Another Gene Therapy Trial Goes Awry.

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Death Points to Risks in ResearchOne Woman's Experience in Gene Therapy Trial Highlights Weaknesses in the Patient Safety Net By Rick WeissWashington Post Staff WriterMonday, August 6, 2007; A01 http://www.washingtonpost.com/wp-dyn/content/article/2007/08/05/AR2007080501636.html [Last year, in March 2006, the case of a genetically altered drug TGN-1412 (an immunomodulator) was highlighted in the press. This drug severely affected six people, one patient's head bloated up so much that he resmbled an elephant, four others developed multiple organ failure, and another developed cancer. The company promoting the drug withdrew it but blamed faulty protocols for the fiasco. This charge was proved false (the protocol was approved) and it was also revealed that the drug was administered in a very minute dose, 500th part of the dose tried on animals. And yet it caused so much devastation. Knowing the nature of the drug, an

immunologist commented, “You don’t need to be a rocket scientist to work out what will happen if you non-specifically activate every T cell in the body". Many such instances have occured making research laboratories go bust, we do not know the fate of the patients. But instead of stopping such trials, they are now being carried out in the sly, as the enclosed article suggests. With India having opened the doors to MNC drug majors' clinical trials, one can only hope and pray that all is well. A nation that cannot stem the tide of spurious drugs obviously cannot keep track of trials going on in myriad clinics all over the country. There is no one to ask any questions, no ungainly sights of patients queing up to file lawsuits, no compensation. It is a win-win situation for all except the uninformed gullible public. My warning to concerned citizen is scan all prescriptions. If a drug bears a number rather than a name, watch out! If your doctor says, "I have just the right remedy for you, it's imported and it does not cost the earth", you know what to do. My experience tells me, most clinical trials take place in ICUs where the patient is obviously compliant and there are no relatives hovering around. Who hover around instead are drug company representatives with feedback forms in their hands. Some drugs could also be marked, "For Hospital Use only". We should then ask why. A doctor in Orissa advises all patients to start questioning the drugs prescribed, the reason for their use and their safety record. I would

agree with him. The days we could blindly believe the doctors are sadly over. - Jagannath] Robb Mohr sat by his wife's hospital bed two weeks ago, trying to take it all in. His wife, Jolee Mohr, was breathing with the help of a ventilator in a Chicago intensive care unit -- her body bloated from internal bleeding, her liver failing -- and no one could figure out what was wrong with her. Robb Mohr had his suspicions. Jolee, 36, had been feeling fine just a few weeks earlier, save for occasional stiffness from her arthritis. Her decline had begun the day after her right knee was injected with an experimental drug made of genetically engineered viruses. Doctors at the hospital shared his concern. Jolee Mohr died from massive bleeding and organ failure July 24, leaving behind a 5-year-old daughter

and a host of questions about why she was recruited into a gene therapy experiment whose chief goal was to test the safety of a novel arthritis treatment that had virtually no chance of helping her. No one knows yet whether the treatment was to blame. Of the dozens of other volunteers who got the injections, only Mohr suffered anything more than short-lived side effects, said officials at Targeted Genetics Corp., the Seattle company that makes the product. The Food and Drug Administration and the company are investigating. But a close look at the events leading to Mohr's death reveals failures in the safety net that is supposed to protect people from the risks of medical experimentation -- and in

particular, the risks of gene therapy, which for 17 years has struggled in vain to live up to its optimistic name. Breaches of clinical research standards and a federal oversight system that allowed key decisions to be made behind closed doors may have helped draw Mohr into an experiment that was not, her husband says, what she thought it was. "It was presented to her like this is going to make her knee better," said Robb Mohr, an agronomist who lived with his wife of nine years in a modest vinyl-sided ranch home near Springfield, Ill. "It was supposed to be just a simple thing." Company officials vigorously defend the study, saying they were upfront about risks, adhered to all regulations and were terribly saddened by the loss. "We're human," said H. Stewart Parker, Targeted

