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March 21, 2003
Office of the Inspector General
Department of Health and Human Services
330 Independence Avenue, S.W.
Washington, DC 20201
Re: FDA / RIHSC Protocol #98-006-F
Army Grant #MIPR-8931 (Army/FDA IAG 224-98-2568)
"Bone 97 A Dietary Strategy to Maximize Bone Mass in U.S. Naval Academy Mid-Shipmen"
Dear Madame Inspector General:
I am writing to inform you about significant concerns I have regarding the clinical trial referenced above and to request that your office initiate an independent investigation into this matter. I have already directed various components of the Food and Drug Administration (FDA) to undertake their own investigations of this matter. However, I believe an independent investigation by your organization is also warranted in this case. As the institution of the federal government that oversees the integrity of much of our nation's clinical trials programs, I want to assure that FDA is held to the same - if not higher - standards regarding clinical trial conduct to which we hold others who conduct clinical trials. Your investigation would be a critical component of helping me assure the integrity of FDA clinical trials.
FDA's Center for Food Safety and Applied Nutrition (CFSAN) is the sponsor of the clinical study in question. This study was funded by the U.S. Department of the Army (DOA) and was conducted at the U.S. Naval Academy (USNA) beginning in 1999. The principal investigator (PI) is an FDA employee, and the co-PI was employed at the time of the study by a private foundation that conducts military research [The Henry Jackson Foundation (HJF)]. This clinical study was initially approved by appropriately constituted institutional review boards (IRBs / ethics committees) at the FDA and at the DOA's Office of the Surgeon General. In addition, the USNA's Office of Institutional Research approved the study.
Recently FDA staff informed me that this study encountered significant difficulties during its implementation. These difficulties raise important concerns about the integrity of the conduct of this study involving the safeguarding of study participant records, the confidentiality of study participants' personal medical information collected as part of study enrollment, adherence to IRB procedures, and possible study protocol violations. At present FDA is unaware of any study participant having been harmed because of these problems. In addition, FDA has no knowledge that any of the information contained in study participants' records has been divulged to any person not associated with the study.
I am committed to ensuring that clinical research conducted under the auspices of the FDA meets the highest scientific and ethical standards possible and complies with all applicable requirements and established Good Clinical Practices. To help ensure that this objective is realized, I have instructed FDA's Office of Internal Affairs to conduct a thorough investigation of the problems identified with the conduct of this study. That investigation is ongoing.
In addition, because one of the PIs for this study is an FDA employee, in the interest of transparency, openness, and objectivity, I request that your office initiate an independent investigation to assess the following issues:
(1) FDA's efforts to locate the missing records and whether there are additional steps that can be undertaken to attempt to locate the missing records,
(2) The sufficiency of FDA's ongoing and planned corrective actions to help assure that the problems that occurred with this study do not occur in the future, and
(3) The financial management practices and financial integrity associated with this clinical study.
Summary of Events
In April 1998, the FDA PI submitted a request to the FDA IRB (the Research Involving Human Subjects Committee) to approve a protocol for a clinical study. Under the protocol, she would enroll midshipmen at the USNA in a clinical study that would involve ingesting specially formulated nutritional products to assess the products' impact on bone mass. After the FDA PI addressed various issues that the FDA IRB had raised regarding the study, FDA's IRB approved the study on April 5, 1999. Thereafter, the PIs enrolled approximately 260 midshipmen in this research study. As part of enrollment, midshipmen completed specific questionnaires and provided additional medical information to the PIs.
On December 18, 2000, FDA's IRB briefly suspended study enrollment when it was noted that the FDA's IRB approval had expired. The FDA PI then submitted necessary documentation to the IRB to allow continuation of the study. At the same time the FDA PI also informed the IRB that her co-PI had made oral allegations of misconduct against her. In addition, the FDA PI informed the FDA IRB that she had directed that the test article be changed from the liquid supplements described initially in the protocol to nutritional bars manufactured by the U.S. Army. The IRB investigated the allegations of misconduct, found no basis for them, and then allowed the study to proceed. The study product was administered under the protocol until March 2001.
In response to concerns about access to study data, on September 25, 2002 the FDA IRB issued a letter to the co-PI requesting all study data he possessed. On November 15, 2002, in response to the September 25 letter, the HJF turned over to the FDA IRB what they believed to be all study records and data held by their employee (the co-PI). A subsequent inventory of the records by FDA, using a study participant list found in one of the boxes of information submitted to the FDA IRB, revealed that at least 92 participant files were not present. The FDA IRB contacted the HJF, the PI, the study monitor, the USNA, and the National Naval Medical Center at Bethesda (NNMC) but was unable to locate the missing records. The FDA IRB did not contact the co-PI directly as he had explained in a signed statement that he did not possess any more documents from the study.
On January 15, 2003, FDA's IRB requested an FDA Bioresearch Monitoring inspection
of the study and informed the Department of Health and Human Services' Office
of Human Research Protection (OHRP) of the situation. FDA's Bioresearch Monitoring
investigators have now completed their investigation of the study. Their findings
are attached to this letter.
Thereafter, I requested that this matter be referred to FDA's Office of Internal
Affairs for investigation.
On March 19, 2003, senior management from CFSAN notified the FDA PI that the
study was to be terminated. Further, at a meeting convened on March 19, 2003,
the FDA IRB voted to terminate the study.
FDA Investigative and Corrective Actions:
To date, FDA senior management:
(1) has notified its IRB, the Department of Defense, the DOA, the NNMC, the USNA, and the HJF of its various concerns with this study,
(2) has requested that the HJF, the USNA and the NNMC each make another concerted effort to locate the missing records,
(3) has plans to notify, in writing, the affected study participants about the concerns we have identified associated with this study, including the loss of control over specific files and the confidentiality of personal medical information,
(4) has instructed the FDA PI to terminate all work on this study, and
(5) has determined that no papers resulting from this work will be published.
To help ensure that these problems are appropriately addressed and that they do not occur in the future, FDA will be initiating in the near future the following corrective actions:
(1) initiate an inventory and audit of all clinical studies sponsored by or involving PIs from any FDA Center to ensure that all are being conducted in accordance with Departmental and FDA regulations and policies,
(2) require that all FDA Centers examine current research monitoring (quality control) programs and develop specific clinical research quality assurance programs,
(3) establish a policy that makes Center Directors directly accountable to the Commissioner for non-compliance with Departmental and FDA policies and regulations regarding clinical research sponsored by their Center or conducted by employees of their Center,
(4) instruct the IRB representative from FDA's Office of the Chief Counsel to help assure that clinical research reviewed by the FDA IRB is being conducted under the appropriate regulatory scheme for the product being tested,
(5) provide additional funding to the Office of Science to strengthen its oversight of the FDA's clinical research program, (This funding will be used to establish a cross-cutting program to improve Center quality control and quality assurance programs and to audit these programs with an independent outside auditor and to report findings to the FDA IRB and directly to the Commissioner], and
(6) initiate a mandatory education and certification program for all FDA clinical investigators and key personnel on the scientific, regulatory, and ethical issues regarding clinical research.
I remain committed to ensuring that a full and complete investigation of the conduct of this clinical study is undertaken and that every effort is made to locate the missing records, or determine, to the best of our ability, the likely disposition of them. In addition, I intend to apply all available resources to identify and respond to the problems associated with this study.
Again, I would appreciate your review and assessment of this serious matter. Please feel free to contact me at any time if I can be of any further assistance to you regarding this matter.
I look forward to and thank you in advance for your valuable assistance.
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Sincerely, Mark B. McClellan, M.D., Ph.D. |
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