Guest guest Posted March 13, 2006 Report Share Posted March 13, 2006 SSRI-Research@ Sun, 12 Mar 2006 23:34:18 -0800 (PST) [sSRI-Research] Out of Control: AIDS & the Corruption of Medical Science_Harper's Out of Control: AIDS & the Corruption of Medical Science_Harper's ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP) Promoting Openness, Full Disclosure, and Accountability http://www.ahrp.org/cms/ FYI For those who thought John LeCarre's 'fictional' Book / Movie, The Constant Gardner, was over the top in its depiction of a ruthless pharmaceutical company and corrupt practices in AIDS drug research, read the non-fictional account, OUT OF CONTROL: AIDS and the corruption of medical science, By Celia Farber in the current issue of Harper's magazine. This riveting, informative article begins by describing the toxic effect of the AIDS drug, Nevriapine, and the rapid physical deterioration and ultimate death of, Joyce Ann Hafford, a 33-year old pregnant mother of a 13 year old boy. As the facts of the case unfold, it seems that her life was sacrificed on the altar of AIDS research . Hafford was told she was HIV positive on the basis of a single screen which, unbeknown to her, is a test known to have a high rate of false-positives. [1] Though she was perfectly healthy and showed no signs of any of the HIV markers, she agreed to participate in a Phase III clinical trial (PACTG 1022) of nevirapine because she was told it would protect the baby she was carrying. " The objective of the trial, PACTG 1022, was to compare the " treatment limiting toxicities " of two anti-HIV drug regimens. " However, women in AIDS drug experiments such as this are not informed that " Of the four drugs in this study, three belong to the FDA's category " C, " which means that safety to either mother or fetus has not been adequately established. " Hafford was enrolled in the trial and in early June, 2003, and " on June 18 took her first doses of the drugs. " Her older sister, Rubbie King, recalled: " She felt very sick right away, within seventy-two hours, she had a very bad rash, welts all over her face, hands, and arms. That was the first sign that there was a problem. I told her to call her doctor and she did, but they just told her to put hydrocortisone cream on it. I later learned that a rash is a very bad sign, but they didn't seem alarmed at all. " Hafford was on the drug regimen for thirty-eight days. " Her health started to deteriorate from the moment she went on the drugs, " says King. " She was always in pain, constantly throwing up, and finally she got to the point where all she could do was lie down. " " On July 16, at her scheduled exam, Hafford's doctor took note of the rash, which was " pruritic and macular- papular, " and also noted that she was suffering hyperpigmentation, as well as ongoing nausea, pain, and vomiting. By this time all she could keep down were cans of Ensure. Her blood was drawn for lab tests, but she was not taken off the study drugs, according to legal documents and internal NIH memos. Eight days later, Hafford went to the Regional Medical Center " fully symptomatic, " with what legal documents characterize as including: " yellow eyes, thirst, darkening of her arms, tiredness, and nausea without vomiting. " She also had a rapid heartbeat and difficulty breathing. Labs were drawn, and she was sent home, still on the drugs. The next day Hafford was summoned back to the hospital after her lab reports from nine days earlier were finally reviewed. She was admitted to the hospital's ICU with " acute and sub-acute necrosis of the liver, secondary to drug toxicity, acute renal failure, anemia, septicemia, premature separation of the placenta, " and threatened " premature labor. " She was finally taken off the drugs but was already losing consciousness. " The family could not afford the $3,000 for an autopsy, so none was performed. " There was a liver biopsy, however,which revealed, according to internal communiqués of [NIH Division of AIDS] DAIDS staff, that Hafford had died of liver failure brought on by nevirapine toxicity. What the family was told about the cause of Hafford's death: " They told us how safe the drug was, they never attributed her death to the drug itself, at all. They said that her disease, AIDS, must have progressed rapidly. " But her sister realized something was very wrong: " 'On the one hand they're telling us this drug is so safe, on the other hand they're telling us they're going to monitor the other patients more closely. If her disease was progressing, they could have changed the medication.' I knew something was wrong with their story, but I just could not put my finger on what it was. " In fact, Farber reports, " Joyce Ann Hafford never had AIDS, or anything even on the diagnostic scale of AIDS. " Of note: Nevirapine was one of the experimental drugs tested in children and babies in foster care in violation of federal regulatory protections. [2] And many of the foster babies in