Navigating 4 key kinds of stem cell studies

kinds of stem cell studiesOver the years and in particular after Dr. Oz’s show a couple weeks ago, I’ve heard from many patients who are absolutely convinced that stem cell therapies do in fact work and are safe. They have been focused particularly on hematopoietic stem cell therapy (HSCT) for MS but also other investigational applications using a variety of stem cell types including adipose stem cells.

Almost without exception the kind of stem cell therapy that patients are referring to in these cases are not conclusively proven to work and be safe. In certain instances the type of stem cell therapy some patients mention are not the same kinds of stem cell therapies as what Dr. Oz and his guests were criticizing. We all need to keep in mind that there are different stages to or kinds of stem cell therapy studies.

What are the main different types of stem cell therapeutic studies? How do we tell the differences and what benefits/risks are possible with each type to patients?

First, there are preclinical studies, which can range from work done in a test tube to cells in a dish to transplants in rodents or other research animals. This kind of research can be exciting and lay the foundation for clinical work. On the flip side, some times it can be hyped as being very close to leading to a human therapy. For instance, just because a paper shows that a certain type of stem cell may have benefit in cells in a dish or in rats doesn’t mean it will do the same in people. Often it won’t. But this kind of research is an important first step even it doesn’t mean a human therapy of the same kind is near on the horizon. So for most patients, this kind of stem cell work is not the basis alone for a therapy you will get any time soon or at least it shouldn’t be, but it is worth paying attention to as part of one’s ongoing stem cell “homework”. The risk at this level is giving patients too much unsupported hope. Yes, this category could probably be subdivided into many categories (e.g. in vitro vs. in vivo, etc.), but hopefully you get the point that this is foundational work overall.

Early phase clinical trials are designed to learn more about the drug in question (yes, stem cells can be drugs) such as its pharmacological properties in vivo and especially its safety. The main question at issue here is in fact whether a therapy has adequate safety.  These studies generally will not use placebo control. When most people refer to early “clinical trials” in the US, they mean FDA-approved trials with INDs in place before even one patient gets involved. I believe this is the most appropriate definition of an early clinical trial. Patients who enroll in early trials are taking risks for the benefit of others and to advance knowledge so I think of it as somewhat of a heroic act.

A concern is whether in some instances those who will be administering the investigational therapy will conduct proper consent. Sometimes there could be, perhaps even unconsciously, some indication given to the patient that they derive some medical benefit from an early trial even though these trials aren’t designed to test efficacy and often use sub-clinical doses. Open-label studies can lead to placebo effects or other confounding outcomes. Patients should not have to pay to enroll in these.

Later phase clinical trials further test safety and now start to tell us as a community about efficacy too. The gold standard is the RCT or randomized controlled trial. In these trials, patients can be in control groups (placebo or standard of care) or receive the therapy being tested such as an investigational stem cell drug. Patients are not typically charged for these also, except under what are supposed to be very rare instances pre-approved by the FDA. If conducted rigorously and yielding successful results, in the end these trials can fairly definitively demonstrate that something is safe and effective. Even then, sometimes safety issues can arise later with more widespread marketing and use as we’ve seen with various non-biological drugs, but that’s fairly rare.

Now moving outside the FDA-approved clinical trials process for the fourth kind of experiment….

Stem cell clinic’s “trials” are a different kettle of fish stem cells. In my opinion these are designed in many cases primarily to generate income taken from patients for the benefit of the for-profit businesses running them. Sometimes those running them truly believe the offerings work. Only very rarely (I would estimate ~1% of the time) here in this domain is data ever published.

Patients have to pay to get the experimental offerings from clinics. Also, these experiments usually do not have preclinical data to strongly support them, they lack control groups, they in some cases enroll large numbers of patients for no defined scientific/medical reason, most often they are not FDA-approved, and usually do not have data released publicly or subject to objective peer review by the wider stem cell community.

Now if a stem cell clinic publishes their study data in a legit peer-reviewed journal, even if it is not data from a RCT and even if it isn’t in some fancy top-tier journal, this can be useful for the community and some credit is due. Publishing in a peer-reviewed journal is not only a valuable step scientifically and medically, but also it means that the patients taking risks by being involved in this (and paying for it) are given an additional level of respect in that the information from their participation can help others.

