Drug study hid chimp deaths

Published March 13, 2004

The founder of the Parker Hughes Institute in Roseville withheld information about the deadly effects of an experimental drug that was once touted as a "magic bullet" for AIDS and cancer.

Dr. Fatih Uckun and a team of researchers claimed that the drug, which he developed, caused no serious side effects in key animal safety tests in 1998.

Yet federal investigators found that it caused the deaths of three of eight chimpanzees used in two tests at a research lab in New Mexico.

The deaths were not mentioned a year later in a medical journal article by Uckun and his colleagues, or in a recent drug patent citing the chimp testing. In both cases, the tests were held up as evidence of the drug's safety.

At least 11 people, including a 7-year-old girl, got the drug after the chimps died. Uckun said all were warned about possible side effects. He halted the research on HIV patients in 2000 because of safety concerns, federal officials said. The drug hasn't made it to the market.

As recently as last August, the drug, TXU-PAP, was hailed as a potential leukemia breakthrough on the Web site of the institute, the Parker Hughes Cancer Center's research arm.

Uckun, who is under investigation by state officials for his patient-care and financial practices, defended his research.

He told the Star Tribune he didn't need to mention the chimp deaths in the journal article. He maintains that one chimp died from anesthesia, not the drug, and that the other two died after getting high doses as part of "a different study."

However, testing records show that the chimps were part of the same research described in the journal article. The research was designed to test the drug at varying doses, partly to see how the animals tolerated it, records show.

"This was a toxicological study. If three of them die, you can't ignore it," said S.J. Enna, a pharmacology professor at the University of Kansas Medical Center, who was editor of the Journal of Pharmacology and Experimental Therapeutics, which published Uckun's research article in December 1999.

Enna said the journal was not notified of the chimp deaths.

"He's got a very serious problem here," Enna said.

The journal's board of trustees will study the matter, said Richard Dodenhoff, journal director.

Enna said a clarification might be warranted if the omission is verified.

"It would not be very flattering for him," he added.

The chimp research turned into "an unmitigated disaster," said Dr. Christopher Staley, a veterinarian who worked at the Coulston Foundation animal research lab in Alamogordo, N.M., which did the testing under contract to the Minnesota researchers. One experiment was halted seven weeks ahead of schedule because of chimp deaths, according to documents and former lab employees.

The chimp deaths prompted a U.S. Agriculture Department investigation of the lab. It shut down in 2002 after being cited for numerous animal welfare violations.

In 2000, an animal-rights activist raised concerns about the animal deaths and Uckun's research in written testimony to a congressional committee, but the issue drew little notice at the time. In recent weeks, several of Uckun's co-authors on the journal article said they were unaware of the chimp deaths, as was a federal agency that had awarded him a three-year grant to test the drug on AIDS patients.

Earlier questions

The Minnesota Board of Medical Practice, which regulates doctors, is investigating Uckun and several others at the cancer center as a result of complaints about patient care and finances. In December, the Star Tribune reported that the cancer center subjected patients to unnecessary tests, gave false hope to patients and overbilled insurers. The paper also reported that Uckun allegedly demanded improper financial contributions from suppliers. Uckun has denied any wrongdoing.

Parker Hughes is best known as a cancer treatment center. But its scientists have received $38 million in grants and contracts since 1995 to research new treatments for cancer and other diseases. Most of that money has come from the for-profit drug development companies co-owned by Uckun.

Two of Uckun's five co-authors on the journal article said they didn't know about the chimp deaths. A third author, Dr. Yoav Messinger, the former director of pediatric oncology at Parker Hughes, says he does not recall the chimps' deaths and that he worked on only the data analysis for the research.

Both Uckun and Messinger defended the integrity of the article. Messinger, who now is at Children's Hospital in St. Paul, said that "to my knowledge, there was never any intention of hiding any toxicity data." Two other co-authors did not respond to the newspaper's questions.

Uckun, a widely published scientist, said the conclusions about the drug's safety applied only to those animals getting the lowest dose, 10 micrograms. In a written response to questions from the Star Tribune, he said the safety claim "is both accurate and supported by the study findings."

Some experts said omitting the deaths is suspect, at best.

