According to Celltex Therapeutics, the mesenchymal stem cells that it selects and expands through cell culture, banks, and releases to physicians for use in individuals with Parkinson’s disease, multiple sclerosis, and other illnesses are administered in the context of clinical studies. Celltex’s studies were submitted for review to a Houston-based institutional review board, Texas Applied Biomedical Services. On September 24, 2012, Celltex received a warning letter from the FDA. The letter notes that because Celltex does not have an approved biologics license application (BLA) or Investigational New Drug application (IND) for the mesenchymal stem cells it manufactures the company is unlawfully marketing a biological drug. The warning letter Celltex received also identifies numerous failures to comply with current good manufacturing practice and good tissue practice. This letter became publicly accessible October 16. Since its release Ed Silverman, Todd Ackerman, and other journalists as well as such bloggers as Paul Knoepfler, Pete Shanks, and Alexey Bersenev have reviewed the violations identified in the warning letter and considered the likely significance of the letter for Celltex. Celltex’s IRB has received less scrutiny than Celltex, even though the FDA sent Texas Applied Biomedical Services a warning letter the same day that it sent a warning letter to Celltex. Since Celltex states that it administers stem cells in the context of IRB-approved clinical studies, it is important to examine the quality of review provided by Texas Applied Biomedical Services and consider what the warning letter TABS received reveals concerning how this IRB functions.
No physicians on IRB
The most surprising disclosure in the warning letter TABS received is that TABS does not have a physician as an active, voting committee member. Failure to have at least one physician as an IRB member prompts questions about the quality of scientific and ethical review provided by TABS. In correspondence with the FDA, TABS’ President and Chairperson M. Joyce Heinrich indicates that TABS “has access to a core group of medical advisors that provide expertise and input for any and all clinical research studies the committee encounters.” However, TABS approved at least three studies at meetings where a physician was not present as a voting member and meeting minutes do not mention consultation with qualified medical specialists. TABS must now provide to the FDA documentation disclosing the identity of the consultants that reviewed studies approved at meetings where physicians were not present. The larger question here is why TABS does not have a physician as an actively engaged, voting member. The failure to have a clinician as a member of the IRB is particularly important given that TABS appears to have shifted from reviewing minimal risk medical devices to reviewing and approving clinical studies involving administration of mesenchymal stem cells to ill individuals.
Another violation identified in the FDA’s warning letter to TABS is that two IRB members review clinical studies despite having a conflict-of-interest. IRB Chair Joyce Heinrich and one unidentified committee member are described as having a conflict-of-interest because they approved study protocols and informed consent documents that they also helped prepare for submission to TABS. The warning letter states, “The two members in question had a conflicting interest when they participated in the initial review and approval of the protocols and informed consent documents, which they assisted in drafting. Conflicting loyalties, whether conscious or not, may influence the IRB’s deliberations.” The letter does not identify the name of the company for which Heinrich and her fellow committee member provided this service. This portion of the warning letter sent to TABS prompts questions concerning how often Heinrich and another committee member voted upon and approved clinical studies that they also helped prepare for submission to TABS.
Unjustified approval of clinical study that included children
Yet another violation identified in the warning letter is that TABS approved a study that included children even though TABS “had not previously reviewed clinical investigational research studies involving pediatric subjects,” the committee meeting did not include a physician, there is no “documentation to show that the IRB invited individuals with competence in this area to assist in the review of this study,” and the IRB lacked written procedures for review of clinical studies that include children. According to the warning letter, “review of the IRB’s records indicates that the IRB lacked the professional competence necessary to review this study and determine whether it met the criteria for approval.” Meeting minutes from January 8, 2012 prompt questions concerning the quality of review at that meeting as well as the general quality of records maintained by the IRB. According to the warning letter, “The meeting minutes do not document the IRB’s determination of the level of risk involved, the potential for direct benefit, the likelihood of yielding generalizable knowledge about the subjects’ disorder or condition, and the opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.” If these issues were not addressed at the IRB meeting there is reason to wonder what basis TABS’ board members had for approving the study. If these topics were discussed, it is unclear why there is no record of the committee’s deliberations.