Bottom line

Taking a probing, critical look at the different kinds of stem cell offerings out there such as those falling into one of the four above sections discussed above, is just practicing good science and medicine. Science is all about asking tough questions.

I understand that for some individual patients it may be only human nature to want to defend that “thing” such as an experimental stem cell offering that they believe helped them, but these things have to be rigorously proven and those administering (and in some cases profiting from) as yet unproven stem cell clinical offerings should be open to answering a range of questions. This goes across the board from stem cell clinics to those running FDA-approved clinical trials with INDs — so there’s no double standard!

Stem cell wish list for 2017

Last week I posted my list of 2017 predictions for the stem cell field. Today a couple of days into 2017 I’m more focused on hope than realism. What would I wish for in the stem cell and regenerative medicine arena in the coming year?stem-cell-wish-list

More stem cell clinical trial data posted and published. There are few things as exciting as stem cell and regenerative medicine clinical trials across the full spectrum of stem cell types including adult, embryonic, and IPSC. But we need to have actual trial data be peer reviewed and published or at least posted. Clinical trial updates only by press release are not helpful to patients or the field.

Clinicaltrials.gov adapts. This vital resource of trial listings adjusts to new realities. It either filters its listings to screen out for-profit entries that aren’t real trials or it provides more practically useful information such as at a minimum clear indications of whether a listing has an IND (this doesn’t need to violate any confidentiality rules) and whether the listing requires payment as an inclusion criteria. See my interview with the leader of Clinicaltrials.gov.

FDA speaks clearly. Whatever the FDA does or does not do in terms of actual stem cell & regenerative medicine-related actions in 2017, it is clear about it. This year I hope the FDA provides concrete, consistent explanations in the public domain that don’t require an FDA-ese jargon dictionary to try to understand.

FDA and its CBER center are consistent with good & bad citizens of the stem cell arena. The FDA has a tough job overall and its CBER branch focusing on biologics including stem cells has its own specific challenging task set. However, for years CBER has held different players in the stem cell arena to different rules and expectations. Paradoxically, essentially the better a citizen you are, the more the FDA expects from you. On the flip side, if you are for instance a stem cell clinic with no intention of following the rules (no BLA, no IND, no pre-IND, no expertise in stem cells, no data, etc.) CBER has historically generally left you alone.

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Stem cell checkup: how are my 2016 predictions doing half way?

Stem Cell PredictionsEach December I make stem cell predictions for the coming year and I did that for 2016 where I made 20 predictions. At around mid year I do a checkup on how my predictions are doing halfway and that is the purpose of this post.

Below are my predictions that I made in 2015 for stem cells in 2016 and my general sense in green of where they stand. Overall, I’m doing reasonably well, but I kind of wish I wasn’t because so many of these are not positive developments. However, in general I remain very optimistic for the field and expect major positive advances in coming years on a number of fronts using both adult and pluripotent stem cells.

The predictions and status so far.

