Credibility Crisis: Survey FDA Scientists – Death in NIH-AIDS Trial – Tauzin Moves to PhRMA

Credibility Crisis:Survey FDA Scientists – Death in NIH-AIDS Trial – Tauzin Moves to PhRMA

Thu, 16 Dec 2004

A credibility crisis in medical research is smoldering: like the Enron accounting scandal, the prescription-drug debacle is a matter of systemic corruption, including gross and widespread failure by the regulatory process. Unlike Enron whose accounting violations resulted in financial loss, medical research violations resulted in preventable deaths. Yet, no criminal charges have ever been filed.

The Washington Post reports (below) that a government survey of 400 scientists at the Food and Drug Administration reveals that the majority expressed lack of faith in the agency’s ability to assess drug safety, to monitor FDA-approved drugs.

The Associated Press reports that the death (2003) of Joyce Ann Hafford, a pregnant woman who was a subject in an AIDS drug trial conducted at the National Institutes of Health was covered-up by NIH officials: "NIH officials acknowledge that experimental drugs, most likely nevirapine, caused her death, and that keeping the family in the dark was inappropriate. But NIH usually leaves disclosures like that to the doctors who treated her."

Although NIH scientists knew since at least 2000, that nevirapine "could cause lethal liver problems or rashes when taken in multiple doses over time," they concealed that fact from the patient: "Lane confirmed the nevirapine bottle Hafford received likely wouldn’t have had safety warnings because the experiment’s rules called for the patient to be unaware of the exact drug effects to avoid the placebo effect, or patient influence, on the test results. That means the consent form would have been her lone warning about potential liver problems, he said.

Inter Press Service reports: "Vast numbers of dead, the compromising of key elements within the medical community and its regulatory structures, the blind pursuit of billions of dollars in corporate profits — all have surfaced in a detonating pharmaceutical industry scandal of global dimension."

Demonstrating that greed knows no shame, Congressman Billy Tauzin, a principal author of the new Medicare drug law, will become president of the Pharmaceutical Research and Manufacturers of America, the chief lobby for brand-name drug companies, House’s Author of Drug Benefit Joins Lobbyists. See: House’s Author of Drug Benefit Joins Lobbyists By ROBERT PEAR December 16, 2004 http://www.nytimes.com/2004/12/16/politics/16drug.html?ex=1104207157&ei=1&en=f83ecb3decf2c478

Contact: Vera Hassner Sharav
212-595-8974

http://www.washingtonpost.com/ac2/wp-dyn/A3135-2004Dec15?language=printer

WASHINGTON POST
Many FDA Scientists Had Drug Concerns, 2002 Survey Shows
By Marc Kaufman
Washington Post Staff Writer
Thursday, December 16, 2004; Page A01

Almost one-fifth of the Food and Drug Administration scientists surveyed two years ago as part of an official review said they had been pressured to recommend approval of a new drug despite reservations about its safety, effectiveness or quality. The survey of almost 400 scientists also found that a majority had significant doubts about the adequacy of federal programs to monitor prescription drugs once they are on the market, and that more than a third were not particularly confident of the agency’s ability to assess the safety of a drug.

The results of the survey, conducted by the Department of Health and Human Services’ inspector general, appear to support some portions of the controversial Senate testimony last month by FDA safety officer David J. Graham. The 20-year agency veteran told senators that the FDA was unable to keep some unsafe drugs off the market, and that scientists who dissented about drug safety and effectiveness were sometimes pressured and intimidated.

Graham’s testimony, at a hearing into the sudden withdrawal from the market of the arthritis drug Vioxx, put a spotlight on the FDA’s safety and management record. Top FDA officials later criticized Graham’s testimony as inaccurate and unscientific, but the survey results indicate that some other agency scientists share similar views. “I think this provides evidence that among the reviewing scientists at FDA, their experiences mirror the testimony I gave before Congress,” Graham said yesterday. “It also shows the unfortunate experience of many mirrors what happened to me when I tried to bring safety issues to my managers and the American public.”

