NEWS 798
Endpoint effort:
Put to the test:
Full disclosure:
Database of core outcome research moves ahead
Drug regulation in India under the microscope
Governments should lead transparency efforts
802
806
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Unregulated stem cell clinics are proliferating throughout the US. A case in point is the Cell Surgical Network (CSN), which has grown over the last two years to encompass 42 independent centers that offer to inject patients’ own stem cells back into their bodies in an effort to treat any of more than 30 different diseases and injuries. Affiliate members of the network, which now spans 22 US states, claim their therapies involve minimal manipulation of a person’s own tissue—specifically, the adiposederived stromal vascular fraction (SVF), a soup of mesenchymal stem cells and other cell populations found in fat—all isolated in a closed, sterile procedure. This surgical procedure, the CSN maintains, falls outside the regulatory authority of the US Food and Drug Administration (FDA). But Leigh Turner disagrees. Turner, a bioethicist at the University of Minnesota in Minneapolis, wrote a letter last year to Celia Witten, director of the Office of Cellular, Tissue and Gene Therapy at the FDA’s Center for Biologics Evaluation and Research, urging the agency to investigate whether the CSN (known then as the California Stem Cell Treatment Center) was violating federal regulations governing the administration of stem cell– based products. After hearing nothing back for 17 months and counting, Turner decided to ask for help from others: at the International Society for Stem Cell Research (ISSCR) Annual Meeting held in Vancouver, Canada, on 19 June, he called on the regenerative medicine community to join him in a letter-writing campaign to pressure the FDA to crack down on CSN affiliates and other clinics offering unapproved stem cell therapies. “The United States looks a lot like the very countries that we tend to disparage as being destinations for so-called stem cell tourists,” Turner told Nature Medicine. “This is a largescale domestic problem.” According to figures compiled by Paul Knoepfler, a stem cell biologist and blogger at the University of California–Davis, there are now more than 100 clinics offering stem 796
Mark Berman, MD, Cell Surgical Network
© 2014 Nature America, Inc. All rights reserved.
Letter campaign sought to pressure FDA action on stem cell clinics
Time Machine heals all wounds? The CSN Time Machine combines a centrifuge and incubator to prepare patients' own fat-derived stem cells.
cell therapies in the US—“and it could even be as high as 200”—with CSN and the Stem MD chain providing the largest known allied networks. Knoepfler, who interviewed the founders of CSN last year (see go.nature. com/bbSfqZ), describes Turner’s decision to go public with his letter as a “gutsy move,” as Turner “now makes himself the public face of opposition to the dubious, unregulated action of the companies about which he is particularly concerned,” Knoepfler says. Although no one has yet publicly announced the intention to write a comparable letter, experts in the field generally support Turner’s call to action. “There is a growing frustration within the community about these kind of clinics,” says Tim Caulfield, a health law and policy expert at the University of Alberta in Edmonton, Canada, who is on the committee tasked with updating the ISSCR’s Guidelines for the Clinical Translation of Stem Cells. “I do think
it is important for the science community to speak up.” “If it comes from a larger group of professionals, and there’s some type of repetition, I think it’s going to get the message out that there are these people doing these fraudulent things,” adds Zubin Master, a bioethicist and stem cell policy researcher at Albany Medical College in New York. At a minimum, Master notes that public letter writing could help counter the voices in free-market think tanks and regenerative medicine companies that are advocating for deregulation for stem cell products generally (see Nature 510, 336– 337, 2014). Such action from the stem cell community is especially important, experts say, following the ISSCR’s aborted ‘Submit a Clinic’ initiative, which, starting in 2010, invited the public to tender the names of specific stem cell providers for review. ISSCR officials planned to then ask those clinics for documentation demonstrating appropriate oversight and medical evidence for the treatments on offer, but within less than a year the society shelved the project in the face of numerous legal challenges. A man of letters Turner has a history of writing letters to the FDA. In February 2012, he appealed to agency officials to examine Celltex Therapeutics, a Texas-based company that was working with South Korea’s RNL Bio to offer autologous stem cell treatments for a range of ailments. (Governor Rick Perry of Texas, who suffered from recurring back pain, was the company’s first patient in July 2011.) Although Turner concedes that he has no way of knowing whether his letter had any impact, within two months of his sending the petition the FDA had inspected Celltex’s manufacturing facilities, finding that the company’s therapy constituted a biologic drug in need of regulatory approval. Celltex now provides only cell-processing and cellbanking services in the US; when clients wish to use the cells for therapeutic purposes,
VOLUME 20 | NUMBER 8 | AUGUST 2014 NATURE MEDICINE
npg
© 2014 Nature America, Inc. All rights reserved.