"I don't think it would take a high-level ethicist to argue that it seems like the investigators were holding back information that would be hurtful to their product and their company, which is really upsetting if in fact it has the potential to be hurtful to humans," said Dr. Alan Fleischman, a medical ethicist and senior vice president of the New York Academy of Medicine.

Scientists have some discretion about what to leave out of reports on animal experiments, experts say.

"There is no formal rule," said Karen Maschke, editor of a journal on research ethics at the Hastings Center, a medical ethics institute in Garrison, N.Y. Although she did not know the details of this case, she said, "it raises questions about withholding important information and why that was done."

Another medical ethicist, when told of the case, was more critical.

"If you are a member of the [scientific] fraternity, you have to play by the rules," said Rabbi J. David Bleich, professor of ethics at Yeshiva University in New York City. "... This certainly would be considered intellectual fraud."

Promising drug

The drug was one of Uckun's most promising discoveries at the University of Minnesota Medical School, where he was a professor until 1997. TXU-PAP was one of a handful of new compounds that Uckun, a childhood-cancer specialist, developed from the pokeweed plant, which has a natural poison that he hoped could fight childhood leukemia.

The drugs are sometimes known as "smart bombs" -- they take aim at cancer cells and deliver a poison in hopes of knocking them out, without harming healthy cells. That's the goal of many cancer researchers, to try to eliminate the harsh side effects of treatment.

Uckun knew, from his own early research and others, that the pokeweed drugs came with risks -- including vascular leak syndrome, in which blood vessels leak fluid into the lung and other organs, causing serious complications. But he also had high hopes for his pokeweed drugs. His research showed that they might work on other diseases as well, including AIDS. And he co-founded a for-profit company, called Alexander Parker Pharmaceuticals Inc., to try to bring his drugs to market.

By the summer of 1998, the Parker Hughes annual report called TXU-PAP a "magic bullet" that "successfully eradicates" the virus that causes AIDS in mice. In lab tests, it said, the drug "was 100 - 1,000 times more active" than conventional AIDS drugs and had other important advantages, including "a lack of harmful effects on healthy cells." The results, it said, "strongly suggest that TXU-PAP could become a potent, yet safe, biotherapy agent for AIDS patients."

But earlier that year, tests at the Coulston lab revealed some problems.

In January, the drug had been given to four HIV-infected chimps at Coulston as part of a study sponsored by Uckun's company. Two got a low dose, 10 micrograms, and the other two got 20 micrograms. On the first day, one of the chimps on the higher dose died -- a 14-year-old named Holly. The lab veterinarians were stunned. "We were told flat out that they expected no side effects," said Staley, the veterinarian who worked for Coulston and examined the chimp's body to learn what killed her. Holly's blood vessels had started to leak blood and protein, causing her heart, liver and kidneys to fail, he said. "All Holly died from, very plain and simple, was vascular collapse," Staley told the Star Tribune.

He said his supervisor, veterinarian Dr. Ronald Couch, told him "it couldn't possibly be the (drug), that this stuff was already in human trials and it was safe and it had to have been something to do with the anesthetic." Couch also told a USDA investigator that anesthesia caused the chimp's death. Uckun said Couch told the same thing to the institute.

Five months later, Coulston gave TXU-PAP to four more chimps. This time, two got 20 micrograms and two got 40. Within days, chimps Terrance, 11, and Muffin, 15, became sick on the higher dose. Once alerted, Uckun's company faxed information about vascular leak syndrome to Coulston and sent an emergency shipment of albumin, which can help counter the effects. But it arrived too late. The two chimps died a day apart, on June 26 and 27, 1998. The research, designed to go on for eight weeks, was abruptly halted, records show.

"It was very traumatic for everyone involved," said Dr. Scott Walden, a veterinarian who worked on the chimp testing and is now at the University of Minnesota. "I would have refused to participate in this study had it continued."

Uckun said in a statement he was "quite upset" about the chimp deaths. In the journal article, Uckun's team mentioned only the results of four of the surviving Coulston chimps and two others tested at a Texas lab. The article said some of the chimps developed a mild form of vascular leak syndrome.

Even before the article was submitted to the journal, USDA investigators had concluded that the three chimps had died unnecessarily from this side effect, and that Coulston should have been prepared to deal with it. The veterinarians who gave the drug agreed.

