To stem cell clinics: do your homework & take FDA “current thinking” seriously

FDA draft guidanceOne of the difficult things about the regulatory sphere that covers stem cells in the US is that many aspects are confusing or puzzling both to the public and so-called experts. We’ve been talking through some of the questions that come up in this area in posts and comments on this blog.

  • What does a warning letter really mean? What triggers it?
  • Why do some businesses selling stem cells get inspected and others don’t?
  • What do some entities get warning letters over the years, while others don’t?
  • What weight does a draft guideline have?
  • How about a finalized one?
  • If a business disagrees with an FDA guideline or action, what should it do?
  • If a business operates without FDA approval (maybe because they disagree with the FDA) when it seems that it should need that approval and yet the FDA takes no action, does that mean anything?

The list goes on and on.

It’s kind of like trying to read tealeaves. One of the FDA reforms I advocated for in my book, Stem Cells: An Insider’s Guide, is more clarity and better communication.

Despite the many questions and confusion out there, I would say one thing is clear: Take FDA “current thinking” very seriously.

While current thinking as articulated in guidances (draft or otherwise) is not formally equivalent to a regulation, it would seem to have the power to trigger action based on the historical record.

Therefore, one broader lesson in this arena would seem to be that the FDA can pull the trigger on actions like visits and warning letters based on their current thinking even if that current thinking is not formally crystalized beyond draft guidances or even without any draft guidances. For instance, it seems pretty clear that the FDA right now views SVF as a drug and while it may not have done much about this action wise yet, the odds are that such action will be coming sooner or later. The same goes for non-homologous use of bone marrow and amniotic stem cells such as for neurologic conditions. In other words, what the FDA staff think is going to be their basis for actions. SVF

As a result, it kind of goes both ways in the sense that guidances (draft or otherwise) are not formal regulations and “only” reflect current FDA thinking, but at the same time “FDA current thinking” shouldn’t be underestimated in terms of importance as it clearly can play a big role as the basis for action.

Too often I’ve heard clinics or other advocates say things like, “these are just draft guidelines” or “the FDA hasn’t been clear on that yet”. The reality is that no matter what any of us might like (e.g. increased FDA clarity), it is not the FDA’s responsibility to make sure everything is crystal clear for every stem cell clinic out there. Rather, it is the physicians’ responsibility to do their homework on the FDA and all relevant regulations, current thinking, etc.

If a clinic wants to challenge the FDA I can respect that if it is done responsibly, but it is a very different matter and a risky game to do such a challenge operationally by administering what by all accounts the FDA considers to be unapproved drugs into patients and then waiting to see if anything happens on the regulatory front.

This game of stem cell chicken is particularly risky if you are “treating” medical conditions outside of your specialty and do not have any rigorous training in stem cells as well as having little if any expertise in FDA regulatory affairs. And, no, a weekend resort or other similar quickie “course” on stem cells doesn’t really count.

Stem cell image contest: $100 prize

Knoepfler Stem Cell Insiders BookScience can come in various forms ranging from numbers to words to images.

In the stem cell field, some of the images can be particularly striking. One of my own favorites is the one above that I took some years ago of differentiation of neural stem cells that ended up on the cover of my first book.

Do you have a favorite stem cell-related image?

I’m doing a stem cell image contest.

The winner receives a $100 prize and their image will be posted here along with a blurb on their research.

If more than one entry is particularly amazing, I may give out more than one prize.

The rules are straightforward. Anyone can enter whether you are in academia or industry.

Email me your favorite stem cell-related image (knoepflerATucdavisDOTedu). The image must be your own. Team entries are allowed.

By entering the contest you agree that the image may be posted on this stem cell blog.

The deadline is September 30th at midnight USA PDT.

Risks for Healthy PBSC Donors? One Family’s Powerful Experience

By Jane Langille

A few weeks ago, I wrote to Dr. Paul Knoepfler after reading his book Stem Cells: An Insider’s Guide because I was intrigued by his stem cell theory of aging. I wondered if his theory might mean that someone who mobilized and donated hematopoietic cells might be shortening their own lifetime supply. After exchanging emails about my daughter’s experience, he invited me to contribute a guest blog as he felt that the complexity of her experience as a donor and the questions I was raising would be of interest to the stem cell community.