Celltex releases the cells to independent physicians in Mexico, where regulations are less restrictive. As for Turner, after he publicly disclosed that he had written to the FDA asking the agency to investigate Celltex, attorneys for the Texas firm wrote to Turner’s employers at the University of Minnesota threatening litigation. “It’s a bit anxiety provoking,” he says. “There’s also the practical matter that these clashes can be exhausting and timeconsuming.” Despite these drawbacks, Turner reached out to FDA officials again in December 2012 to voice concerns over Precision StemCell, an Alabama clinic that was offering autologous stem cell therapies to treat amyotrophic lateral sclerosis, multiple sclerosis and joint pain. (He blogged about the letter six months later.) There is no public record of an FDA inspection or agency warning letter to Precision StemCell, but by mid-2013 the company had moved its operations to Bogotá, Colombia. Besides those publicly disclosed, Turner says he has sent letters relating to another half-dozen business operations marketing similar stem cell interventions in the US. “Hopefully the FDA is paying attention,” he says, “and hopefully they do something.” Awaiting an answer At press time, Turner was still awaiting an answer from the FDA regarding his letter about the CSN. (Agency officials declined
to comment for this story, citing FDA policy not to discuss complaints submitted by individuals or the status of companies in dispute.) CSN founder Mark Berman, a cosmetic surgeon who specializes in fat transfer, believes that the FDA has rightly cracked down on certain stem cell products, such as the one sold by Colorado-based Regenerative Sciences, which a US appeals court ruled earlier this year falls under the agency’s purview. He stresses, though, that CSN does not require FDA oversight because the SVF used in the network’s therapy is obtained using off-label surgical methods, not laboratory procedures, in a way that poses no risk of disease transmission. Berman told Nature Medicine that he has no intention to pursue litigation against Turner. He wrote to Turner personally after the ISSCR presentation in June to explain his position. And he is already in communication with the FDA about running a clinical trial to validate the network’s cell preparation equipment, all of which is currently approved for other surgical applications but which the CSN would test specifically for the extraction of SVF in the trial. According to Berman, such a trial is not required other than for marketing purposes relating to the equipment (which he has dubbed the CSN Time Machine), but he hopes it will help add scientific weight to the therapy and thus quiet the network’s
Mark Berman, MD, Cell Surgical Network
NEWS
Stromal salve: The stromal vascular fraction is filtered ahead of transplantation.
vocal critics. He also notes that CSN has an ongoing safety study listed on ClinicalTrials. gov (registered under NCT01953523) that has documented few adverse effects of the SVF therapy to date. “We’re not a fly-by-night organization,” Berman says. “We’re not exploiting anyone. We’re involved with doctors who are highly regarded within their own specialties. We’re not doing anything for which the FDA should or does have opposition.” Elie Dolgin
Better standards sought for range of stem cells entering the clinic It may be best known for housing the kilogram prototype against which all weights in the US are calibrated, not to mention for building the world’s most accurate official atomic clock, but in recent years the US National Institute for Standards and Technology (NIST) has been expanding its reach in the biological sciences. Two years ago, the agency launched the Genome in a Bottle Consortium to develop reference materials and methods for DNA sequencing. And now, NIST is hoping to lay the groundwork for standards in cellular therapies. “Stem cells are fast becoming a product,” says Franz-Josef Müller, a stem cell scientist at Kiel University in Germany who is not involved with the NIST effort, “and as soon as you have a product, you need to define standards.”
To date, the US Food and Drug Administration (FDA) has approved only one stem cell therapy: Hemacord, a cord blood–derived hematopoietic stem cell product from the New York Blood Center that hit the market in 2011. With many more cell therapies expected to come down the regulatory pike, NIST now hopes to set a number of quality control benchmarks for stem cells intended for human use. To evaluate NIST’s efforts in this arena, members of a 22-person committee convened by the US National Research Council toured the Biosystems and Biomaterials Division of the agency’s Materials Measurements Laboratory (MML) in Gaithersburg, Maryland, over three days in mid-June. The committee is tasked with evaluating all of the MML’s activities; a report is expected early next year.