the AIDS drug / vaccine trials did not have AIDS either. " The conclusion of the PACTG 1022 study team was published in the journal JAIDS in July of 2004. " The study was suspended because of greater than expected toxicity and changes in nevirapine prescribing information. " The authors reported that within the nevirapine group, " one subject developed fulminant hepatic liver failure and died, and another developed S t e v e n s -Johnson syndrome " (i.e. skin necrolysis-a severe toxic reaction that is similar to internal third-degree burns, in which the skin detaches from the body). Patients recruited for clinical trials in experiments that involve high risk and high financial stakes---particularly those from disadvantaged populations-all too often encounter an arrogance bordering on unconscionable disregard for the rights and dignity of the subjects whose lives are devalued by an elitist corps of powerful intersecting self-interest groups who are not held accountable by anyone. Disadvantaged, members of a minority cannot possibly challenge powerful doctors who are shielded by powerful institutions. They and subsequently their families have no leverage. John Solomon, of the Associated Press, who first reported about the controversy surrounding Nevirapine, and Joyce Ann Safford's death, noted that Nevirapine had been hailed by the vested AIDS community as a " life saving " drug and a " very important tool " to combat HIV in the Third World. In fact, President Bush allocated $500 million for the drug to be given to African nations as a " cheap solution " for protecting African babies from AIDS. AP reported the President had not been informed by NIH officials that the drug had in fact been found to cause " thousands of severe reactions including deaths. " [3] Farber sheds light on the apparent disconnect between what the evidence from clinical trials (PACTG 1022) and the highly publicized Nevirapine trials conducted in Uganda (HIVNET 012) show, and the false claims made for public consumption. When the drug's manufacturer, Boehringer Ingelheim inspected the Uganda trial (HIVNET 012): " They were the first to discover what a shambles the study was. " According to Boehringer's pre-FDA inspection report, " serious non-compliance with FDA regulations was found " in the specific requirements of reporting serious adverse events. Problems also were found in the management of the trial drug and in informed-consent procedures. " Farber writes that the DAIDS then hired a private contractor, a company named Westat, to go to Uganda and do another pre-FDA inspection. This time the findings were even more alarming: the major problems that clearly disqualified the trial included: .. " loss of critical records " including " one of two master logs " that included follow-up data on adverse events, including deaths. " .. " The records failed to make clear which mothers had gotten which drug, when they'd gotten it, or even whether they were still alive at various follow up points after the study. " .. " Drugs were given to the wrong babies, documents were altered, and there was infrequent follow-up. " .. " The infants that did receive follow-up care were in many cases small and underweight for their age. It was thought to be likely that some, perhaps many, of these infants had serious health problems. " .. " The Westat auditors looked at a sample of forty-three such infants, and all forty-three had " adverse events " at twelve months. Of these, only eleven were said to be HIV positive. " Clearly, the Uganda trial failed to meet minimal safety and scientific standards. Yet, Farber reports, though the two inspections had now declared HIVNET to be " a complete mess, " and DAIDS officials were well aware of the facts, " the ways in which the various players were tethered together made it impossible for DAIDS to condemn the study without condemning itself. " Thus, according to DAIDS' public version of events, which was dutifully echoed in the AIDS press, " the trouble with HIVNET was that it was unfairly assailed by pedantic saboteurs who could not grasp the necessary difference between U.S. safety standards and the more lenient standards that a country like Uganda deserved. " Framed another way, DAIDS trivializes Ugandans' human right to protections ensured by minimal standards of safety and scientific validity in medical experiments that they are asked to participate in. Within two weeks of the devastating report by Westat, DAIDS officials knowingly deceived the public by issuing the following patently false statement: " There is no question about the validity [of the HIVNET results] . . . the problems are in the rather arcane requirements in record keeping. " Farber then comments on the politics and undisclosed pervasive conflicts of interest that undermine the credulity of most claims made by vocal AIDS activists about treatment success, noting the uncritical media that broadcasts propaganda: " So-called community AIDS activists were