A Cry for Help? FDA Bares Concerns in NEJM
Jessica Mehta • Wed, April 26th, 2017
In December 2016, FDA Commissioner Dr. Robert Califf along with his two top deputies in the Center for Biologics Evaluation and Research (CBER) Peter Marks, M.D., Ph.D. (Director of CBER) and Celia Witten, Ph.D., M.D. (Deputy Director of CBER) wrote a clear call for caution and care with regards to using stem cells in patients.
Are stem cells safe? Are they effective for the intended use?
And, what is a stem cell anyway? Is it a real thing therapeutically? Or have we progressed to the point that the words “Stem Cell” are more a figment of marketing then they are descriptive of an actual therapy?
The top FDA officials titled their article “Clarifying Stem-Cell Therapy’s Benefits and Risks”. It appeared three weeks after the presidential election ended.
There is no doubt that this paper was the FDA speaking.
Califf, Marks and Witten wrote: “To ensure that this emerging field fulfills its promise to patients, we must first understand its risks and benefits.” Creating therapeutic strategies founded in science, they said, is key.
“Without a commitment to the principles of adequate evidence generation that have led to so much medical progress, we may never see stem-cell therapy reach its full potential,” they went on to say.
Using stem cells from bone marrow or peripheral blood to address hematopoietic reconstitution is relatively safe and effective. Using stem cells from one eye to treat the other eye in the same patient…old news too.
But regarding hematopoietic stem cells or stem cells from adipose tissue to treat other problems including diseases, orthopedic and neurologic issues, Califf, Marks and Witten are worried and, it appears, somewhat incapable of slowing their progression into the marketplace.
According to Califf, Marks and Witten, stem cells derived from allogeneic or autologous sources are currently being used by doctors to treat patients with little research backing their efficacy or safety.
In some cases, according to the authors, these stem cell therapies are dubbed by their suppliers as “revolutionary” and suitable for a host of conditions without substantial research and testing to back it up.
Where are the “well-controlled clinical trials?” Say Califf, Marks and Witten, they don’t exist in a reasonable amount. Furthermore, they say, that lack of foundation coupled with potentially hyperbolic claims is a recipe for a medical disaster.
Where the Problem “Stems” From
Where’s the research, the testing, the evidence?
Despite, literally, billions of dollars spent on stem cell research at virtually every major academic research facility in the planet Califf, Marks and Witten are not seeing it land on their desks to support what is currently in the market.
For example, the top FDA docs point to advertisements for “stem cell therapies” that claim that stem cells restore health on an intuitive level. That they have the ability to “sense their environment,” seeking out defects to repair.
That, of course, stems from one of the most cited papers ever written about stem cells—the Pittinger Paper—which described how mesenchymal stem cells (MSC) respond to inflammatory signals, travel to points of inflammation in the body and express different proteins and other compounds to reduce inflammation.
But taking that general, and well researched discovery, and attaching those attributes to a specific therapy is obviously troubling.
According to the three authors, there have been a handful of randomized, well controlled trials plus a few uncontrolled, small trials which back some of these claims. However, they point out, even these sporadic trials don’t fully demonstrate the effectiveness of such a treatment. This is true even in very systematically studied conditions like heart failure. “This lack of evidence is worrisome,” say the FDA in the NEJM.
As for safety, Califf, Marks and Witten do note that the autologous stem cell therapies appear pretty safe. But even here, the data is incomplete and that, to the FDA is also concerning.
Some stem-cell therapy supporters, like Dawn Hamilton, have personal positive experiences with the therapy. The 42-year-old public relations professional is based in Los Angeles, California. Her daughter is now six years old, but began receiving stem-cell therapy at 14-months-old. She says stem-cell therapy “isn’t a cure, but it can certainly help significantly.” When asked if she thinks it’s safe, she says,
“If done through a reputable clinic/doctor and with adult stem cells, I think the risk is very low … for us, stem cells offer hope. With a severely disabled child (cerebral palsy) we are willing to try alternative therapies or treatments to help her achieve her highest potential and best quality of life. We’ve seen improvements from stem cells first hand—improved vision, awareness, seizure reduction, better health, more strength, [and] better cognition.”