The complete survey will be made public today by the Union of Concerned Scientists and Public Employees for Environmental Responsibility, two public interest groups that received the documents through the Freedom of Information Act process. The Washington Post obtained a copy yesterday. When the inspector general’s report on the effectiveness of the FDA’s drug review process was released in March 2003, administration officials focused on the conclusion that FDA reviewers and drug sponsors “have confidence in the decisions FDA makes.” The report also highlighted the agency’s effectiveness in reducing the time it takes to review a new drug approval.

The survey was conducted as part of the inspector general’s inquiry, but only parts of it were included in the report. The dissenting voices of some FDA scientists were not generally represented in the study, by former inspector general Janet Rehnquist. In a statement, the FDA said yesterday that the study showed that overall, “FDA medical reviewers found their work at the agency to be rewarding — a result consistent with many other quality of workplace surveys conducted throughout the government which have shown that FDA workers are proud of the agency and the service it provides to the American people.”

While the final inspector general’s report emphasizes the agency’s successes, the survey, conducted at the FDA’s request, found underlying concern and discord. For instance, 36 percent of scientists said they were only somewhat confident, or not confident at all, in the FDA’s decisions regarding drug safety. When it came to drug effectiveness, 22 percent of scientists said they were only somewhat confident, or not confident at all, in the agency’s decisions. As described in the report, drug manufacturers reported significantly greater confidence in both categories.

Some of the most dramatic Senate testimony that Graham delivered involved what he described as efforts by FDA supervisors to silence him and pressure him to limit his criticism of the safety of some drugs. In the survey, 63 of 360 respondents — 18 percent — said they had been “pressured to approve or recommend approval for a [new drug application] despite reservations about the safety, efficacy, or quality of the drug.”

Similarly, 21 percent of survey respondents said the work environment at the FDA’s Center for Drug Evaluation and Research either allowed little dissent or stifled scientific dissent entirely. Steven K. Galson, acting director of the center, has acknowledged some problems regarding safety reviews and the handling of internal scientific dissent at his agency but has described them as limited. Nonetheless, the agency last month asked the congressionally chartered Institute of Medicine to look into the FDA’s system for assessing drug safety.

The FDA drug reviewers were also highly skeptical of the agency’s ability to monitor the safety of prescription drugs once they are on the market. In all, 6 percent said they were “completely confident,” 28 percent said they were “mostly confident,” 47 percent said they were “somewhat confident” and 19 percent said they were “not confident at all.” Rehnquist’s report found that some FDA reviewers believed that the speeded-up process for reviewing drugs required by Congress was causing morale problems among overworked scientists. More than half of respondents said they did not think there was sufficient time to conduct an in-depth, science-based review in the six months required for drugs given “priority” status.

Graham, who participated in the inspector general survey, said he had never seen the complete survey results before. The findings are consistent with a 2001 study conducted by Public Citizen’s Health Research Group.

© 2004 The Washington Post Company

http://hosted.ap.org/dynamic/stories/A/AIDS_DRUG_DEATH?SITE=FLTAM&SECTION=US
December 15, 2004
AP Exclusive: Woman Died During AIDS Study
By JOHN SOLOMON and RANDY HERSCHAFT Associated Press Writers

Joyce Ann Hafford died without ever holding the son she had tried to save from contracting AIDS by taking an experimental drug regimen administered by government-funded researchers during her pregnancy.

But even before her stunned family could grieve, the 33-year-old’s death was reverberating among the government’s top scientists in Washington. They quickly realized the drugs the HIV-positive woman from Memphis, Tenn., was taking likely caused the liver failure that killed her.

Reports of her declining health were being monitored in late July 2003 at the National Institutes of Health as she lay on a respirator, and the case eventually reached the nation’s chief AIDS researcher, according to documents obtained by The Associated Press.

“Ouch! Not much wwe (we) can do about dumd (dumb) docs,” Dr. Edmund Tramont, NIH’s AIDS Division chief, responded in an e-mail after his staff reported that doctors continued to administer the drugs nevirapine and Combivir to Hafford despite signs of liver failure.

