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?

12 thoughts on “Important, endangered species in stem cell medicine: the phase III trial


  1. Regulatory approval to market a therapy doesn’t mean health insurers will necessarily cover costs. Any drug given approval after Phase II but still lacking compelling safety and efficacy data is unlikely to complete with others that have proven their worth. Hence, I think big pharma will still perform Phase III studies if they want access to national health service budgets.

    Also wouldn’t approval after Phase I/II only be given for the specific populations (cohorts) sampled? That’s usually not many patients, and it would be necessary to run multiple Phase II studies to extend approval to further patient types. A Phase III would likely be cheaper.


  2. The reason for the change is stem cells are safer and they’re tackling unmet needs. Don’t drop Phase III for stem cells, allow prospective patients to bid to participate in trial in an auction so company is reimbursed for trial. Limits patient risk and provides earlier reward to companies, helping keep costs down and encouraging companies to stay small instead of going to big pharma. You’d think this is unfair to poor people, but instead it’s asking the rich to pay for development costs by giving them early access to promising treatments.


  3. Hi Paul, I am confused by:
    “In some cases, this “stem cell tourism” has led to the deaths of patients even as they are trying to improve their health abroad [20]”

    The paper that you cite:
    http://www.ncbi.nlm.nih.gov/pubmed/22420449
    seems to have nothing to do with stem cells, let alone stem cells causing deaths. The paper does indicate that it might reference other:
    “peer-reviewed articles identifying patient deaths in cases where patients traveled abroad for commercial kidney transplantation or stem cell injections”
    Perhaps it would be better to cite those papers? That way the reader might be able to access evidence as to whether or not stem cells were really killing patients — or was it some other medical error/complication or even the disease itself that caused death. I guess I could work my way through the literature… but that would mean paying for access to papers just to find where the real meat of the matter might be found and I might still not end up covering the same ground upon which you have based your thinking.


  4. “Bench-to-bedside” is one path. I accept that it’s the path that may best describes the combined workings of Big-Pharma/FDA and academics.

    Physician innovation also happens at the bedside, the “bedside-to-bedside” path.

    Science does not restrict us to one meritorious pathway, there should be many. In a nutshell, that is why the FDA should be kept in a small box. I suspect that even within the FDA there are some who understand the dangers of being hegemonic.


  5. @Brian – would you agree that all paths should nevertheless be evidence based, appropriately controlled and peer-reviewed?


  6. @Jeff
    Evidenced based seems to be a murky term, like “sustainability”.

    I favour paths that are science based. And I mean science in the sense that Feynman talked of science and in the way I have tried to practice it. I do NOT mean science in the way that “philosophers of truth” talk about it (eg Karl Popper).

    In my view there is a fundamental disconnect between regulation and science.

    I appreciate what Paul tries to do even if I don’t totally agree with him. The law that prevents both of us from saying what we really think is the same law that Paul seems to take comfort in because it found in favour of FDA over Regenerative Sciences.


  7. @Brian – I’m surprised you think evidence-based medicine is a murky term. In clinical medicine it is the systematic translation of the scientific method that you describe. Maybe you’re worries about the way some dubious clinics may also use the term to describe n=1 results, which obviously don’t hold water according to scientific methods.

    Anyways, would you agree that all paths should nevertheless be clearly based on sound scientific evidence, appropriately controlled and peer-reviewed?


  8. @Jeff — I am not an insider in the field of medicine and medical research so I can only judge “evidence-based medicine” from what I hear experts say in the media. I have often been dismayed by the blurring of regulation INTO science.

    As I have pointed out before, regulators throw a yes/no switch. Nothing rankles me more than the misuse of the word “proven”. It would be wrong to say that that’s good science. It’s not even science!

    In science we know things to a certain accuracy to within a certain range of circumstances…

    I struggle with the way that the usefulness of science should be tied to a bunch of regulations. I wonder if you do also?


  9. @Jeff — The n=1 outcome is an interesting thing. It all depends upon context.

    Background radiation from the “big bang” could be called an n=1 experiment. It gains credibility due to context — being mathematically related to other knowledge.

    Similarly, if a disease has always been observed to be irreversible, an n=1 recovery becomes very interesting. The important thing is to report the next n, and the next… There are “for profit clinics” that do do that. I don’t think that they should be maligned.

    Sometimes we see that an n=1 (out of N>>1) bad outcome from one type of “stem cell procedure” at one clinic is used to argue against other types of procedure at another clinics when the only thing they have in common is that the clinics were “for profit”.

    There are no simple methodological ways to distinguish the good stuff from the bad stuff. I’m reminded of Popper’s “falsificationism” method to distinguish science from pseudo science. Hansson showed that the empirical evidence falsified falsificationism. Yet the long shadow remains.

    Hansson, S.O. (2006) “Falsificationism Falsified”, Foundations of Science, Vol 11, Springer pp 275-286.


  10. @Brian – evidence-based decisions of therapeutic safety and efficacy are not always successful, but are more successful than unsuccessful. It sounds like you want to throw the baby out with the bathwater with some of your inaccurate and populist comments. But you’re missing the core problem – how to make sure that evidence-based medicine is performed to include the majority of therapeutic assessments.

    The n=1 question may or may not be resolved by multiple n=1 cases – it depends if there are controls and whether data is presented for peer-review. At many stem cell clinics this is not the case, but in others much data has accumulated and there is hope that an evidence base exists. However, a mass of data and even a 20%+ success rate (i.e. unlikely to be placebo in at least some) is still not sufficient for health authorities to cover treatment costs for all, if e.g. the benefit over current therapy is not shown or their are non-responsive patient subpopulations.

    Back to the question – don’t you agree that all therapies be assessed through solid scientific evidence, controlled studies and peer-reviewed published data?
    You wrote that “the criterion for sorting the wheat from the chaff is to make sure that the stem cell clinic is publishing outcomes in a respectable scientific/medical journal.” I agree with you.

    Btw, how do you know the big bang was a n=1? 😉

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