Hamilton’s story is what all medical professionals and patients hope to achieve. However, not all patients share Hamilton’s experience. Barby Ingle of San Tan Valley, Arizona, is a 44-year-old chronic pain patient advocate, and pain patient herself for 20 years. She says stem-cell therapy was very effective for her at first. She received it via her own fat extraction in October 2015 and March 2016. She says she thought it was safe initially, but “now I do have questions.”
Ingle says the first time she received the therapy, it was for ischemia in her intestines and heart (to address “two heart valves that went bad”). According to Ingle,
“It fixed my intestines within 24 hours and heart issues in seven days. It saved me from having 26 inches of my intestines cut out and open heart surgery. I was doing very well. A few months later I broke my foot and was having trouble healing due to another neuro-autoimmune disease that I have. I underwent the stem-cell infusion therapy again and healed from the break. I would say that the down side is that I have gained 28 pounds since stem cell therapy. Not that I am over eating, but I am able to eat more. But most of the weight came on in my chest. It was like a free boob job. I am currently undergoing testing for breast cancer now. In 2012 I had a mammogram that showed no signs or symptoms of breast cancer, it was 100% negative. About two weeks ago my mammogram now shows four areas of possible cancer.”
Although Ingle says no doctor has said the possible breast cancer and breast issues are from the stem-cell therapy, she’s now wary. “Due to the growth in breast size and now the positive mammogram, I see a strong correlation to the stem cell therapy as to why my breast grew from a 32D to a 32E size,” she says.
In Ingle’s case, could more extensive testing and research on stem-cell therapy provide additional information on possible side effects? Possibly.
My Friend’s Brother’s Cousin Knows Someone Who …
A lack of well-controlled research has led to stem-cell infused urban legends and games of “Telephone.” According to the researchers, “The [current] literature is replete with instances of therapeutic interventions pursued on the basis of expert opinion and patient acceptance that ultimately proved ineffective or harmful when studied in well-controlled trials comparing them with the standard of care.” Does this mean stem-cell therapy isn’t safe or effective? Not necessarily, but it suggests that the rumors swirling about this “miracle therapy” might be dangerously over-stated.
The FDA execs point to the exploding use of autologous stem-cell transplants for metastatic breast cancer treatment. For a small window of time, it was hailed as a medical breakthrough. However, it was eventually “outed” as not very effective, high-risk and expensive.
But, biology is complex. Over time, will researchers find the best progenitor cell to use when treating breast cancer, figure out a dosing protocol, support that information with strong clinical studies and FDA oversight? There may be a there, there. It shouldn’t necessarily scare medical professionals away from using stem-cell transplants, but should serve as a reminder that all claims have to be founded on evidence.
The Federal Food, Drug, and Cosmetic Act was forever changed by the Kefauver-Harris Amendments in 1962. Also known as the “Drug Efficacy Amendment,” the amendment required drug manufacturers to include proof of safety and effectiveness on all drugs prior to approval. It also required all drug advertising to disclose information on side effects that were accurate. Finally, it prevented inexpensive generics from being advertised as expensive drugs via sketchy trade names marketed as “breakthroughs.”
Like many amendments, the Kefauver-Harris stemmed from a tragedy. In the 1950s – 60s, thousands of newborns were diagnosed with birth defects because their mothers took Thalidomide for morning sickness. All incidents took place in Canada and Europe, as Thalidomide wasn’t approved for use in the U.S. at the time. Rarely used now, Thalidomide was sold under the Immunoprin brand name, and is an immunomodulatory drug largely used to treat leprosy and certain cancers in modern times. The Kefauver-Harris amendment was introduced by U.S. Senator Estes Kefauver from Tennessee and U.S. Representative Oren Harris from Arkansas. FDA reviewer Frances Oldham Kelsey ultimately refused to approve the drug.
