ANN ARBOR—The University of Michigan has suspended the clinical research privileges of one of its leading cancer surgeons after an extensive internal investigation uncovered numerous regulatory infractions in five human clinical trials. The investigation was initiated by the University’s own audit, begun in March 2000.

The University’s action means the principal investigator in the trials, Alfred E. Chang, M.D., professor of surgery, will not be allowed to conduct research with human volunteers for a three-year period. During this time, he will receive education in research regulations. This prohibition is retroactive to Oct. 20, 2000, the date on which all of Chang’s studies were suspended by the U-M Medical School‘s Institutional Review Board.

“The protection of human volunteers in research is vital—it is one of our most fundamental responsibilities,” said Gilbert S. Omenn, M.D., Ph.D., U-M executive vice president for medical affairs. “The fact that the University began its own internal audit and that such a thorough investigation was conducted is evidence of how serious we are about these protections.”

There is no evidence that any patients died from the treatments. Many of the patients included in the studies benefited from their participation, noted Allen Lichter, M.D., dean of the Medical School. All of the patients involved had cancers for which no effective standard treatments exist, Lichter said. Any deaths that occurred were the result of the patients’ cancers.

“Dr. Chang is a caring and compassionate doctor whose goal has been to give his patients the best medical care available,” said Lichter. “For many of his patients, these research protocols offered the only hope of putting their cancer into remission.”

The trials have been suspended for almost a year and no new patients have been enrolled in them since May 2000. Medical care for the cancer patients in the trials has continued during the investigation.

Fawwaz T. Ulaby, Ph.D., U-M vice president for research, the office responsible for overseeing the University’s investigation, said, “Our review of Dr. Chang’s research protocols has been comprehensive, and the sanctions imposed by the University are appropriate to the types of problems we found.”

The U-M has sent a detailed report of its findings to the federal Office of Human Research Protections, the Food and Drug Administration and the Office of Biotechnology Activities at the National Institutes of Health. The final report is based on an extensive and thorough review that required more than 3,000 hours of work by a committee of physicians appointed by Ulaby, in addition to the assignment of dedicated staff support to the committee by the University.

The U-M investigation found breaches in IRB rules across five studies and involving 94 research volunteers. The breaches were “frequent and pervasive” and were “touching on virtually every aspect of clinical research, from data management and recordkeeping to subjects’ rights and protocol adherence,” Ulaby wrote in a letter to the agencies.

In its interaction with Chang, the committee found that his actions did not appear to have been driven by willful or arrogant behavior, said Ulaby. “Rather, Dr. Chang was driven by compassion for his patients and a commitment to help cure their diseases. Unfortunately he did not adhere to federal and University rules and regulations governing the conduct of research projects involving human participants.”

The IRB breaches included:

• inadequate documentation of informed consent or informed consent obtained after the study began;
• deviations from the protocol steps he had submitted to the IRB;
• instances in which patients were enrolled in a study after the study was closed;
• adverse events that were either not reported or not reported in a timely matter.

(An adverse event is an undesirable, unintended—although not necessarily unexpected—event occurring during therapy or other intervention. The event may or may not be caused by the intervention. Examples of adverse events include rashes, sudden fevers, death due to the disease itself or even a car collision.)

In addition to the suspension of clinical research privileges, Chang also must undertake extensive study of clinical research rules and procedures during this time and be assessed at the end to ensure his successful completion.

Upon completion of Phase I, Chang may apply to enter Phase II of his educational program, a one-year period during which he would be allowed to participate in human volunteer research as a sub-investigator. Once completed, he can apply for reinstatement of privileges and responsibilities as a principal investigator on research involving human participants.

“Dr. Chang will continue to treat cancer patients and will continue to contribute his research ideas through his work in the lab and his support of our larger cancer team,” Lichter said.

As both the volume and complexity of biomedical research have grown during the past decade, the U-M has continued to strengthen its process for protecting human research participants. Recent changes include increasing the number of Institutional Review Boards in the Medical School from one to four; greatly increasing the amount of staff and administrative support for the IRBs; enhancing training for researchers and IRB members; instituting a program of random audits of research compliance; and formulating and broadly disseminating more precise University policies regarding the use of human participants.