NATURE MEDICINE VOLUME 20 | NUMBER 8 | AUGUST 2014
Committee member Jeanne Loring, a stem cell biologist who directs the Center for Regenerative Medicine at The Scripps Research Institute in La Jolla, California, was impressed by what she saw: systems for cell line authentication, quality control platforms for three-dimensional cell cultures, machine learning analytics for cell shape identification and much more. “The technology they have—it’s like a candy store,” Loring says. Assay development For now, NIST’s main efforts in the stem cell domain are centered on developing assays that provide quality assurances for researchers working with human pluripotent stem cells. One example has to do with the tests currently used to assess 797
Endpoint effort:
Put to the test:
Full disclosure:
Database of core outcome research moves ahead
Drug regulation in India under the microscope
Governments should lead transparency efforts
802
806
npg
Unregulated stem cell clinics are proliferating throughout the US. A case in point is the Cell Surgical Network (CSN), which has grown over the last two years to encompass 42 independent centers that offer to inject patients’ own stem cells back into their bodies in an effort to treat any of more than 30 different diseases and injuries. Affiliate members of the network, which now spans 22 US states, claim their therapies involve minimal manipulation of a person’s own tissue—specifically, the adiposederived stromal vascular fraction (SVF), a soup of mesenchymal stem cells and other cell populations found in fat—all isolated in a closed, sterile procedure. This surgical procedure, the CSN maintains, falls outside the regulatory authority of the US Food and Drug Administration (FDA). But Leigh Turner disagrees. Turner, a bioethicist at the University of Minnesota in Minneapolis, wrote a letter last year to Celia Witten, director of the Office of Cellular, Tissue and Gene Therapy at the FDA’s Center for Biologics Evaluation and Research, urging the agency to investigate whether the CSN (known then as the California Stem Cell Treatment Center) was violating federal regulations governing the administration of stem cell– based products. After hearing nothing back for 17 months and counting, Turner decided to ask for help from others: at the International Society for Stem Cell Research (ISSCR) Annual Meeting held in Vancouver, Canada, on 19 June, he called on the regenerative medicine community to join him in a letter-writing campaign to pressure the FDA to crack down on CSN affiliates and other clinics offering unapproved stem cell therapies. “The United States looks a lot like the very countries that we tend to disparage as being destinations for so-called stem cell tourists,” Turner told Nature Medicine. “This is a largescale domestic problem.” According to figures compiled by Paul Knoepfler, a stem cell biologist and blogger at the University of California–Davis, there are now more than 100 clinics offering stem 796
Mark Berman, MD, Cell Surgical Network
© 2014 Nature America, Inc. All rights reserved.
Letter campaign sought to pressure FDA action on stem cell clinics
Time Machine heals all wounds? The CSN Time Machine combines a centrifuge and incubator to prepare patients' own fat-derived stem cells.
cell therapies in the US—“and it could even be as high as 200”—with CSN and the Stem MD chain providing the largest known allied networks. Knoepfler, who interviewed the founders of CSN last year (see go.nature. com/bbSfqZ), describes Turner’s decision to go public with his letter as a “gutsy move,” as Turner “now makes himself the public face of opposition to the dubious, unregulated action of the companies about which he is particularly concerned,” Knoepfler says. Although no one has yet publicly announced the intention to write a comparable letter, experts in the field generally support Turner’s call to action. “There is a growing frustration within the community about these kind of clinics,” says Tim Caulfield, a health law and policy expert at the University of Alberta in Edmonton, Canada, who is on the committee tasked with updating the ISSCR’s Guidelines for the Clinical Translation of Stem Cells. “I do think
it is important for the science community to speak up.” “If it comes from a larger group of professionals, and there’s some type of repetition, I think it’s going to get the message out that there are these people doing these fraudulent things,” adds Zubin Master, a bioethicist and stem cell policy researcher at Albany Medical College in New York. At a minimum, Master notes that public letter writing could help counter the voices in free-market think tanks and regenerative medicine companies that are advocating for deregulation for stem cell products generally (see Nature 510, 336– 337, 2014). Such action from the stem cell community is especially important, experts say, following the ISSCR’s aborted ‘Submit a Clinic’ initiative, which, starting in 2010, invited the public to tender the names of specific stem cell providers for review. ISSCR officials planned to then ask those clinics for documentation demonstrating appropriate oversight and medical evidence for the treatments on offer, but within less than a year the society shelved the project in the face of numerous legal challenges. A man of letters Turner has a history of writing letters to the FDA. In February 2012, he appealed to agency officials to examine Celltex Therapeutics, a Texas-based company that was working with South Korea’s RNL Bio to offer autologous stem cell treatments for a range of ailments. (Governor Rick Perry of Texas, who suffered from recurring back pain, was the company’s first patient in July 2011.) Although Turner concedes that he has no way of knowing whether his letter had any impact, within two months of his sending the petition the FDA had inspected Celltex’s manufacturing facilities, finding that the company’s therapy constituted a biologic drug in need of regulatory approval. Celltex now provides only cell-processing and cellbanking services in the US; when clients wish to use the cells for therapeutic purposes,
VOLUME 20 | NUMBER 8 | AUGUST 2014 NATURE MEDICINE
npg
© 2014 Nature America, Inc. All rights reserved.