However, the unfortunate events kickstarted the “proof-of-efficacy requirement” for the very first time. President John F. Kennedy signed the law into effect on October 10, 1962, strengthening the FDA’s governance of human experimentation. It permanently changed how new drugs get approval. Before the Thalidomide crisis, U.S. drug companies simply had to showcase that their products were safe. After the Act, they had to prove drugs were both safe and effective. The Drug Efficacy Study Implementation quickly worked to classify drugs approved prior to 1962 as “effective,” “ineffective,” or “needing further study.”
According to Kefauver, securing that amendment was his “finest achievement.” Before the amendment, “thousands of ineffective and dangerous therapies were routinely used despite their merely anecdotal support,” says researchers Drs. Marks, Witten, and Califf. Initially in the post-1962 era, phased product development was required with a capstone consisting of evaluation in randomized, controlled trials. Since then, Congress has peppered in a little more flexibility to help speed up product development and/or support development programs.
Safe or Sorry?
Califf, Marks and Witten urged in their article that “the safety of stem-cell therapies for indications other than hematopoietic reconstitution … not be taken for granted.”
Recently, a patient was given numerous allogeneic stem cell injections from a variety of sources. The goal? Help minimize neurologic deficits from a middle cerebral artery stroke. According to the researchers, the injections led to a glioproliferative lesion, which in turn led to paraplegia requiring radiotherapy. While it’s generally accepted that autologous stem cells tend to have less safety issues than allogeneic stem cells, they’ve been more commonly linked to “significant adverse events.”
For instance, autologous hematopoietic stem cells were placed into a patient’s kidneys during renal failure from lupus. This injection led to a tumor according to researchers, and eventually nephrectomy. Autologous stem cells from adipose tissue have also been injected into the eyes when macular degeneration is present. However, in three cases, it led to worse vision—including blindness in two cases.
Stem-cell therapy has been linked with a variety of negative effects according to the researchers. “Such adverse effects are probably more common than is appreciated because there is no reporting requirement when these therapies are administered outside clinical investigations,” says the research team. Such events showcase how important controlled clinical studies are. How else can researchers figure out if allogeneic cellular therapy is effective and safe?
A lack of such studies leads to ignorance. Medical professionals won’t be able to figure out clinical benefits or gauge possible harm. With thousands of lipids, proteins, carbohydrates and such interacting in complicated ways, it makes predicting cellular behavior nearly impossible when they’re put in a new environment. Data is a must to document and assess safety.
Why is stem-cell therapy being treated differently than any other biologic product? “There is no scientific reason to believe that demonstration of efficacy for stem-cell products should be any different,” says Califf, Marks and Witten. The FDA doesn’t require anything more or different for therapies that potentially offer an unprecedented benefit. No bigger studies are required, and even when benefits may be impressive, the trials can be of moderate size.
How moderate? A therapy that offers 100% improvement requires a randomized trial of just 42+ participants. The idea that the current regulatory approval standards for stem cell therapies, and all therapies are too demanding comes from “a lack of familiarity with the available pathways for developing cellular therapy products,” says the researchers. When there are life-threatening diseases and an unmet medical need, “expedited pathways are readily available,” say these top FDA officials.
However, in most cases, stem cell therapy isn’t used for urgent, life-threatening situations. The researchers specifically point to orthopedic surgery and how stem-cell therapy is used to aid in healing. In these cases, “modestly sized trials could most likely demonstrate a favorable benefit-risk profile, given the relatively large number of patients who undergo such surgeries.” These trials have the promise to allow solid cell preparations.
What can the medical industry do to help stem-cell therapies safely move forward? Engage often with developers, urges the researchers. Make sure they are optimizing programs created to speed up new product approval. Designing innovative pathways to evidence generation is also key, letting in smaller research teams or sponsors to gather data. “We believe that addressing the unique challenges of stem-cell clinical research provides an important pathway for ensuring that safe, effective stem-cell therapies are readily available to patients in need and for building the scientific foundation for further advances,” concludes the FDA’s top guns.