Nevirapine is an antiretroviral AIDS drug used since the mid-1990s, and the government has warned since at least 2000 that it could cause lethal liver problems or rashes when taken in multiple doses over time. Hafford’s family says they were never told NIH had concluded that the experimental drug regimen likely caused her death until AP gave them copies of NIH’s internal case documents this month. They were left to believe Hafford had died from AIDS complications but began pursuing litigation to learn more.

“They tried to make it sound like she was just sick. They never connected it to the drug,” said Rubbie King, Hafford’s sister. “If it were the disease, solely the disease, and the complications associated with the disease, that would be more readily acceptable than her being administered medication that came with warnings that the medical community failed to get … to her.”

NIH officials acknowledge that experimental drugs, most likely nevirapine, caused her death, and that keeping the family in the dark was inappropriate. But NIH usually leaves disclosures like that to the doctors who treated her. “We feel horrible that something like this would happen to anyone in any circumstance,” said Dr. H. Clifford Lane, NIH’s No. 2 infectious disease specialist. “There are risks in research and we try to minimize them.”

Jim Kyle, a lawyer representing Regional Medical Center in Memphis where Hafford died, declined comment because of the family’s pending litigation. The doctors there deferred to NIH to comment. The study during which Hafford died recently led researchers to conclude that nevirapine poses risks when taken over time by certain pregnant women. “Continuous nevirapine may be associated with increased toxicity among HIV-1 infected pregnant women” with certain liver cell counts, the study concluded.

Lane said Hafford should have signed a 15-page, NIH-approved consent form at the start of the experiment specifically warning her of the risks of liver failure. The family says Hafford seemed unaware of the liver risks. They even kept the bottle of nevirapine showing it had no safety warnings. “My daughter didn’t know any of the warning signs,” said Rubbie Malone, Hafford’s mother and now caretaker of Hafford’s new baby and older son. “She never got to hold her baby.”

Lane confirmed the nevirapine bottle Hafford received likely wouldn’t have had safety warnings because the experiment’s rules called for the patient to be unaware of the exact drug effects to avoid the placebo effect, or patient influence, on the test results. That means the consent form would have been her lone warning about potential liver problems, he said.

And that 15-page, single-spaced consent form is chock full of complex medical terms like “hypersensitivity reactions” and “pharmacokinetic test.” The warning about potential liver problems shows up on the 6th page, where it said liver inflammation was possible and that it “rarely may lead to severe and life threatening liver damage and death.”

Hafford, who was HIV-positive but otherwise healthy, agreed to participate in the NIH-funded research project that provided her multiple doses of nevirapine, also known as Viramune, to protect her soon-to-be-born son, Sterling, from getting HIV at birth. The project was an outgrowth of earlier research in Africa that concluded the drug could be taken in single doses safely to protect newborns half the time.

“She didn’t want her baby to be born with HIV infection if it could be prevented at any cost,” said King, her sister. Hafford died Aug. 1, 2003, less than 72 hours after giving birth. Sterling was delivered prematurely by Caesarean section as his mother was dying. Though premature, he was spared from HIV and is healthy.

NIH’s documents suggest Hafford’s life might also have been spared if the drug had been stopped when the first liver problems showed up in her blood work two weeks before death. “This case was particularly unfortunate b/c (because) the PI (principle investigative doctor) didn’t stop drug when grade 3 liver enzymes were reported,” Dr. Jonathan Fishbein, NIH’s chief of good research practices, told Tramont in an August 2003 e-mail.

NIH’s official review determined the Memphis hospital failed to react to lab results that showed her liver failure was starting well before she died. “The site had identified that there was a delay in reviewing laboratory evaluations from the clinic visit the week before she presented with clinical hepatitis,” an Aug. 15, 2003, report concluded.

The official investigative files cited “drug-induced hepatitis” of the liver as the cause of death. As is routine after a research-related death, NIH ordered changes to the rules its researchers followed in the nevirapine studies to ensure the early detection of liver problems, the memos show.

On the Net: Documents gathered by AP for this story are available at: http://wid.ap.org/documents/nevirapine3.html

National Institutes of Health: http://www.nih.gov

© 2004 The Associated Press

http://www.ipsnews.net/interna.asp?idnews=25724
HEALTH:
Drug Industry Scandal a ‘Crisis’
Ritt Goldstein

Vast numbers of dead, the compromising of key elements within the medical community and its regulatory structures, the blind pursuit of billions of dollars in corporate profits — all have surfaced in a detonating pharmaceutical industry scandal of global dimension.