Longstanding record of inadequate record-keeping
During the FDA inspection of TABS, IRB Chairperson Joyce Heinrich told the FDA investigator that the IRB met twice in 2011. However, when asked to provide meeting minutes that are supposed to document committee deliberations, list which board members were present, and record whether they voted to approve or reject studies, Heinrich informed the FDA that she was unable to provide meeting records for 2011. Instead, Heinrich informed the FDA “that due to a computer crash all minutes and data for that time frame were lost.” In a letter to the FDA Heinrich reported that she would “re-create” meeting minutes and submit them to the FDA at a later date. TABS’ failure to maintain adequate meeting minutes is a recurrent problem. FDA inspections in 2000 and 2007 identified the same violation and on both occasions TABS was informed that this deficiency must be addressed. TABS has now displayed a record of inadequate record-keeping for over a decade.
Failure to maintain IRB membership rosters
The warning letter TABS received also notes that TABS “failed to maintain IRB membership rosters for 2008 through 2012.” The letter states, “The IRB membership rosters do not identify members by their representative capacity and any employment or other relationship between each member and the institution.” There appears to be no public record of who serves as a board member of TABS and what makes them qualified to serve in this capacity. The website for TABS does not disclose the identify, credentials, and professional affiliations of IRB review members and this information is not available in the database of IRBs maintained by the Office for Human Research Protections. Though I have contacted Ms. Heinrich five times and requested the names and qualifications of IRB members she has to date refused to disclose this information. The only meaningful detail known about TABS’ board members is that one of them is an immediate family member of Joyce Heinrich.
The warning letter TABS received does not identify sponsors of clinical studies, the names of clinical investigators, or the types of clinical studies both reviewed and approved by TABS and also audited by the FDA investigator. It is therefore impossible to know whether any of TABS’ violations of federal regulations are related to clinical studies sponsored by Celltex. It is conceivable that the warning letter sent to TABS is a product of auditing studies submitted by sponsors other than Celltex. It is also possible that some or all of the violations identified in the warning letter are connected to TABS’s approval of clinical studies sponsored by Celltex. Since TABS does not include a physician as a voting member it seems reasonable to propose that studies submitted by Celltex were not reviewed and approved by a physician board member. Whether an independent physician-consultant reviewed studies submitted to TABS by Celltex is unclear. TABS claims to use such consultants but the names of any clinicians serving in this capacity were not provided to the FDA before the warning letter was sent. Despite lacking protocols and expertise to evaluate clinical studies that include children as research participants, TABS has approved clinical studies that involve children. Both Celltex and TABS should address whether clinical studies sponsored by Celltex and including administration of adipose-derived mesenchymal stem cells have included children as research subjects. Greater transparency could also be achieved if Celltex or TABS disclosed the identities of the principal investigators who conducted studies sponsored by Celltex, described the qualifications of these individuals, and also revealed the identities and professional qualifications of all TABS board members who approved clinical studies involving administration of adipose derived mesenchymal stem cells to research subjects. It would also be illuminating to know upon what basis they approved such studies given that Celltex did not have an approved biologics license application, had not submitted an Investigational New Drug application to the FDA, and was administering to study participants an unapproved biological drug.
It is possible that TABS’ violations of federal regulations and Celltex’s violations of federal regulations are not related to one another, and the two companies are only connected because TABS happened to review and approve clinical studies submitted by Celltex. It is also possible that Celltex sponsored some of the studies audited by an FDA investigator during the FDA’s inspection of TABS. If so, it is conceivable that one or more studies submitted by Celltex was reviewed and approved by a board that: does not include a physician; to date has not disclosed the identities and qualifications of independent consultants; does not maintain adequate records of meeting deliberations and votes; does not publicly disclose the identities and professional qualifications of board members; includes board members who are paid by companies to assist with preparation of study protocols and then review and approve the very protocols they prepare; and allows clinical studies to include children without having proper protocols and review practices in place. Questions can be replaced with answers if Celltex and TABS provide a forthright account of their relationship to one another and address the many issues identified in the warning letter sent to TABS.