Peripheral blood stem cell (PBSC) donation is a miraculous treatment that provides people with high-risk forms of blood cancers and other immune diseases a last chance for a cure when other treatment options are exhausted.

As of December 2012, the number of hematopoietic stem cell transplants worldwide passed the 1 million mark, a remarkable accomplishment reported in a retrospective study published recently in The Lancet Haematology. Data collected by the Worldwide Network for Bone and Marrow Transplantation showed that across 75 countries, 42% of hematopoietic stem cell transplants (HSCTs) were allogeneic and 58% were autologous.

The preparation for cancer patients prior to receiving a donation is brutal. Their immune system is wiped out with high doses of chemotherapy and/or radiation therapy so their body is ready for an infusion of healthy, donated hematopoietic stem cells that hopefully find their way into niches in the bone marrow where they divide and produce healthy blood cells. The human leucocyte antigen (HLA) match between the donor and recipient must be as close as possible to minimize the risk of rejection.

It’s a remarkable treatment that helps many critically ill people. But what are the short and long-term risks for healthy donors?

Those were the questions I was contemplating in the spring of 2013 when my daughter Katherine, 22 at the time, turned up as a perfect match for an unknown patient in the bone marrow registry. I was worried about her decision to donate from two different perspectives: as her mom; and as a health journalist.

Short-term issues

As her Mom, I was proud that Katherine had a big heart and the courage to donate a gift of life to a complete stranger. According to some reports, only about half of the people who are identified as matches in the bone marrow registry follow through. This was the child who had to be bear-hugged for childhood vaccines, so I was surprised she was volunteering for a procedure that would mean self-injecting a growth factor drug, twice a day for four days, followed by leukapheresis, which requires being tethered to blood filtering equipment with cannula in both arms for hours.

I also wondered how she would manage the stress, given that the donation was squeezed in between grad school interviews, final exams and her thesis presentation in her final year of university. The information provided by Canadian Blood Services’ OneMatch Stem Cell and Marrow Network said that donors would feel tired and achy for 5-7 days and there were possible complications of spleen rupture, but those symptoms would return to normal fairly quickly after donation was completed.

Long-term worry

As a health journalist, I had another worry. I didn’t like that the growth-factor drug she had to inject for four days prior to donation had an unproven safety profile among healthy donors and was an off-label use. The consent forms said, “No long-term safety information is available.”

The FDA approved the drug Neupogen in 1991. The drug contains the active ingredient filgrastim, a granulocyte colony-stimulating factor. The FDA approval and subsequent updates show that Neupogen was approved for autologous use among cancer patients, with no mention of allogeneic use by healthy donors. There is also no mention of healthy donors in the prescribing information.

Neupogen

A 2007 paper in the British Journal of Haematology mentions that since 1997, the US National Marrow Donor Program has maintained an Investigational New Drug application for the manufacture of PBSC products from unrelated donors and that “it is unknown whether filgrastim increases or decreases an individual’s risk of developing cancer” but added, “based on limited long-term data from healthy people…no long-term risks have been found so far.” Not exactly reassuring.

The only prospective trial I could find assessing the safety of filgrastim-mobilized stem cell donation and PBSC leukapheresis among healthy donors is currently underway and will not be completed until January 2022. The description says that filgrastim is “not a licensed indication,” and mentions that data collection began in February 1997.

The decision to donate

So the crux of the decision came down to this: should she risk an unproven drug treatment so that she could give a complete stranger another chance at life?

As a 22-year old adult, it was Katherine’s personal decision to follow through. She self-injected filgrastim twice a day and had the usual symptoms of bone aches, headache, and fatigue. She donated over two days, tethered to the apheresis machine for about 5 hours each day in a room where the other 10 treatment chairs were filled with cancer patients receiving chemotherapy and plasma treatments.

