Cancer Researcher Runs Afoul of FDA in Human Experiments
Dr. Charles A. Linker has been touted as one of the best oncologists in the Bay Area and praised by his colleagues at UC San Francisco as a promising young researcher.
Last year, the 40-year-old Harvard- and Stanford-educated cancer specialist published the results of a seven-year study that offered what some thought to be the first major advance in the treatment of adults with an incurable form of cancer known as acute lymphoblastic leukemia.
This spring, however, his career and reputation were dealt a serious, if temporary, setback by the federal government. In March, the Food and Drug Administration placed a “total restriction” on Linker’s research activities for two years. The sanction followed the FDA’s finding that Linker had violated a number of drug safety standards--involving consent forms, drug logs and other research protocols--designed to protect humans from undue harm in experimental treatments. And because he continues to play a prominent role in research at UCSF, despite the sanctions, an FDA official has said that the drug agency will continue to investigate his activities.
UCSF has never publicly announced the results of the government’s investigation or even that the university had conducted its own internal inquiry more than a year ago. And, according to UCSF physicians involved in the inquiry, patients who were part of the trial were never informed of the problems because no patient was harmed by them.
Linker was not accused of fraud or of harming his patients, but the violations were so numerous and the sanctions against him so serious that similar restrictions have been imposed on only one other scientist so far this year and just a half dozen in the past three years, according to documents obtained by The Times through the Freedom of Information Act.
How could a highly respected researcher have successfully treated so many patients and yet have been at odds with the government agency that oversees such treatments?
The case illustrates how increasingly stringent federal drug testing regulations can collide with a physician’s own values regarding the treatment and care of patients. Moreover, the problems at UCSF also reflect the impatience of some researchers in getting government approval for drugs they believe could help in treating large numbers of people suffering from cancer and other diseases.
Pointing to the fact that only one new anti-cancer agent has made it to the shelves in the past five years, physicians and patients alike have complained that the FDA drug approval process is far too slow and cumbersome in the very areas that are most in need of new therapies. Yet the FDA continues to insist, as it has since 1962, when the Food, Drug and Cosmetic Act was last amended, that both the safety and efficacy of a drug must be demonstrated before it can be marketed.
In some ways, Linker’s case represents a change in attitude by the federal government in recent years, said Dr. Dorothy K. MacFarlane, head of the National Cancer Institute’s quality assurance and compliance section.
Even as late as 1980, cancer research was not so tightly controlled as it is today, she said. Linker began his study in a period of laissez-faire policies and ended it in an era of intense scrutiny, she said.
Among the findings against Linker, according to the FDA report, were that he used a highly toxic, experimental anti-cancer drug known as teniposide, or VM-26, without proper authorization from his university, without adequate evidence that patients had consented to the experimental therapy and without following the treatment protocol that had been approved by the FDA.
Many at UCSF chalk up Linker’s problems not only to years of inattention on the part of the government, but also inexperience on his part, lack of knowledge of the whys and wherefores of government drug regulations, and inadequate administrative support on the part of the university.
In a recent telephone interview, Linker said he does not agree in all cases that the findings are as serious as the FDA suggests, but acknowledged “full responsibility” for the errors and omissions in the trial. Further, he said he understands that if he wants to use experimental drugs to treat his patients, which is the situation in which most university-based oncologists find themselves, he will have to follow government regulations scrupulously.
Although there is no reason to believe that Linker could not be reinstated, only a handful of researchers who have been similarly sanctioned have gotten approval from the FDA to resume drug testing, according to Gurston D. Turner, an FDA scientist and one of the investigators in the Linker case.
The problem, Turner said, is that most drug manufacturers who want new drugs tested in FDA-approved clinical trials find it easier to recruit physicians who have never been in trouble with the FDA and thus avoid the agency’s long and arduous reinstatement process.
The deficiencies in Linker’s methods came to light in the spring of 1987 during a routine audit by the National Cancer Institute, MacFarlane said. Because of the number and magnitude of the problems the institute uncovered, the matter was turned over to the FDA, which launched its own investigation last fall, said Dr. Frances O. Kelsey, the FDA’s director of the division of scientific investigations.
More Than 100 Patients
According to Linker, the drug trial, which was being conducted for the National Cancer Institute, began with only a handful of subjects but ended up involving more than 100 patients. It was Linker’s first major clinical study after completing medical training at Stanford and beginning a fellowship in hematology-oncology at UCSF in 1978.
According to FDA investigators, Linker’s problems began almost as soon as he started work on VM-26 in the fall of 1980. The documents show that Linker did not get advanced approval for his activities from a university review board charged with overseeing human experimentation and that he failed to keep adequate records of how much medication was used throughout the trial. In addition, he never informed the FDA or the National Cancer Institute that he was distributing experimental drugs to physicians at Stanford University Medical Center, Kaiser Hospital in Oakland, City of Hope National Medical Center in Duarte and other hospitals in the state.
“The case was serious because the rules weren’t followed,” said Dr. Edwin C. Cadman, former director of UCSF’s Cancer Research Institute and now chief of medicine at Yale University. “But it was not like the police losing 10 pounds of cocaine. There was nothing personal to be gained.”
The most serious charge against Linker, according to the FDA, was that he had made numerous and often undocumented changes in the way he used the experimental drug that he was supposed to be testing.
According to the FDA investigator’s report, the method of administration had been adjusted and schedules had been altered. Doses were given in combinations with varying amounts of other drugs and radiation. The FDA investigators examined the records of 36 of Linker’s patients who participated in the trial and found that in 30 of the cases Linker was judged to have “violated federal regulations by not following the plan of investigation.”
