Last week, RNL Bio issued a press release announcing that the company has filed an Investigational New Drug application with the Korea Food and Drug Administration. According to the press release, RNL Bio wants to conduct a “Phase II/III” clinical trial that will assess efficacy of the “stem-cell drug” RNL-Astrostem™ in individuals with cerebral palsy.* The purpose of the proposed study “is to assess conclusive efficacy of stem cells for the treatment of cerebral palsy in 45 subjects over 11 months.” The press release doesn’t specify that the proposed study will enroll minors, though it states, “RNL Bio believes that with successful trials and approval of the KFDA, it will be possible to commercialize RNL-Astrostem™ by 2014, revolutionizing the possibility to cure this incurable disease of children.”
On February 8th, the very day that RNL Bio issued the press release about its proposed trial, I was busy contacting Dr. Jeong Chan Ra, RNL Bio’s founder, CEO, President, and largest shareholder, concerning a recent publication for which he is listed as corresponding author. The article describes a case in which a female child with cerebral palsy was administered autologous human adipose derived mesenchymal stem cells (HAdMSCs) processed at RNL Bio’s Stem Cell Research Center in Seoul, South Korea. I also sent emails to the two co-authors who reportedly were involved in providing care for the child. I contacted these individuals because of concerns that I have about various claims made in the case report as well as confusing gaps and omissions in the article. While I have not yet received responses to my queries, I want to identify several disturbing features of this case study. I will provide an update if my questions for the authors are answered.
Why did scientists at RNL Bio publish their case study in an online “journal” that has published no other articles, is not indexed in PubMed, has no identified editors, and appears to be an “open-access” journal that requires payment of a subscription fee to read the one article it has published?
RNL Bio’s press release claims that before filing an investigational new drug application for the proposed Phase II/III study, RNL Bio researchers published in an “internationally renowned journal” a case report involving administration of stem cells for cerebral palsy. This assertion is false. To the contrary, the case report, the only RNL Bio article that describes a case involving an individual administered mesenchymal stem cells for cerebral palsy, appears in an obscure online journal that has not published any articles other than this single case study. The article, “Therapy of Autologous Human Adipose Tissue-Derived Mesenchymal Stem cells for the Cerebral Palsy: A Case Report,” is available on a subscription only basis at the Journal of Medical Research. This so-called journal does not appear to be indexed in PubMed, has no impact factor, and—though it lists members of the editorial board—does not identify any editors. The publisher of Journal of Medical Research, Valleys International, is listed by Jeffrey Beall, critic of poor-quality and unreasonably expensive open access journals, under the category, “Predatory Publishers.” Rather than appearing in an “internationally renowned journal,” this case report was “published” in what is fairly described as a marginal publication.
Did a national regulatory body determine that “Compassionated (sic) stem cell therapy” could be administered to a minor?
According to the case report, “This case was conducted as compassionated (sic) stem cell therapy.” Mention of what the authors presumably intend to call “compassionate use” or “compassionate access” to stem cells is perplexing for two reasons.
First, most federal regulatory bodies have compassionate use, expanded access, or compassionate access programs that, under certain conditions, provide special access to unproven interventions in cases where patients suffer from immediately life-threatening conditions. For example, some individuals optimistic about the current status of stem cell research in the area of amyotrophic lateral sclerosis argue that individuals with ALS should have “compassionate access” to stem cell interventions that have not undergone full pre-marketing review and approval. Acknowledging the importance of studying the causes of cerebral palsy as well as investigating safe and efficacious interventions for cerebral palsy, cerebral palsy is classified as a non-progressive neurological disorder. It is unclear why a child with cerebral palsy would receive infusions of mesenchymal stem cells via the “compassionate use” pathway instead of within the framework of a Phase I, II, or III clinical trial. The authors of the study do not explain the regulatory, scientific, and ethical basis for administering “compassionate stem cell therapy” to a single minor instead of submitting an IND to the Korean Food and Drug Administration (or regulatory authorities in Japan, depending upon where infusions occurred) before commencing research.
Second, the case report is perplexing because it fails to identify the regulatory body that permitted administration of stem cells to a minor on a compassionate access basis. Researchers and parents or parental guardians do not decide for themselves whether children should receive stem cells of unknown safety and efficacy on a compassionate access basis. Rather, regulatory bodies such as the FDA in the United States and South Korea’s KFDA are authorized to make such decisions. I have contacted three of the article’s authors and asked them to address whether a national regulatory body in South Korea or Japan approved administration of mesenchymal stem cells to a minor on a compassionate use basis. I hope the authors of the study can explain whether permission was provided before the study commenced or why stem cells were administered to a child without first obtaining permission to proceed.
Did an institutional review board or comparable institutional body review the study before the minor received an unlicensed stem cell-based medical product?
Where the child described in the case report received stem cell infusions is unclear. The affiliations noted in the list of authors suggest that the stem cells might have been administered to the minor at ACT Clinic in Tokyo, Japan, Bethesda Hospital in Yangsan, South Korea, or perhaps at both facilities. Wherever stem cells were administered to the child, the case report makes no mention of the study undergoing review by an institutional review board, research ethics board, or comparable body before the child began receiving infusions of stem cells. The seven authors of the case report are listed as having ties to ACT Clinic, the Department of Rehabilitation Medicine and the Department of Pediatrics at Bethesda Hospital in Korea, the Department of Veterinary Medical Imaging at Seoul National University, and RNL Bio’s Stem Cell Research Center in Seoul. I have asked three authors of the study to address whether institutional review boards at all or any of these institutions reviewed this study before it commenced and approved administration of stem cells into a minor with cerebral palsy.