  1. Another stem cell biotech acquisition by pharma (recall Ocata (now finally sold to Astellas) & CDI in 2015). Checkup: Not yet.
  2. Charging patients for clinical trial participation, particularly in Japan due to the new policy and here in the US related to predatory clinics remains a hot topic. Checkup: Correct.
  3. Stem cell clinics and doping in sports flares up more. Checkup: Clinics yes, doping not yet.
  4. Organoids continue to excite. Checkup: Correct. What a great technology.
  5. Bioheart and some other small stem cell companies struggle. Checkup: Correct so far. The PPSs of small stem cell biotechs have generally not been pushed up this year by investors, but rather the reverse. Note that Bioheart is now called US Stem Cell, Inc. We can all hope that there is a turnaround for small stem cell biotechs in the market in the 2nd half of the year.
  6. Stem cell stocks overall have a bad year. Checkup: Correct so far also sadly. Note, by way of disclosure I do not currently have any direct stem cell stock investments.
  7. Stem cell clinics ever more aggressively use celeb clients for PR and marketing Why? It is powerful, effective, and essentially free advertising. Checkup: Correct.
  8. More news on human-animal chimeras. Checkup: Correct. Another hot topic.
  9. FDA continues its slow-go approach to action on stem cell clinics/unapproved stem cell products. Checkup: Correct.
  10. Pressure from industry and some academics on FDA to not regulate adipose products as drugs and/or to not enforce some other draft guidances including at the upcoming public hearing on the draft guidances. Checkup: Correct. REGROW and other efforts have been unprecedented. Note that the FDA public meeting will now be held in September rather than in April.
  11. FDA receives increasing public criticism for “slowness” on approving new stem cell therapies including from beyond the stem cell clinic industry. Checkup: Correct in a big way. 
  12. One or more lawsuits against a stem cell clinic. Checkup: Correct and several more seem to be brewing. Note that it appears that the part of the suit involving US Stem Cells, Inc. has been settled, while a separate part of the case against other defendants continues.
  13. A new stem cell scandal pops up related to publication issues. Checkup: Correct. You just have to go visit Retraction Watch (e.g. the Spain mess) or PubPeer, and then also see the continuing Macchiarini saga.
  14. Some hiccups on mitochondrial transfer/3-person IVF in the UK or China. Checkup: Correct. Diseased mitochondrial carry-over and mito-nuclear cross-talk issues have popped up and deserve serious attention.
  15. The trend last year of increasingly blurred lines between legit research entities such as universities and dubious stem cell enterprises continues. This is worrisome. Checkup: Correct.
  16. Stem cell-derived human germ cells stay in the headlines. This has exciting potential for providing new windows into human development and tackling infertility, but also raises thorny issues such as human genetic modification. Checkup: Correct.
  17. ViaCyte has some big newsCheckup: Not yet. What a great company.
  18. High-profile developments on veterinary use of stem cells. Checkup: Correct. For instance see this piece in Scientific American. Cool stuff!
  19. Animal cloning, particularly in China, continues to proliferate. Checkup: Correct.
  20. More rumblings on possible human reproductive cloning attempts. Checkup: Not much concretely yet. See this piece on cloning focusing on 20th Anniversary of Dolly.

Stay tuned as near the end of 2016 I will do a final assessment of how I did on my stem cell predictions and then make stem cell predictions for 2017. What are your stem cell predictions?

Do for-profit stem cell studies have inherent potential biases?

There’s been an interesting and diverse discussion going on here on this blog lately related to some stem cell translational things including a stem cell clinic operating in Sacramento (see 50+ comments on that post) and then more recently on a new paper from the Centeno clinic.

Over on Twitter, Leigh Turner raised the valid point that he didn’t see a conflict of interests or competing interests statement in the Centeno paper. I didn’t see one either. Most journals require such statements. In this case, such a statement would have been important because unless I missed something, one or more of the authors profited from the study itself via charging patients.

This also raises the question of whether any given for profit stem cell clinical study has inherent biases, which could even be unconscious. Why? Providers in such a context benefit if the results are encouraging and patients who pay for experimental medical therapies may have a stronger placebo effect.

On one level the same kind of bias could come into play to some extent in certain academic or biotech stem cell clinical settings too if those running the studies have potential financial interests in the outcomes.

The best way to deal with such potential factors is to have rigorous controls and for those running the studies to be aware of and disclose potential conflicts and biases as well as potentially consulting with a bioethicist.

Stem cells on Mother’s Day, clinical trials, and more

One of the many interesting ways in which “stem cells” are named in different languages around the world is “mother cells”. For example, in Spanish, you can learn more about these “mother cells” here in ¿Qué son las células madre?Stem Cell Symbol

On Mother’s Day it is worth thinking about where the stem cell field stands at this time.

There has never been a more exciting time than today for stem cell research and the related area of regenerative medicine. There is good reason for hope that stem cells may translate into real, proven safe and effective treatments for a many conditions in coming years and decades.

The total number of stem cell trials continues to grow. While not an exact measure and as we’ve seen some minority of “trials” are really more about making money than anything else, the number listed in clinicaltrials.gov is pushing 5,000 when I search for “stem cells”. All around the world there are much-loved moms who are facing difficult health issues and perhaps the “mother cells” of stem cells in the future can be the answer to help.stem cell clinical trials map

I get contacted by patients almost every day now and probably at least half of the patients I communicate with are women. Some are mothers inquiring about stem cells for their children who might face various conditions such as autism or cerebral palsy. Others are asking about treatments for themselves or their moms, in particular for multiple sclerosis (MS) the last few years.Today we should be careful if our moms are considering stem cells to advise them to use caution, as there are many challenges out there in the for-profit stem cell world. But it is important too to talk about real hope as the stem cell field continues to develop.

Happy Mother’s Day!