sprung like cuckoo birds from grandfather clocks at the appointed hour to affirm the unwavering AIDS cathechism: AI D S drugs save lives. To suggest otherwise is to endanger millions of African babies. Front and center were organizations like the Elizabeth Glaser Pediatric AIDS Foundation, which extolled the importance of nevirapine. Elizabeth Glaser's nevirapine defenders apparently didn't encounter a single media professional who knew, or cared, that the organization had received $1 million from nevirapine's maker, Boehringer Ingelheim, in 2000. " " This was no scandal but simply part of a landscape. Pharmaceutical companies fund AIDS organizations, which in turn are quoted uncritically in the media about how many lives their drugs save. This time the AIDS organizations were joined by none other than the White House, which was in the midst of promoting a major program to make nevirapine available across Africa. " [note] " Africa, as the news media never tires of telling us, has become ground zero of the AIDS epidemic. The clinical definition of AIDS in Africa, however, is stunningly broad and generic, and was seemingly designed to be little other than a signal for funding. It is in no way comparable to Western definitions. The " Bangui definition " of AIDS was established in the city of Bangui in the Central African Republic, at a conference in 1985. The definition requires neither a positive HIV test nor a low T-cell count, as in the West, but only the presence of chronic diarrhea, fever, significant weight loss, and asthenia, as well as other minor symptoms. These happen to be the symptoms of chronic malnutrition, malaria, parasitic infections, and other common African illnesses. " AIDS advocates may be largely responsible legislation (1997 FDA Modernization Act , FDAMA) that speeded up the drug approval process by short circuiting safety tests. The unintended consequences are that the bar for drug safety has been lowered. Furthermore, their lobbying efforts have undermined the sin quo non of medicine-which requires proof of safety and effectiveness for treatments. This has set us back to the time when snake oil purveyors roamed the countryside selling their, at best, worthless potions, at worst, lethal ones. The buzzword in AIDS (as well in psychiatry) is neither effectiveness nor safety-it is " access, " which has the advantage of short-circuiting the question of whether the treatments actually work. Prior to FDAMA, the burden of proof that a drug was safe and effective rested on manufacturers. Since then, under pressure from manufacturers who were emboldened by the AIDS activists' demand for speedy approval, the FDA (in essence) presumes safety and efficacy unless someone proves otherwise. Hence, we are again confronted with unsafe, lethal drugs such as Vioxx being approved without evidence of their safety. While reading Farber's riveting account of the documented scientific facts that emerged in clinical trials of the AIDS drug, Nevirapine-evidence that belies the claims made by stakeholders in the AIDS drug enterprise--one is struck by the similarity of the disconnect in psychiatry between the scientific data and claims made. One is also struck by the similarity between the politics of AIDS and psychiatry. In both there is a disconnect between the scientific data and the ideology upon which practice guidelines rest. In both of these contentious fields the prevailing opinions rest on theories, but no firm scientific knowledge. And most troubling of all, in both fields there is an aversion for debate and intolerance of critics who dare to challenge the prevailing ideology in AIDS and psychiatry--critics are shunned as pariahs. This sorry state of affairs--so antithetical to the essence of academia and the Socratic tradition--leads one to suspect that those in the seats of power--in AIDS and psychiatry --are unable to refute any opposing arguments. Thus, they adopt a position akin to academic Stalinism or, if one prefers, religious dogma that tolerates no dissent. By abusing their power to stifle ideas that contradict their own for fear their authority and the status quo would be toppled, they impose intellectual stagnation that hinders discovery of new improved paradigms of care. References: 1. Is a Positive Western Blot Proof of HIV Infection? Eleni Papadopulos-Eleopulos, Valendar F. Turner and John M. Papadimitriou BIO/TECHNOLOGY VOL.11 JUNE 1993 http://www.virusmyth.net/aids/data/epwbtest.htm ; see also, http://www.virusmyth.net/aids/index/hivtests.htm 2. See, letters of determination by the Office of Human Research Protections, May, 2005: http://www.hhs.gov/ohrp/detrm_letrs/YR05/may05c.pdf February, 2006: http://www.ahrp.org/cms/content/view/82/31/ 3. See: Woman Died During Aids Study http://www.ahrp.org/infomail/04/12/16.php Contact: Vera Hassner Sharav 212-595-8974 veracare OUT OF CONTROL: AIDS and the corruption of medical science, By Celia Farber in the current issue of Harper's magazine. See