Linker said he viewed the changes as routine and well within the purview of a physician because they had been made to accommodate knowledge about the drug that had been gained over the years of the trial and to meet the needs of individual patients who reacted in a variety of ways to the treatment.
Wanted to Provide Care
Perhaps the reason he ran afoul of government regulations, he said, is that his main concern in the trial had been in providing the best possible care for gravely ill patients rather than in attending to the minute details of government reporting requirements.
“Following protocol is not always commensurate with being compassionate with the patient,” acknowledged Dr. Alan B. Lisook, chief of FDA’s clinical investigations branch. “The (required) dose may make the patient sick.” To take that into consideration is “perfectly legitimate” for the physician, but it is not always “good research for a drug trial . . . and it is certainly not good research when they don’t report what they do.”
Oncologists at other universities acknowledge the conflicts between good patient care and detailed government reporting. “The rules governing FDA trials are often maddeningly detailed,” said one UCLA oncologist. “And they (FDA regulators) are unbelievably bureaucratic, but a physician who uses experimental drugs on his patients knows what he’s getting into when he begins a trial--or at least he ought to know.”
In the last eight years, Lisook said, the FDA has sanctioned about 90 researchers who have not followed these rules. Linker is probably “about in the middle of those” who have gotten themselves into serious trouble with the government. It is probably significant, he said, that most of the scientists who are sanctioned are either in the field of psychiatry, where research standards are not always as clear cut as they in other areas of medicine, or oncology, where virtually all treatments are experimental and therefore subject to the often conflicting demands of government regulations and to judgments of individual physicians.
FDA investigators also said they found that 29 of the 36 files they reviewed either did not contain written informed consent forms signed by the patients or had forms that had been signed after treatment had begun, in violation of federal regulations governing human experimentation.
Over the years, Congress has tried to introduce numerous safeguards in human research including FDA requirements that drug manufacturers demonstrate both the safety and efficacy of a substance before it can be placed in the marketplace. In recent years, the paper work obligations associated with patient consent to drug testing have been steadily increased and have come to be more strictly enforced, despite arguments of some physicians that simply requiring forms and signatures on forms does not necessarily guarantee that patients truly understand what is being done to them.
Many physicians who know Linker say he has a reputation for spending a great deal of time explaining the risks and potential benefits of experimental treatments to patients. “I am blunt . . . some might say brutally blunt,” Linker himself said.
Unknown Risk
One of the problems in cancer research, however, is that physicians don’t always know what the risks of certain drugs are--which is why they were classified by the government as experimental.
Many government physicians familiar with VM-26 said that there is more than enough evidence with childhood leukemia to make a persuasive case for more flexible distribution of the drug. But it is unclear what impact, if any, the FDA investigation and sanctions will have on Linker’s published findings with adults.
In an article in an April, 1987, issue of the journal “Blood,” Linker and six co-authors reported that in their trial, which they said involved 81 patients treated with VM-26 and Ara-C, 94% had entered complete remission and 53% were projected to be disease-free for at least three years. They were considered to be the best results by far ever achieved in the treatment of the disease in adults.
Although there is certainly nothing irregular in having journal articles authored by more than one researcher, one of the problems the FDA had with the study is that Linker never reported to the drug agency or the National Cancer Institute, which sponsored the trial, that he was distributing VM-26 to these other researchers at other institutions.
Dr. John W. Adamson, editor-in-chief of Blood, which is published by the American Society of Hematology, said he had never been informed that there was a government investigation of Linker. Like most scholarly publications, Blood is not equipped to make its own formal inquiry to determine if the drug trial alters the results that Linker reported with patients, Adamson said. But he added: “It is quite possible that problems that concern the FDA, which are quite genuine, may well not affect the outcome of a study at all.”
When UCSF first learned of the government’s concerns it conducted its own inquiry, and took responsibility for some of the problems Linker faced, said Cadman, the former director of UCSF’s Cancer Research Institute. As a result, UCSF increased the overall administrative staff of the cancer center, established a permanent oversight committee to monitor all ongoing clinical research and began requiring that all experimental drugs be routed through a central pharmacy which maintains detailed records of physicians’ use of such agents.
In a May, 1987, letter to Linker, Cadman announced that he was putting Linker on probation for two years and stripping him of all responsibility for investigational drugs. Linker could conduct research only under the supervision of a designated senior professor at the medical center and the medical center would make quarterly reports on all studies in which he was a participant, Cadman said. The FDA accepted the university’s sanctions and put Linker on a two-year “total restriction” retroactively, which means that the FDA sanctions will come to an end next May when the university’s sanctions will also be lifted.
Linker remains under probation, according to university officials, but since the time of the investigation he has been promoted from an assistant clinical professor to an associate clinical professor, reflecting the view of many of his colleagues that he is, in the words of one UCSF professor, “one of the best, if not the best, oncologist in the Bay Area.”
New Program
This spring, the university news office sent out a press release saying that Linker was “directing” a “new program” using self-donated bone marrow transplants in the treatment of multiple myeloma. An investigational drug developed at Johns Hopkins University is to be a key element in the treatment, the release said.
FDA officials, having been informed of the release by The Times, expressed concern that Linker’s new project may be in violation of the sanctions imposed by the university and approved by the FDA and said the agency will investigate the situation.
But Marvin H. Sleisenger, acting director of hematology-oncology at UCSF, said that Linker was not really directing the project even though the release said he was. Although it had been Linker’s idea and Linker was actively involved in running it, his activities were being supervised until next spring, as required by the agreement with the FDA, Sleisenger said. Information that led to the press release was the “mistake of a staff member within the department,” which Sleisenger said was being investigated.