Kat-OneMatch-Donation-2

It was an odd juxtaposition for everyone involved, but the equipment and staff were located there. A second day is not always required, but it turned out that the recipient was apparently 15 kg (33 lbs.) larger than she was and the target collection calculation depends on body weight.

After her donation days, she traveled by train back to her university town three hours away to study for final exams and work on her thesis presentation. Three weeks later, she had an enlarged spleen scare, which prompted a visit to her local hospital ER via ambulance and had to restrict her activity to prevent a ruptured spleen. The donation hospital in Toronto then requested she travel back for a check a couple of weeks later. By then, thankfully, her spleen was back to normal size. She was well enough to do a karate grading a few weeks later and over the last two years, has had no complications.

At the one-year mark, she contacted OneMatch to find out if it would be possible to exchange contact information with the recipient, as the rules allow for that if both donor and recipient agree. She learned that the recipient lives in a country where there is a two-year restriction on information exchange. She doesn’t really want to know the recipient, but someday would like to know how they fared with her gift and if it made a difference.

There’s no question I’m proud she followed through with a donation. Even better — she’s proud. Katherine says, “In any case, I’m happy to know that my gift likely brought hope to the recipient and their family.”

The stem cell theory of aging

Dr. Knoepfler provided some helpful perspective about how a one-time mobilization of stem cells might affect a donor’s long-term health. He said, “In principle, boosting production of stem cells for a PBSC donation could have long-term effects. My feeling in the grand scheme of life is that a short-term, one-time mobilization of PBSC is unlikely to have a lasting effect on an otherwise healthy young person. Given the massive turnover in blood cells (something like a trillion blood cells are replaced per week for each of us), our hematopoietic stem cells have got to be very robust and for the dozens of times in our lives when we get sick enough to mount a major immune response, our stem cells are mobilized repeatedly each time.”

Bottom line

Is it admirable to donate and give someone else a chance at life? Of course! But I wish donors could have more information on how the procedure might affect them in both the short and long term, to understand more about what they are risking in order to help someone else. Here’s hoping that the study currently underway finds minimal risks for donors. In the meantime, it was great to get some perspective and reassurance from a scientist working in the stem cell field.

Jane Langille is a health journalist and mom based near Toronto, ON, Canada.

Are babies from same-sex couples really possible?

Since Shinya Yamanaka reprogrammed first mouse and then human ordinary cells into powerful pluripotent stem cells, termed induced pluripotent stem (iPS) cells, back in 2006-2007 many new research avenues have opened up.

The impossible suddenly seemed a lot more possible with the report of iPS cells (aka IPSC). People started asking many more creative questions, The biomedical sciences now had more potential to make the seemingly impossible become reality.

One question that has come up: could same sex couples have their own biological children?

There’s been a lot of hype on this question in the media in the last week including these headlines and stories:

One article claimed that same sex parents could have their own biological offspring within 2 years. That’s just total baloney. However, in the long run within 1-2 decades this very well could be achieved. The excitement and over-exuberance in some cases with the media over this issue stems from recent work published in Cell from the labs of Drs. Azim Surani and Jacob Hanna on a more efficient way to produce human primordial germ cells (PGCs) via iPS cell-related methods.

Hanna was quoted thusly by Newsweek:

“This is very exciting biology,” says Dr Hanna. “We have succeeded in the first and most important step of the process, where we have reached the progenitor cell state for sperm and egg. We have not yet achieved mature sperm and eggs. So we are now focusing on completing the second half of this process.”

stem cell gametesThere’s no doubt that this is important work in this paper, but it’s a long, complicated road to get from the point A of the state of this research today to point B, where it could actually be used to produce human babies.

Still, what is so different now is that one can see a roadmap how to possibly get to that new reality.

Update: It’s also notable that Katsuhiko Hayashi and Mitinori Saitou have been able to produce living mice from stem cell-derived gametes (image above of method from one of their papers and another relevant paper to read; hat tip to Andrew Childs).

“It is probably a long way off, but it would be a way for people who have had treatment for conditions such as childhood leukaemia, which has left them infertile, to have children of their own,” Robin Lovell-Badge, head of stem-cell biology and developmental genetics at the National Institute for Medical Research, told The Sunday Times.”

