FDA Warnings to State Researchers Rise Sharply

California medical researchers lead the nation in Food and Drug Administration warnings, receiving nine of the 22 reprimands since the start of 1999 for violating regulations that protect study volunteers from exploitation and undue harm.

Though the most populous state might be expected to get the most warnings, the agency issued just two warnings to researchers here in 1997 and none in 1998, according to public records analyzed by The Times.

The spate of California warnings reflects the FDA’s stepped-up monitoring of clinical study programs nationwide, the explosion of biomedical research and, according to patient advocates, the growing number of for-profit clinical research firms. Some of those firms have been criticized for cutting ethical corners.

The warnings, which the agency issues to fewer than 5% of the researchers it audits, cited a range of violations, from poor record keeping to lax supervision of junior researchers to apparent fraud. Among the allegations:

* Dr. Ronald Cotliar, a dermatologist, oversaw one or more workers who fabricated clinical measurements on scores of patients in an undisclosed drug company-sponsored study at the Irvine Center for Clinical Research, a commercial firm.

* A prominent Los Angeles surgeon, Dr. Lawrence Dorr of Good Samaritan Hospital, illegally imported parts for an experimental hip joint and inserted the steel device into about 40 patients months before it received government approval.

* A San Luis Obispo eye doctor, Dr. Michael Limberg, put eight cataract patients into a study that the FDA said was not appropriate for them, thus exposing them to a potentially harmful laser treatment.

The sanctioned researchers are top experts. They also include Dr. Ernest Beutler, chairman of molecular and experimental medicine at the Scripps Research Institute; Dr. Demetrios Demetriades, director of trauma and critical care at the USC School of Medicine; Dr. Bruce Ettinger, a UC San Francisco-affiliated kidney expert; Dr. Abdool Moossa, UC San Diego’s chief of surgery; Dr. Robert Rand, a UCLA-affiliated cancer surgeon; and Dr. Thomas Tooma, a noted eye specialist in Newport Beach.

The FDA closed the cases involving six of the researchers--Beutler, Cotliar, Dorr, Ettinger, Moossa and Rand--after they vowed to improve practices and avoid future violations. The three most recent cases--involving Demetriades, Limberg and Tooma--remain open.

Helping Humanity, Not Placating Bureaucrats

The warning letters, which the FDA posts on its Web site, frustrate and anger the researchers, who say their goal is to help humanity, not placate Washington bureaucrats. UC San Diego’s Moossa said his brush with the regulators has all but killed his desire to do clinical trials. “Our lives were made miserable,” he said.

Several of the researchers said the FDA was dinging them for studies initiated years ago, when, they maintain, regulations were looser. “If you review any study from 10 years ago, you’re going to find it deficient by today’s standards,” said UC San Francisco’s Ettinger.

No patient was physically harmed by the alleged wrongdoing, according to the researchers. But the infractions nonetheless undermined patients’ rights or jeopardized studies’ scientific validity and usefulness, scholars and advocates say.

California’s jump to the top of the most-warned list coincides with deepening public interest in the welfare of people who agree to serve as research subjects. Partly in response to public pressure, the FDA has steadily boosted inspections of research programs--for example, auditing 213 Institutional Review Boards in fiscal year 1997, 253 in 1998 and 336 in 1999.

At the same time, said Dr. David Lepay, director of investigations for the agency’s drug and research center, there has been an “upward blip” in the number of warnings and other official FDA actions by his division, which conducted 400 inspections of review boards, individual researchers and other entities in the last fiscal year.

Besides the nine warnings slapped on California doctors since the beginning of 1999, those in Texas got three, those in Wisconsin received two, and those in eight other states got one apiece.

Lepay urged caution in interpreting the numbers. They are too low to be statistically significant and are not based on a scientific survey of national research programs. And the overall percentage of audits resulting in a warning has dropped, from 10% or 20% in the 1960s to 2% or 4% today, he said. “I frankly think that American clinical research is in very good shape,” Lepay said.

Some Say FDA Should Be Tougher

But patient advocates and some scholars argue that the FDA is still doing too little. That such a small fraction of FDA audits results in warnings does not jibe with academic and government studies showing that ethical shortcomings in research are common. Several widely accepted analyses show that informed consent violations, for instance, have occurred in one-third of all clinical studies.

“The [FDA’s] increased enforcement activities are encouraging,” said Dr. Peter Lurie, co-director of health research at Public Citizen, a Washington, D.C.-based advocacy group. “But there are large residual amounts of research activity out there that the agencies are not willing or able to take action against.”

The FDA issues a warning after field officers inspect a clinic, interview research staff and audit study records. Roughly 20% of the visits are triggered by a complaint to the agency about a research program, and 80% reflect routine monitoring, Lepay said.