Genetics' chief executive. "This is not just a patient. This is a person, and this is a horrible tragedy." A two-sentence paragraph halfway through a 15-page consent document that Jolee Mohr signed warns of the possibility of "unknown side effects," including, "in rare circumstances, death." Further in, after long descriptions of how the product may help, a single sentence states: "We do not expect you to receive any direct medical benefits from participation in this study." Mohr was in an early-phase study, the prime goal of which was to see whether the treatment was safe, not to provide a therapeutic benefit. If the drug passed muster, other studies would determine whether it was an effective treatment. Her rheumatologist, Robert Trapp, whose Springfield clinic got payments from Targeted Genetics for each subject he recruited, also defended the

study. "The theory behind it seemed good, and the science seemed good," he said. "There's nothing I knew of that could have predicted this." Arthritis is a disease in which the immune system attacks the joints, causing painful inflammation and degradation. Even when treated with powerful medicines, up to 40 percent of patients have ongoing pain in at least a few joints. That medical reality is an economic opportunity worth as much as $3 billion a year, Parker has said. The company hopes to tap that market with tgAAC94, a virus engineered to have an extra gene. Injected into a joint, the virus infects cells and continuously produces proteins that sop up inflammatory molecules, according to the company. Like other gene therapies -- hundreds of which have been tested since 1990 and all of which are still experimental -- the approach has the potential advantage of having the body crank

out its own medicine for months or years after treatment, right where it is needed. That sounded good to Mohr when Trapp, one of 20 U.S. doctors testing tgAAC94, invited her to join the study on Feb. 12. There would be two injections, months apart, he explained. The first might be real, or it might be a placebo, but the second would definitely be the test product. She signed up immediately, and Trapp drew several tubes of blood to get the study going. Two fundamental rules of clinical research were violated that day, experts said. First, consent forms are to be taken home and considered, not signed on first sight. Second, when a patient's own doctor is a principal investigator in a study, someone else is supposed to make the proposal. "Because of the relationship . . . you have to worry that they won't listen carefully enough to the risks," said Hank Greely, director of

the Center for Law and the Biosciences at Stanford University. Patients, he said, may think, " 'After all, if my doctor is doing this, it must be good for me.' That can be difficult to overcome with words in a consent form." Trapp said he thoroughly explained the risks to Mohr. Jonathan Moreno, an expert in the ethics of medical experiments at the University of Pennsylvania, said the consent form used by Targeted Genetics to outline the drug's potential dangers was thick with technical descriptions and thin on explaining "what's really going to happen." "Even a smart person would have a very hard time figuring out what they're talking about," said Moreno, who examined the form at the

request of The Washington Post. The form was approved by one of the growing number of for-hire review boards that contract with biotechnology companies to ensure studies meet patient-protection standards. Targeted Genetics noted that the review firm it used is accredited and accepted by the FDA. But the use of private boards, as opposed to those run by universities or government agencies, has raised alarms among some medical ethicists since a for-profit review board risks losing repeat business if it is too tough on its clients. Mohr's first shot, administered on Feb. 26, had no noticeable effect, and she wondered whether she got the placebo. But she was excited that the next one would be the real thing, Robb Mohr said. That happened on July 2, a Monday. She was tired and out of sorts

after a weekend of boating with her husband and daughter, but she had gone to her data-entry job at the secretary of state's office in Springfield and later to Trapp's office. He recorded her temperature at 99.6, then gave her the shot. "The next day she woke up and didn't feel good at all. By afternoon she started vomiting," Robb Mohr recalled. "By evening her temperature had shot up to 101." She spent July Fourth feverish and vomiting. Her family physician told her it was probably just a virus. When her symptoms worsened and her temperature hit 104.1 on Saturday, she went to the emergency room. Tests indicated a possible infection and signs of liver damage, but she was sent home for more care from her family doctor, according to Robb Mohr and medical records. Aware of the experiment, Mohr's family doctor called Trapp,

who reassured him that the virus was safe -- something Trapp said he had learned at a training session sponsored by Targeted Genetics. But Mohr only got worse, and on Thursday she was admitted to the hospital. Things went downhill fast, with Mohr's body showing signs of being ravaged by an infection. But tests for standard bacteria and viruses came up negative. With breathing problems and the possibility she might need a liver transplant, she was transferred to the University of Chicago hospital. Suspecting a possible link to the experimental drug, the doctors in Chicago contacted the FDA. Federal regulations require a company to report any serious complications that are even