Why was someone with a degree in veterinary medicine involved in caring for a child with cerebral palsy?
According to the case report, one of the article’s authors, Kyeong Chin Song “cared patient and collected the data.” However, Kyeong Chin Song has a DVM, or Doctorate in Veterinary Medicine, and is listed as having an appointment at the “Departement (sic) of Veterinary Medical Imaging at Seoul National University. I sent Kyeong Chin Song an email and asked why she or he was involved in caring for the minor described in the study despite having a DVM rather than a degree in medicine. While I am not an expert on the clinical practice of medicine in South Korea, it seems reasonable to ask why someone with a degree in veterinary medicine provided care to a minor with cerebral palsy undergoing an unproven stem cell intervention apparently outside the framework of a clinical trial.
Why was an unlicensed stem cell-based medical product administered to a child rather than tested on an adult capable of making informed decisions concerning whether or not to receive a mesenchymal stem cell-based intervention?
Another disturbing feature of this case report is that it does not explain why an unlicensed stem cell-based medical product was administered to a minor rather than to an adult. At the time stem cells were first administered, the child described in the study was three years and seven months old. The child’s “parental guardians” provided what the study describes as “informed consent” to undergo stem cell intervention. The case report fails to address why a child with cerebral palsy underwent stem cell infusions rather than an adult capable of making her or his own choices about receiving an unproven stem cell-based biologic. I have asked three of the study’s authors to explain why stem cells were administered to a minor instead of an adult capable of assessing risks and making an informed decision about whether to participate in research. Acknowledging the need to conduct research involving minors, and recognizing that various research protections can be used to reduce risk in research with children, there are good reasons for testing unproven and unlicensed stem cell-based medical products on adults capable of comprehending risks and benefits and deciding whether or not to participate in research rather than using minors unable to make their own choices and dependent upon the decisions of adults. RNL Bio is interested in testing mesenchymal stem cell based interventions for many diseases. It makes sense to establish safety and efficacy for treatment of a particular disease in adults before using children as study subjects. Where minors are involved in safety and efficacy testing of unlicensed medical products, special protections should be in place to minimize risks.
What information was provided to “the parental guardians of the patient” before they provided “informed consent” for the minor to participate in this study?
The article mentions that “the parental guardians of the patient” signed an informed consent form prior to “stem cell therapy”. It does not specify whether the informed consent form was signed by the child’s parents or by individuals authorized by the state to serve as “parental guardians.” The article also fails to describe the informed consent process, does not detail what risks and benefits were conveyed to the parental guardians, and does not indicate whether the intervention was described as an experiment testing a medical product of unknown safety and efficacy or as a “stem cell therapy” as the article states in both the title and body of the text. In addition, the article does not mention whether the parental guardians consented to the liposuction procedure noted in the study. While the article states that an informed consent form was signed, it provides no insight into what information was provided to parental guardians by researchers and whether the parental guardians made an informed decision to consent to participation in the study. The meaning of the “informed consent” provided by the child’s “parental guardians” is unclear.
Red flags flying as RNL Bio seeks to initiate Phase II/III clinical study
I hope the authors of this case report respond to my queries. While there might be reasonable answers to my questions, this case report contains many red flags. The article was “published” in what appears to be a “journal” of dubious status; there is no explanation concerning why mesenchymal stem cells were administered on a “compassionate use” basis instead of within the framework of a clinical trial preceded by submission of an investigational new drug application; there is no mention that the study was reviewed by an institutional review board or comparable body even though the authors all have affiliations at hospitals, clinics, or research facilities; the study does not explain why someone with a background in veterinary medicine was involved in providing care to a minor with cerebral palsy; there is no explanation of why an unlicensed stem cell-based medical product was administered to a minor incapable of providing informed consent rather than an adult better positioned to assess risks and benefits and make an informed decision about whether to participate in research; and the study fails to explain what risks and benefits were described to the “parental guardians” before they signed an informed consent form and permitted a three year old child to undergo liposuction and receive infusions of adipose-derived mesenchymal stem cells.
Whatever responses the authors of this study provide to my questions, it is unacceptable for RNL Bio’s recent press release to claim that this case report was published in an “internationally renowned journal.” To the contrary, this case report was published in a “journal” that has published nothing other than this case study. It is difficult to imagine a more obscure place to publish an article. When such hyperbolic spin is detected, there is reason to wonder whether other assertions made by RNL Bio are credible. Trustworthiness surely matters when a company proposes to conduct research that will involve administering an experimental stem cell-based medical product to children. Of course, publication of this article in a bottom-of-the-barrel-journal will seem trivial if it emerges that an unlicensed medical product was administered to a child without adequate regulatory review, IRB review, and informed consent, and someone with a degree in veterinary medicine was involved in providing care to a child with cerebral palsy. I hope that Dr. Ra and his co-authors take time to answer my questions and address these concerns.
*Note: Whether RNL Bio has sufficient safety data to proceed to Phase II/III study is an important question for the KFDA to consider. RNL Bio apparently believes it established safety of this stem cell-based biologic in a study involving eight individuals with spinal cord injuries. The press release does not explain how the safety study involving research subjects with spinal cord injuries is relevant to an efficacy study that is supposed to involve minors with cerebral palsy. It appears that RNL Bio wants to proceed to “Phase II/III” without first conducting a relevant Phase I study.