I agree with Dr. Lovell-Badge on his view of this. Such technology could not only facilitate same sex couples have their own children (in the sense of genetically related to both parents), but also have a number of medical benefits such as tackling the general problem of infertility and more specifically allowing cancer patients who were treated with chemo to still have their own children later on in life as Dr. Lovell-Badge indicated. There’s great potential here even as we should be careful to note a realistic timeline and the health of children produced this way could be an issue.

IPS cell cloning

An additional cautionary note is needed as well related to cloning.

Unfortunately, there’s a ‘dual use issue’ here. This same kind of technology, if applied by some rogue scientists, could be used to clone human beings as well. This kind of technology could lead to both sperm and egg production from a single individual, which when followed by IVF, could in principle produce a human clone. See diagram above of how this could work with an individual male to be cloned (from Stem Cells: An Insider’s Guide). In theory this cloning method could work just as well with a woman too, but for male offspring somehow a Y chromosome would need to come into play. Even if it wouldn’t be easy to get this cloning to work, it might well work with enough money and effort. There are people out there who really want to clone themselves or others too so the motivation is there.

I’m not trying to freak people out, but this possibility of cloning is very possible in coming decades. It’s probably well past time for reproductive human cloning to be formally banned in the US. We still should allow therapeutic cloning of human ES cell lines. Realistically, given national politics, can we hope that politicians would be able to ban one kind of human cloning (reproductive) and still allow the other (therapeutic) to be legal in the US? I don’t know. Probably not any time soon.

As I said at the beginning of this article, amazing new things are possible that once seemed only in the realm of sci-fi, but with the good will also come some complicated baggage.

Stem Cells, Nukes, & Bikini Experts

How are stem cells, nukes, and bikini experts connected?

Let’s go back in time a bit…

The idea of stem cells has been around more than a century. For example Dr. Artur Pappenheim made a cell fate tree including stem cells in 1905. You can read more about this amazing, more than 100-year old stem cell model in my book, Stem Cells: An Insider’s Guide. Even earlier in 1885, Dr. August Weismann discussed stem cells using the term “germ plasm” and in 1868 seems to be one of the earliest ever mentions of stem cells in science by Ernst Haeckel, who had a model including “stammzelle’, which means “stem cell” in German.

So the reality is that scientists have been thinking about stem cells for at least almost 150 years.

I was curious what the first ever mention of “stem cells” or “stem cell” was in the media. I’m not sure, but I did check it out in the NY Times. When did this great paper first mention these great cells?

The September 19, 1948 edition contained the first ever mention of “stem cell” in the NY Times that I could find. Nuclear tests on Bikini Island (aka Bikini Atoll) had been going on for some time and scientists in the military were studying the effects on animals including goats. They noted that the “stem cell” component of bone was unusually resistant to radiation:

The white cells were extremely susceptible, but the recticulum, or “stem cell” of the bone marrow, was ray resistant.

Ray in this case refers to “atomic rays” or radiation. Recticulum appears to be an alternative spelling of reticulum.

NY Times stem cells

The April 21, 1949 edition is the first mention of “stem cells” in the NY Times. The topic of the piece is similar to that of the 1948 article, but contains more on stem cells. The piece is entitled “Some blood cells resist radiation” with subtitle “Finding Spurs Recovery Hope for Atomic Victims, Bikini Expert Reports in Detroit”. Now we are talking about regenerative or cellular medicine way back 65 years ago. It was reported that radiation exposure victims whose stem cells had survived had the best chance to survive overall.

For you history buffs, just to show how long ago this was, the all-knowing Wikipedia says that the bikini swimsuit was “invented” or at least given that name around 1946, just a few years before these articles. Thus, readers of the NY Times piece in 1949 that alludes to a “Bikini Expert” would likely have not thought of a bathing suit. Although now, if you can believe it, there is an electric stem cell bra (see “Stranger than fiction: the electric stem cell bra for breast enlargement“.

The history of stem cells is far more complicated than I ever imagined until a few years ago. Keep in mind that stem cell history is being made today too with new discoveries.