The suicide deaths of numerous young people, despite the existence of information that could have precluded them, sparked the revelations. But a far broader, systemic and devastating problem has emerged regarding the full spectrum of newer prescription medications. “It’s a general healthcare crisis, I think, at this point in time,” famed British drug scientist and psychiatrist David Healy said in an interview. “If the pharmaceutical companies in this area — in the area of a hazard like a child being made suicidal by these drugs — if they’re prepared to sweep a thing like this under the carpet, then there isn’t anyone taking any other drugs who can really be confident.”

On Sep. 29 Merck & Co withdrew its popular arthritis drug Vioxx from the market, acknowledging it caused increased risk of stroke and heart attack. Just a month earlier the firm had strongly disagreed with a study by U.S. regulatory agency the Food and Drug Administration (FDA) that had revealed such problems, reported the Associated Press.

Since the late 1990s, the number of drugs either pulled from the U.S. market or given a “black box” label (a warning of side-effects that could lead to death or serious injury) has “mushroomed,” according to Dr Joel Lexchin, professor in the School of Public Health Policy and Management at Toronto’s York University. “A lot of people, including me, are attributing that to faster approvals in the U.S. à faster reviews by FDA officials have resulted in drugs getting onto the market which shouldn’t have,” Lexchin told IPS, commenting on newer medicines generally.

On Sep. 30 business magazine ‘Forbes’ noted that in Vioxx’s five years on the market, 84 million people have used it, four million are presently taking it, and that safety concerns first emerged in 2001. “Is there equivalent data on other drugs? It’s not clear,” ‘Forbes’ added. Death estimates and resurfacing medical studies are now providing another kind of clarity, one of horrific proportion.

The highly respected British medical journal, ‘The Lancet’, published a 1998 study by University of Toronto researchers showing that adverse drug reactions (ADRs) are “a leading cause of death.” It noted the study examined “only ADRs attributed to drugs that were ‘properly prescribed and administered’.” The study’s authors suggested, “many adverse reactions result from the use of drugs with unavoidably high toxicity,” and that medicine “cannot expect to reduce this burden until drug-induced illness is actually defined as a problem.”

In the May 1 2002 issue of the ‘Journal of the American Medical Association’ (JAMA), five physicians from Harvard Medical School reported adverse drug reactions “are believed to be a leading cause of death in the United States.” The authors urged the FDA to raise “its threshold for approving new drugs when safe, effective therapies already exist, or when the new drug treats a benign condition”, citing the “frequent introduction” of drugs where serious side-effects occur. And they emphatically advised that “clinicians should avoid using new drugs when older, similarly efficacious agents are available.”

Lexchin, who consults on pharmaceutical policy for groups such as the World Health Organisation (WHO) and governments including Australia and Canada, estimated that in the last five years, “biased research, suppression of negative studies, over-publication of positive studies and, all their (the pharmaceutical industry’s) promotional activities, which includes their funding of continuing medical education,” has meant, yearly, “one death per 1,500 people” in the general population.

That translates into 6,670 deaths a year for every 10 million of a nation’s populace. For perspective, about 3,000 people died in the 9/11 terrorist attacks on New York and the Pentagon. In contrast, the 1998 ‘Lancet’ article viewed it likely that adverse drug reactions “could account for more than 100,000 (in-hospital alone) deaths in the USA each year, making them the fourth commonest cause of death.”

The figures are likely “much the same” throughout the developed world, it added. On Sep. 9 the ‘Washington Post’ reported that the U.S. House of Representatives energy and commerce subcommittee for oversight and investigations was holding hearings on the pharmaceutical industry, in response to “the growing outcry over suppressed medical studies.”

