the tumor.

Q: Was the surgery difficult for the lady (1st patient)?

MT: Yes the surgery was the most risky part. We were worried a little but the procedure was successful with no adverse events so far.

Q: And the next patient?

MT: We tried, we prepared but decided to go quickly to the allogeneic because the cells are already there from Shinya Yamanaka’s cell line stock. He made the 1st iPS cell line and they have come to our lab.

Q: Have they been approved as clinical grade by the Japanese regulators?

MT: Yes but about the protocol, we will apply within this year for approval. We should reapply as it’s allogeneic, different from autologous.

Q: Will this line be available to others?

MT: Shinya Yamanaka will distribute to various centers with one of the institutions being mine. So there will be a Spinal Cord Injury protocol, maybe the Parkinson’s disease trial will go to an allogeneic protocol, the hematopoietic (platelets) will also. So the various protocols will use that cell stock.

Q: Japan is moving very quickly, is that of concern in the community or is that in your mind appropriate?

MT: Most patients are supportive but some people worry we move too fast but really we prepared, labored and accumulated the data and the people who don’t know the whole data usually say you have the risk – that’s very stressful. So actually we don’t care what they say because they don’t know. Maybe it’s a social balance.

Q: Are you taking the trials also outside of your home market?

MT: In the near future. We made a start-up company, Healios, they made an IPO last week, they plan to do a clinical trial in 2 or 3 years time in the US as they need the time to apply the protocol.

Q: I’d like to get your opinion on the use of a monolayer versus the selection of a suspension protocol.

MT: The people who don’t know the disease think the big sheet is the best but there are many, various situations with the disease, various stages, various lesion sizes, so some patients need a large sheet. Ours is 1 x 3mm, people in the US are preparing a 3 x 5mm sheet, so some people don’t need such a big sheet and earlier stage patients don’t require a big incision, so cell suspension is more feasible.

Q: What is your current disease state target?

MT: Advanced Wet AMD and we pull out the neovascular tissue, so a big defect of RPE, and cell sheets are appropriate but if the neovascular damage isn’t large we don’t want to cut and therefore cell suspension is better.

Q: The market is fragmented – is there a synergy with other programs?

MT: The regenerative medicine area is different than the small molecules, it’s more adaptable, so the judgment should return to the clinical scene and not the big pharma. The clinical reality will determine application and the Japanese government knows very well about this issue and we cooperated to make the new law. The Ministry of Health accepted that regenerative medicine is different than small molecules and that all is needed is a small number of patients to get approval, which is a great advance, a revolution.

Q: Is safety sufficient in a small population study?

MT: Of course the accumulation of the animal data needs to be reconfirmed by 10 or so patients for safety but the statistical significance of the efficacy needs more patients to prove the probable efficacy. Companies can sell the products based on smaller numbers so we don’t need big big pharma for promoting regenerative medicine. Companies can sell but they must register and prove efficacy within 7 years with regular exams. Success will be a collaboration between regulatory and academia with insurance reimbursement playing a commercial role which is incredible and kind of a risky law. The background of that is that academia promoted the regenerative medicine mainly so we cooperate very tightly with government and will decide where to provide treatment after approval with rules later.

Q: Do you plan enhanced cell products?

MT: Manipulated cells can work better, yes. So far natural cells are the most feasible, as regulators don’t like manipulated cells or “supercells.” In future but for now natural cells are good.

Q: Can you speak to the adult cell types?

MT: MSCs are safe. iPS/ES are hard to control so are limited to institutes that can maintain them/control them properly but the industrialization for a standard treatment iPS/ES is very good because we can have one lot otherwise many donors and always a lot of changes so that’s not very good industrially. In the future the ES & iPS cells people can control will be the way to industrialize and standardize treatment.

Q: What are your future plans / next steps?

MT: Our next steps are to have combined stem cell sheets – not only RPE but RPE with Photoreceptors and perhaps the vessel layer. Like a dream in our institute, that has a very high developmental biology focus, we talk about the whole retina with blood vessels and will try to deliver the entire retina for retinal disease conditions that destroy all the layers. For now we are working on monolayers, suspension, photoreceptors, combined layers and ganglion etc with 2016 for the allo, 2017 for the Healios suspension and 2018 for the photoreceptors.

Q: Are you collaborating with other institutions – is that part of your plan, UCL for example?

MT: We are not actually collaborating. We have a communication and information exchange, like a think tank. We know how they promote and we are doing very well. We don’t have to hide. They use similar technology adapted from our work. The aim is to make a standard treatment.

