JOINT STATEMENT FROM CASE WESTERN RESERVE UNIVERSITY AND UNIVERSITY HOSPITALS OF CLEVELAND

General Background

Case Western Reserve University (CWRU) and University Hospitals of Cleveland (UHC) were deeply saddened by the death this past May of a 69-year-old woman who had participated in a research study. Following several months of review, including an internal investigation by a board that oversees human subjects research, the U.S. Department of Health & Human Services' Office for Human Research Protections on November 30 issued a final letter that dismisses earlier concerns about the research study. The OHRP letter also accepts as satisfactory the corrective actions implemented since April to strengthen oversight of research studies, and offers additional guidance for researchers and for the committees that oversee their work.

The study, aimed at learning more about the causes and prevention of Alzheimer's Disease, was funded by a grant from Phillip Morris to CWRU. It was led by a physician holding a joint appointment at CWRU and UHC. The study was fully reviewed and approved by the Institutional Review Board at UHC.

The study participant had hypertension but was otherwise in good health. She became ill April 4 several hours after drinking a solution of the amino acid "methionine" mixed with orange juice. (Methionine is an essential amino acid commonly found in meat and milk. It is not a prescription medication. Methionine is available for purchase at many health food stores as an over-the-counter nutritional supplement.) She began vomiting, and within hours developed significant breathing problems that led to pulmonary failure, and she was placed on a respirator. She continued to receive care at the hospital for more than a month until her death on May 6. Her clinical diagnosis was Acute Respiratory Distress Syndrome (ARDS).

The woman participated in the study at the General Clinical Research Center, which is located at UHC and funded by CWRU under a grant from the National Institutes of Health. CWRU and UHC promptly reported the incident to the appropriate federal agencies, and an internal investigation was conducted by CWRU and UHC, with the support of two independent, external experts. CWRU and UHC continue to cooperate fully with the federal Office for Human Research Protections and the Food and Drug Administration.

The autopsy confirmed the clinical diagnosis of ARDS. While the internal investigation could not pinpoint the exact cause of ARDS, it could not rule out the possibility that she received an incorrect amount of methionine. Therefore, we have strengthened the procedures for dispensing of nutritional supplements in the General Clinical Research Center to lessen the possibility that anyone could ever receive an incorrect amount.

The study, which was immediately suspended on April 5 following the incident, has since been withdrawn by the principal investigator. There had been only one other participant, and that person experienced no problems related to the study.

Any unexpected death in medical research is tragic. We hope the public understands the many precautions taken to review all levels of research. Each year, CWRU and UHC receive more than $150 million in federal research funding, and additional support from private resources, enabling us to conduct life enhancing and life saving research.

In the many years that our two institutions have worked together, and among the many thousands of volunteers who have participated in these studies, there is no record of any other death of a control subject in a research study.

We have expressed our sincere condolences to the family, and will continue to take every precaution possible to ensure the safety of all study participants, which must always be our first priority.

About the Study

This study, "Methionine and Homocysteine Studies in Alzheimer's Disease and Healthy Aging," was a collaborative effort by researchers from both institutions regarding methionine. Methionine is converted into the normal amino acid "homocysteine" in the body. It has been reported recently that patients with Alzheimer's disease have abnormally high levels of homocysteine circulating in their blood. These high levels of homocysteine may be an important part of the disease and may be an early sign of the illness. Elevated levels of homocysteine in the blood are a risk factor for heart disease and stroke, and it is believed that vascular processes may be an important component of Alzheimer's disease. The researcher hypothesized that patients with Alzheimer's disease have an altered metabolism of methionine and homocysteine in the body different from healthy people of the same age. The standard way to measure homocysteine metabolism precisely is to give people a specific dose of methionine and then measure the blood levels of the amino acids. This method for measuring methionine metabolism in people has been widely used in the USA and Europe for many years without any ill effects. The study was designed to show (1) if there is a difference in homocysteine levels between Alzheimer's disease patients and aged-matched, non-disease persons; and (2) if there is a difference, what problem in the metabolism of methionine and homocysteine is responsible.