The California legislature held a hearing in August on the potential link between anti-depressant drugs and suicide. According to State Senator Tom Torlakson, “our offices were deluged with requests to testify from family members of suicide victims.” Speaking to the questions surrounding clinical trials, which test a medication’s effectiveness and safety, the group representing the U.S. drug industry, the Pharmaceutical Research And Manufacturers of America (PhRMA), noted on Sep. 9 that its board had approved principles to be used in the conduct and reporting of clinical trials two years ago. “These principles express the commitment of PhRMA member companies to communicate the results of all hypothesis-testing clinical trials, both positive and negative, for drugs that are on the market,” a PhRMA vice president said.

PhRMA represents industry firms “which are devoted to inventing medicines that allow patients to live longer, healthier and more productive lives,” added the prepared statement. No one from PhRMA was immediately available for comment for this article.

Similar to the Enron accounting scandal in the United States, the present prescription-drug debacle appears to be a matter of systemic corruption, including a gross and widespread failure within the regulatory process. Unlike Enron, enormous fatalities have resulted, though no criminal charges regarding these deaths have yet been announced.

On Sep. 21, UK newspaper ‘The Guardian’ reported that the drugs Seroxat and Prozac “can make people homicidal,” according to results of drug trials revealed by Healy. The paper described him as “an expert on psychiatric drugs from north Wales whose warnings that the drugs (SSRI antidepressants) could cause suicide led to the entire class of drugs, except Prozac, being banned last year (in the UK) from use in children.” Healy’s recent book, ‘Let Them Eat Prozac,’ examines the “divide between the research” and what “‘spin’ that the marketing divisions of the pharmaceutical companies put on.”

Speaking to antidepressants, he added, “the published data for Prozac, Paxil and Zoloft all claim that these drugs reduce the likelihood of people going on to harm themselves the raw data from these clinical trials indicates that the drugs are more linked to people going on to harm themselves,” the exact opposite of what had been claimed.

On Sep. 14 the FDA’s medical advisory group decided that antidepressants should come with a “black box warning” that they can “spur suicidal behaviour in children and teenagers.” Psychiatric medications are leading drug industry money makers. Last year, U.S. sales of just the class of antidepressants known as SSRIs (including Prozac, Paxil, Zoloft, Seroxat) were reported at 10.9 billion dollars. In 2002 the Fortune 500’s 10 drug companies’ combined profits of 35.9 billion dollars surpassed the combined profits of the remaining 490 firms together, (33.7 billion dollars), according to MSNBC.

“The regulators aren’t showing themselves to be on the side of the patient,” said Healy. “If they think they are on the side of the patient, the way they’ve generally handled the issues has come close to being incompetent.” Of particular note, the Sep. 9 ‘Washington Post’ article reported, “In February, an internal agency report found that the medications (certain antidepressants) were associated with an increased risk of suicidal behaviour. Top FDA officials played down the report at the time and refused to make it public until recently.” A day later the paper reported that the FDA “repeatedly urged antidepressant manufacturers not to disclose to physicians and the public that some clinical trials of the medications in children found the drugs were no better than sugar pills.”

According to Lexchin, “this is a reflection of the fact that the FDA seems to have been captured by the industry it’s supposed to be regulating.” He sees the FDA as “looking after the interests of the pharmaceutical companies, putting their interests above the interests of the general public.”

During the 1990s, when the new wave of anti-psychotic drugs (including Risperdal and Zyprexa) was approved by the FDA, it did so with the proviso the drugs could not be marketed as superior to any existing anti-psychotic medication in terms of “safety or effectiveness,” according to Dr John Read, one of the Pacific’s leading authorities on psychiatric medication, author of ‘Models of Madness’ and director of clinical psychology at the University of Auckland.

The drug companies “proceeded to totally ignore that and to market their drugs at six to nine times the cost of the older drugs,” managing to “pull off this incredible scam internationally,” Read added in an interview. “There’s a very powerful mythology out there that these drugs are used quite rarely, and that they’re only used on people diagnosed schizophrenic,” he added. But, warned Read, the pharmaceutical companies have “actually pushed the market into younger people, ages five-10 into old-age facilities to people who do not have the diagnosis of schizophrenia.”

Critics charge these drugs are often used as “chemical restraints,” to subdue those who take them. Read added caustically: “And why wouldn’t they do that (expand the market for their medications) — the purpose of a company is to write a good return for their shareholders. (END/2004)

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