Q: Is ownership not an issue?

For the company it’s an issue – I don’t care. Patients don’t care. Healios is very good and they are in contact with the NIH group and the Ali group (UCL) – maybe they collect good procedures from the world.

Q: Are companies in Japan are looking at this sector as a team approach – does this help?

MT: Yes, society of regenerative medicine companies in Japan are maybe 100 companies now under the F.I.R.M association. Fuji, industry, pharma – all diverse companies. Not as a Keiretsu but more an association. Companies are now interested unlike 5 or 6 years ago. I told many companies to help us but they didn’t in the beginning but now they do. The government has helped a lot having supported the industry 10 years ago but they see the reality now as we have the clinical application.

Q: How do you see yourself, as a leader, role model – is there pressure?

MT: Shinya Yamanaka is like an Emperor now – everyone adores him. About the pressure, we have accumulated the data so I don’t fear anything. I have a scheme for 10 years plus and a plan. I know all – from the cells, the pluripotency, genes, animals, disease, patients and social and no worries only a process to move along. There are some against us but if I listen to their talks I’m not convinced by them, I mean persuaded, something wrong in their logic. As a role model – maybe I should behave myself! Patients happiness is what I believe – not papers or money, not interested. Patients first, outpatient clinic is very important to me.

Q: How do you view Lucentis/Eylea?

MT: Wonderful – we saw AMD 25 years ago and there was nothing at all. So we just explained the disease as incurable for 10 years but finally it came out, it was wonderful. We knew AMD very well and knew Lucentis wouldn’t cure everything. The treated patient had 10 injections before surgery and her condition deteriorated from 0.3 to less than 0.1 even though she had the available treatment, so we stabilized her visual acuity with radical treatment without any injection.

By way of disclosure: I have no conflict of interest, financial relationship with anyone or company mentioned in this article.

Japan Aiming For a Commanding Position on New Stem Cells

Masayo Takahashi ISSCRStem cell technology is poised to wow the world with biomedical advances in the coming decades.

Japan wants to lead the way, particularly with applications that focus on a relatively new kind of stem cells called induced pluripotent stem cells or iPS cells.

Japanese researcher, Shinya Yamanaka, first reported production of iPS cells in 2006 in mice and in 2007 in humans.

Japan has raced ahead of other countries and they appear to have the intellectual property rights and drive to do so. And Japan wants to accelerate further.

According to a quote attributed to Dr. Masayo Takahashi, the leader of a Japanese team pursuing an iPS cell-based therapy for the leading cause of blindness, macular degeneration, Japan is aiming to be in a commanding position.

 “I want us, Japan, to dominate the world in the area of therapies using iPS cells,” Masayo Takahashi, who is leading the study at government-funded research center Riken, said in an interview. “It feels like the government is opening one door after another to help.”

This is a very striking quote so I emailed Dr. Takahashi a few days ago asking her to confirm it and talk a little more about what she meant. If I get a response I will let you know. She may have been misquoted on that “dominate” word?

While I worry that researchers in Japan may be moving a bit too fast to human studies, at the same time I have to admire their dedication and commitment to translating iPS cells into clinically relevant medicines.

In addition, the Japanese government has definitely stepped up to the plate, committing more than $1 billion USD specifically to iPS cell research.

For reference, the entire NIH budget in the US to study all biomedical applications is just under $30 billion and sadly is shrinking, particularly compared to inflation….and there’s no way that anywhere close to $1 billion of that NIH funding is for iPS cells, not even over a period of many years. I’m hoping to get some hard numbers on NIH funding of iPS cells in the coming months, but I suspect it is more like one hundred million. I hope I am wrong and it is much higher.

Another US example is that the total CIRM (California stem cell agency) budget for 10 years is $3 billion for all kinds of stem cell research. CIRM has funded a sizable amount of iPS cell research so the state of California is a serious competitor to Japan on iPS cells. Other entities in the US such as the Harvard Stem Cell Institute and some companies such as Cellular Dynamics are important players too.

Still Japan is remarkably committed to being the iPS cell leader and iPS cells are understandably a source of pride for Japan given Yamanaka’s achievements including the Nobel Prize.

I can only imagine where the currently 7-year old iPS cell field will be in another 7 years.

It’s tricky when it comes to getting iPS cell-based therapies to patients. The sweet spot–not too slow or too fast–for the speed of iPS cell clinical translation is not entirely clear today.

I hope Japan and other countries including the US as well as the research teams doing the translational work find that sweet spot.