"possibly" related to an experimental treatment "as soon as possible" and no later than seven days after learning of it. But Targeted Genetics and Trapp had at first classified the problems as not serious, and later classified them as serious but unrelated to the treatment. So no FDA report was made, and the study went on, with other volunteers unaware of the problems. That reflects a widespread problem in clinical trials, said Adil Shamoo, a professor at the University of Maryland School of Medicine and editor in chief of the journal Accountability in Research. "There are no uniform standards for 'adverse events' reporting," Shamoo said. "And there is no motivation to report them. . . . No one wants to show their dirty linen." Dirty linen can drag down a company's bottom

line, and Targeted Genetics, like all companies, puts a lot of work into keeping that line afloat. An interim report on tgAAC94, for example, spoke in June of "very encouraging results" and evidence of "clinical benefit," although, by one measure the company considered key, patients who got high, medium or low doses of the drug did the same as those who got placebos. "The company was talking about lucrative markets and a promising product much too soon," said Marcy Darnovsky, associate executive director of the Center for Genetics and Society, an Oakland, Calif.-based public interest group that focuses on genetic technologies. Company officials said the drug does show promise by some measures. "We don't know what the best indication of

efficacy is yet," said Barrie Carter, the company's chief scientific officer. Finally, on July 20, a day after Mohr's emergency transport to Chicago and four days before she died, the company sent a "serious adverse event" report to the FDA and suspended the study, conceding that her life-threatening symptoms were "possibly" due to the treatment. Three weeks after Mohr got the injection that she had hoped would cure her, she was unconscious and beyond hope of recovery. With family and friends gathered around, her life support was removed. "Basically, I told my daughter that her mommy has died and gone to live with Jesus," Robb Mohr said. "She prays every night that Jesus will make her better so she can come back home." Tests on Jolee's Mohr's tissues may tell the story of what happened, but for now scientists say they are scratching their heads.

One reassuring aspect of tgAAC94's engineering is that genes required for replication have been removed, so the viruses cannot make more of themselves. But animal studies conducted by the company have shown that the product can escape from the joint space and travel about the body, perhaps catching the attention of the immune system. In general, the immune system mounts much more robust -- sometimes dangerously robust -- responses after a second exposure. In fact, both shots Mohr got were the real thing, the company said. Further complicating matters, Mohr was on three conventional but potent arthritis drugs, each of which can cause serious side effects. Years ago, when Targeted Genetics first sought permission to test tgAAC94 in people, federal reviewers approved a single dose in patients who were not taking other drugs but said they would think twice about approving multiple shots or testing in people

taking other arthritis medications. Some questioned whether the risk of even a single shot was worth it for a non-life-threatening disease such as arthritis, according to the minutes of meetings at the National Institutes of Health, which used to review, in public, every proposed human gene therapy experiment. After completing its initial study of single shots, Targeted Genetics sought permission to start giving two -- and to patients taking other drugs. Whatever discussion led up to that approval is hidden from the public because of a federal rule change in 2000 that placed most such follow-on studies under confidential FDA review rather than a public NIH process. In testimony before a congressional subcommittee in 2000, a chief executive representing the

Biotechnology Industry Organization spoke out for the rule change, to streamline oversight and harmonize NIH and FDA regulations. Among other things, the change gave companies up to a year to report serious adverse events as long as the doctor overseeing the study does not think the problem is caused by the test product. The chief executive was H. Stewart Parker of Targeted Genetics. Staff researcher Madonna Lebling contributed to this report.What if a “dirty bomb” exploded over a large segment of U.S.population that simultaneously exposed citizens to Hepatitis B,Hepatitis A, tetanus, pertussis, diphtheria, three strains of polio viruses, three strains of influenza, measles, mumps, and rubella viruses, two types of meningitis, four strains of herpes viruses, the chickenpox virus, 7 strains of Streptococcus bacteria, and four strainsof rotavirus.

• We would declare a national emergency.• It would be an “extreme act of BIOTERRORISM• The public outcry would be immense and our government would react accordingly.And yet, those are the very organisms we inject into our babies and our small children in multiple doses, with immature, underdeveloped immunesystems, many at the same time with vaccines. But instead of bioterrorism, we call it “protection.” Reflect on that irony.- Dr Sheri Tenpenny, MD

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