A warning is one of the most serious actions that the FDA can take against a researcher, short of barring access to experimental treatments. Warned researchers must account for the violations and explain how others will be prevented. Those replies usually satisfy the agency, records show.

Perhaps the most serious warning of the recent California lot was the one sent to Cotliar and the Irvine contract-research firm. An FDA inspection in March 1999 found that one or more study workers did not take the required body temperature and respiration readings on 191 patients, but instead falsified readings and entered them in the records. “The data generated from these efficacy assessments may be inaccurate,” the FDA said.

Cotliar, who is in private practice in Tustin, said through an attorney that the study coordinator who fabricated data was fired and that patient safety was not compromised.

He declined to name the treatment being tested or the company that sponsored the research, citing confidentiality agreements. The Irvine firm declined to comment. It is FDA policy to remove the names of drugs, study sponsors and other proprietary details from released warning letters.

The FDA’s Lepay said the agency would not comment on specific cases. Generally, though, he said a study that turns out to be useless because of faulty data undercuts the rights of patients, who often undergo risky experimental treatments precisely to advance medical knowledge.

Moreover, Lurie, of Public Citizen, said faulty data may end up harming people if the agency approves a product for marketing based on the information.

The welfare of patients as well as the validity of studies can be threatened when researchers ignore the criteria determining whether a person is eligible for a study, regulators and scholars say. Studies with the “wrong” patients can make a treatment seem either more or less effective than it really is.

An FDA warning sent last month to Limberg, the San Luis Obispo ophthalmologist, said eight of 24 cataract patients who underwent an experimental laser procedure “did not meet the inclusion/exclusion criteria for the study. . . . This included subjects who did not meet the age criteria; had a cataract grade outside of the acceptable range; and had poorer visual acuity than required.” The FDA described that problem and others as “serious violations.”

Limberg referred calls to a regulatory consultant for Paradigm Medical Industries, which makes the laser device. Greg McArthur, the consultant, said the problems were “clerical errors” and denied that some subjects did not belong in the study. He said the FDA inspector “absolutely” did not understand the research. The case remains open.

Several of the warned physicians said regulators do not fully consider what it means to care for sick or injured people who clamor for promising new treatments, whether FDA-approved or not.

In March 1999, the FDA reprimanded Dorr, the Good Samaritan surgeon, for “significant violations” in a hip-replacement study after a complaint was lodged with the agency. The study evaluated stainless steel hip parts from an overseas supplier, and Dorr had FDA clearance to import enough parts to treat 46 patients.

After doing so, he said, the replacement appeared to work so well that he imported the parts from another overseas source without FDA permission and treated another 40 patients on his own. And though he said he informed the extra patients of the device’s experimental nature, the FDA charged that he obtained written consent from many of them only after the operation.

Dorr admitted the infractions to the FDA. “Everyone who got the operation was significantly helped by it,” he said in an interview. “And that was what we were trying to do.”

Irregularities in Use of Consent Forms

A somewhat unusual case was that of Rand, of the John Wayne Cancer Institute in Santa Monica. The noted 77-year-old surgeon said he had never done a drug trial before and was not aware of all the regulations.

He received an FDA warning last October for a study of an experimental brain tumor drug, iL4. FDA inspectors, prompted by a complaint to the agency, found inadequate record keeping, failures to promptly notify hospital review boards of adverse reactions and deaths, and inclusion of a subject who did not fully meet the study criteria.

In an 11-page letter to the agency, Rand said he stopped doing a previously specified brain scan because it was unnecessary and he wanted to save subjects money. And he delayed reporting several deaths because the patients lived out of state or overseas and word of their demise did not reach him for months, he said.

Most of the warnings cited problems with the subjects’ consent, including forms that were not in their first language, consent elicited from patients after a procedure and consent forms that failed to mention an experimental treatment’s risks. Ethics scholars find such problems particularly troubling because informed consent has been the preeminent moral ethic of human subject research since World War II.

Researchers who complain about the FDA’s warnings and other actions often miss the point, suggested Dr. Theodore Friedmann, director of the gene therapy program at UC San Diego: “The FDA exists to ensure not the well-being of the investigator, but of the patient.”

In addition to auditing individual researchers, FDA officials formally inspect research sponsors and local research review committees. Since the start of 1999, the agency has sent warnings to two California review boards and one company for violations such as keeping insufficient meeting records and neglecting to monitor study results.

“When you’re at the receiving end, it can be frustrating,” said Michael Gendreau, chief medical officer at Cypress Bioscience, a San Diego company that received an FDA warning last June for failing to keep up-to-date study records. “But better to be cautious than reckless.”