"We should have known about this information," another former Coulston veterinarian, Dr. Debra Stauffer, told USDA investigators. Information about how to cope with the leakage "could have saved the animals' lives," she added.

Coulston never gave the drug to another chimp.

Testing in humans

The next month, the research continued -- on humans.

The drug was given to nine HIV-infected patients in Minnesota and Florida. None of them had serious side effects, according to the same research article that mentioned the chimp testing. Uckun has not published any other scientific articles about the drug's effect on people, including leukemia patients who received it.

Patients signed consent forms that stated the danger of vascular leak. The forms said that the drug "can cause leakage of fluids from blood vessels into the soft tissues and lungs," and that it can lead to breathing problems and even "may lead to death."

Uckun told the Star Tribune that "no severe" vascular leak syndrome was observed in 38 HIV patients who got the drug in California and Florida. He did not say whether they got the drug before or after the chimp deaths.

In 1999, at least two leukemia patients also received the drug. One was Sydney Hickman, a 7-year-old girl from Las Vegas who had a deadly form of leukemia. It seemed like her last chance at survival, her mother, Shelly, said in an interview, so she came to Minnesota to get TXU-PAP. They were warned about the danger of leaking blood vessels, Shelly said, but were told it was controllable.

The family did not know about the fatal reactions in the chimps, she said in an interview last month.

"It probably wouldn't have made a difference anyway since we were at a last resort," she said. But she said they should have been told.

She does not recall whether Sydney experienced any side effects but said her daughter was quickly taken off the drug for other reasons. In any case, the treatment didn't help, she said. Sydney died of leukemia the following spring, at age 8.

When the journal article came out in December 1999, Parker Hughes issued a glowing news release saying that TXU-PAP "shows great potential as a new anti-AIDS drug." It went on to say, "The treatment was found to be safe and effective in four out of four chimpanzees." It added that, based on "these encouraging results," more HIV studies were underway. It even said that South Africa had approved the use in patients.

Yet Dr. Glenda Gray, the South African researcher who once planned to collaborate with Parker Hughes, said Uckun never told her about the chimp deaths.

"I would have remembered if he had mentioned deaths!" she said in an e-mail response to the Star Tribune. "Certainly, any deaths should have been reported. An omission like that should not occur in a clinical or scientific report."

Gray, an AIDS researcher at the University of Witwatersrand, Johannesburg, said the plan to test TXU-PAP on patients in South Africa was dropped for other reasons but that the animal deaths would have troubled her.

"The chimp deaths would have definitely given us pause, and we would have not run trials with that data," she wrote.

'Real questions'

Meanwhile, Uckun sought a patent related to the drug in December 1999. The patent, issued this February, mentioned the three HIV-infected chimps that survived but omitted any mention of a death. The patent states that "none of the chimpanzees experienced any significant side effects. ... Therefore, TXU-PAP is active and safe."

In 2000, Uckun abruptly halted a three-year study of TXU in AIDS patients because of "concerns about the safety of the treatment," according to a written statement issued by the National Institute of Allergy and Infectious Diseases in response to questions from the Star Tribune. The federal research institute indicated Uckun discontinued a federal grant that would have paid him $750,000 to continue the research.

Uckun told the Star Tribune that he "changed the direction of the research" to work on genetically engineered drugs that he hopes will not cause vascular leak syndrome even at high dose levels.

The federal institute said in its statement that it didn't know about the chimp deaths until the newspaper contacted it recently. The deaths were reported in a USDA news release about the Coulston lab in 1999, although it didn't mention Uckun's connection to the lab.

In March 2000, before the TXU human study ended, an animal-rights activist who had looked into the chimp deaths told a House committee about the connection to Uckun and asked for an investigation into how the government oversees federally funded research.

"When we find this kind of dishonesty in both a published paper and a patent, that raises real questions about how widespread this is," said Eric Kleiman, the activist who investigated Coulston for eight years as research director for In Defense of Animals, based in California. "This isn't just animal welfare concerns; we are talking about human safety as well."

For previous coverage of Parker Hughes, visit www.startribune.com/cancerclinic.

Glenn Howatt is athowatt@startribune.com or 612-673-7192.

Paul McEnroe is at pmcenroe@startribune.com or 612-673-1745.

Maura Lerner is at mlerner@startribune.com.