Celltex releases the cells to independent physicians in Mexico, where regulations are less restrictive. As for Turner, after he publicly disclosed that he had written to the FDA asking the agency to investigate Celltex, attorneys for the Texas firm wrote to Turner’s employers at the University of Minnesota threatening litigation. “It’s a bit anxiety provoking,” he says. “There’s also the practical matter that these clashes can be exhausting and timeconsuming.” Despite these drawbacks, Turner reached out to FDA officials again in December 2012 to voice concerns over Precision StemCell, an Alabama clinic that was offering autologous stem cell therapies to treat amyotrophic lateral sclerosis, multiple sclerosis and joint pain. (He blogged about the letter six months later.) There is no public record of an FDA inspection or agency warning letter to Precision StemCell, but by mid-2013 the company had moved its operations to Bogotá, Colombia. Besides those publicly disclosed, Turner says he has sent letters relating to another half-dozen business operations marketing similar stem cell interventions in the US. “Hopefully the FDA is paying attention,” he says, “and hopefully they do something.” Awaiting an answer At press time, Turner was still awaiting an answer from the FDA regarding his letter about the CSN. (Agency officials declined
to comment for this story, citing FDA policy not to discuss complaints submitted by individuals or the status of companies in dispute.) CSN founder Mark Berman, a cosmetic surgeon who specializes in fat transfer, believes that the FDA has rightly cracked down on certain stem cell products, such as the one sold by Colorado-based Regenerative Sciences, which a US appeals court ruled earlier this year falls under the agency’s purview. He stresses, though, that CSN does not require FDA oversight because the SVF used in the network’s therapy is obtained using off-label surgical methods, not laboratory procedures, in a way that poses no risk of disease transmission. Berman told Nature Medicine that he has no intention to pursue litigation against Turner. He wrote to Turner personally after the ISSCR presentation in June to explain his position. And he is already in communication with the FDA about running a clinical trial to validate the network’s cell preparation equipment, all of which is currently approved for other surgical applications but which the CSN would test specifically for the extraction of SVF in the trial. According to Berman, such a trial is not required other than for marketing purposes relating to the equipment (which he has dubbed the CSN Time Machine), but he hopes it will help add scientific weight to the therapy and thus quiet the network’s
Mark Berman, MD, Cell Surgical Network
NEWS
Stromal salve: The stromal vascular fraction is filtered ahead of transplantation.
vocal critics. He also notes that CSN has an ongoing safety study listed on ClinicalTrials. gov (registered under NCT01953523) that has documented few adverse effects of the SVF therapy to date. “We’re not a fly-by-night organization,” Berman says. “We’re not exploiting anyone. We’re involved with doctors who are highly regarded within their own specialties. We’re not doing anything for which the FDA should or does have opposition.” Elie Dolgin
Better standards sought for range of stem cells entering the clinic It may be best known for housing the kilogram prototype against which all weights in the US are calibrated, not to mention for building the world’s most accurate official atomic clock, but in recent years the US National Institute for Standards and Technology (NIST) has been expanding its reach in the biological sciences. Two years ago, the agency launched the Genome in a Bottle Consortium to develop reference materials and methods for DNA sequencing. And now, NIST is hoping to lay the groundwork for standards in cellular therapies. “Stem cells are fast becoming a product,” says Franz-Josef Müller, a stem cell scientist at Kiel University in Germany who is not involved with the NIST effort, “and as soon as you have a product, you need to define standards.”
To date, the US Food and Drug Administration (FDA) has approved only one stem cell therapy: Hemacord, a cord blood–derived hematopoietic stem cell product from the New York Blood Center that hit the market in 2011. With many more cell therapies expected to come down the regulatory pike, NIST now hopes to set a number of quality control benchmarks for stem cells intended for human use. To evaluate NIST’s efforts in this arena, members of a 22-person committee convened by the US National Research Council toured the Biosystems and Biomaterials Division of the agency’s Materials Measurements Laboratory (MML) in Gaithersburg, Maryland, over three days in mid-June. The committee is tasked with evaluating all of the MML’s activities; a report is expected early next year.
NATURE MEDICINE VOLUME 20 | NUMBER 8 | AUGUST 2014
Committee member Jeanne Loring, a stem cell biologist who directs the Center for Regenerative Medicine at The Scripps Research Institute in La Jolla, California, was impressed by what she saw: systems for cell line authentication, quality control platforms for three-dimensional cell cultures, machine learning analytics for cell shape identification and much more. “The technology they have—it’s like a candy store,” Loring says. Assay development For now, NIST’s main efforts in the stem cell domain are centered on developing assays that provide quality assurances for researchers working with human pluripotent stem cells. One example has to do with the tests currently used to assess 797