excerpt below: " ...Joyce Ann Hafford was thirty-three years old and had always been healthy. She showed no signs of any of the clinical markers associated with AIDS-her CD4 counts, which measure the lymphocytes that are used to indicate how strong a person's immune system is, and which HIV is believed to slowly corrode, were in the normal range, and she felt fine. In early June 2003, she was enrolled in the trial and on June 18 took her first doses of the drugs. " She felt very sick right away, " recalls her older sister, Rubbie King. " Within seventy-two hours, she had a very bad rash, welts all over her face, hands, and arms. That was the first sign that there was a problem. I told her to call her doctor and she did, but they just told her to put hydrocortisone cream on it. I later learned that a rash is a very bad sign, but they didn't seem alarmed at all. " Hafford was on the drug regimen for thirty-eight days. " Her health started to deteriorate from the moment she went on the drugs, " says King. " She was always in pain, constantly throwing up, and finally she got to the point where all she could do was lie down. " The sisters kept the news of Hafford's HIV test and of the trial itself from their mother, and Hafford herself attributed her sickness and nausea to being pregnant. She was a cheerful person, a non-complainer, and was convinced that she was lucky to have gotten into this trial. " She said to me, 'Nell' -that's what she called me-'I have got to get through this. I can't let my baby get this virus.'... " This situation has had particularly tragic ramifications on the border between the class of Americans with good health insurance, who are essentially consumers of pharmaceutical goods, and those without insurance, some of whom get drugs " free " but with a significant caveat attached: They agree to be experimented on. These people, known in the industry as " recruits, " are pulled in via doctors straight from clinics and even recruited on the Internet into the pharmaceutical industry and the government's web of clinical trials, thousands of which have popped up in recent years across the nation and around the world. Such studies help maintain the industry's carefully cultivated image of benign concern, of charity and progress, while at the same time feeding the experimental factories from which new blockbuster drugs emerge. " I call them what they are: human experiments, " says Vera Hassner Sharav, of the Alliance for Human Research Protection in New York City. " What's happened over the last ten to fifteen years is that profits in medicine shifted from patient care to clinical trials, which is a h u g e industry now. Everybody involved, except the subject, makes money on it, like a food chain. At the center of it is the NIH, which quietly, while people weren't looking, wound up becoming the partner of industry. " By June 2004, the National Institutes of Health had registered 10,906 clinical trials in ninety countries. The size of these trials, which range from the hundreds to more than 10,000 people for a single study, creates a huge market for trial participants, who are motivated by different factors in different societies but generally by some combination of the promise of better health care, prenatal care, free " access " to drugs, and often-especially in the United States-cash payments. Participating doctors, whose patient-care profits have been dwindling in recent years because of insurance-company restrictions, beef up their incomes by recruiting patients. Dr. Jonathan Fishbein is hardly a rabble-rouser. But he is a passionate advocate of " good clinical practice, " or GCP, a set of international standards that were adopted in 1996, as clinical-trial research boomed. The GCP handbook states: " Compliance with this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. " During the decade prior to his arrival at DAIDS, Fishbein had overseen and consulted on hundreds of clinical trials for just about every pharmaceutical company. Fishbein knew, before he took his job as director of the Office for Policy in Clinical Research Operations at DAIDS, that there was a troubled study haunting the whole division. Nobody was supposed to talk about it, but it hung heavily in the air. " Something about Uganda, that's all I knew, " he says. There was a trial staged there, a big one, that had been plagued with " problems, " and there was also a lot of talk about one particular employee connected to this trial who would need to be disciplined. Soon he discovered just how bad the situation was. " The HIVNET thing, " he recalls, " it hit me like a fire hose when I walked in there. " Fishbein's position was new. " It sounded like a very important position, " he says. " I was to oversee the policies governing all the clinical research operations, both here and abroad. " He was told he would have " go-no go " authority over individual trials. It wasn't long before Fishbein realized that he was, in effect, taking a job that was the equivalent of piloting an already airborne plane. " They had all these trials going on, and hundreds of millions of dollars flowing in every year, but there was apparently no one in a senior position there who really had clinical expertise-who knew all the nuances, rules, and regulations in the day-today running of clinical trials. " DAIDS, when Fishbein came to work there in 2003, was running about 400 experimental trials both in the United States and abroad. A DAIDS project officer close to the HIVNET study closed the door when she had her first meeting with Fishbein. She had also crossed over from the private sector, and so she and Fishbein shared disillusionment over how much shoddier and more chaotic the research culture was within the government, compared with industry. " I'm really frightened about the stuff that goes on here, " she told him. " We really need somebody. " This project officer, who for her own protection cannot be named, told Fishbein that the division's fla gship study in Africa-HIVNET 012-had been wracked with problems and completely lacking in regulatory standards. She told Fishbein that the trial investigators were " out of control, " and that there was no oversight of them, and nobody with either the inclination or the authority to make them adhere to safety standards. What Fishbein subsequently learned entangled him in a story with eerie echoes of John Le Carré's Constant Gardener. For our purposes, the story of nevirapine begins in 1996, when the German pharmaceutical giant Boehringer Ingelheim applied for approval of the drug in Canada. The drug had been in development since the early 1990s, which was a boom time for new HIV drugs. Canada rejected nevirapine twice, once in 1996 and again in 1998, after the drug showed no effect on so-called surrogate markers (HIV viral load and CD4 counts) and was alarmingly toxic. In 1996, in the United States, the FDA nonetheless gave the drug conditional approval... " ........ Although HIVNET was designed to be a randomized, placebocontrolled, double-blind, Phase III trial of 1,500 mother/infant pairs, it wound up being a no-placebo, neither double- nor even single-blind Phase II trial of 626 mother/infant pairs. Virtually all of the parameters outlined for HIVNET 012 were eventually shifted, amended, or done away with altogether, beginning with perhaps the most important- the placebo controls. By a " Letter of Amendment " dated March 9, 1998, the placebo-control arms of HIVNET were eliminated. The study as reconstituted thus amounted to a simple comparison of AZT and nevirapine. On September 4, 1999, The Lancet published HIVNET's preliminary results, reporting that " Nevirapine lowered the risk of HIV-I transmission during the first 14-16 weeks of life by nearly 50 percent. " The report concluded that " the two regimens were well-tolerated and adverse events were similar in the two groups. " The article also reported that thirty-eight babies had died, sixteen in the nevirapine group and twenty-two in the AZT group. The rate of HIV transmission in the AZT arm was 25 percent, while in the nevirapine group it was only 13 percent. As H o p k i n s Medical News later reported, the study was received rapturously. " The data proved stunning. It showed that nevirapine was 47 percent more effective than AZT and had reduced the number of infected infants from 25 to 13 percent. Best of all, nevirapine was inexpensive-just $4 for both doses. If implemented widely, the drug could prevent HIV transmission in more than 300,000 newborns a year. " With the results of the study now publ ished in The Lancet, Boehringer, which previously had shown little interest in HIVNET, now pressed for FDA approval to have nevirapine licensed for use in preventing the transmission of HIV in pregnancy. There were complications, however. On December 6, 2000, a research letter in The Journal of the American Medical Association warned against using nevirapine for post-exposure treatment after two cases of life-threatening liver toxicity were reported among health-care workers who'd taken the drug for only a few days. (One of them required a liver transplant.) The January 5, 2001, issue of the CDC's M o rbidity and Mortality Weekly Report (MMWR) contained an FDA review of MedWatch-an informal reporting system of drug reactions-that highlighted an additional twenty cases of " serious adverse events " resulting from fairly brief nevirapine post-exposure prophylaxis. " Serious adverse events " were defined as anything " life-threatening, permanently disabling, " or requiring " prolonged hospitalization, or [. .. . ] intervention to prevent permanent impairment or damage. " The MMWR stressed that there probably were more unreported cases, since the reporting by doctors to MedWatch is " voluntary " and " passive. " But NIAID was on another track altogether, either oblivious of or undeterred by the toxicity controversy. " In 2001, Boehringer Ingelheim submitted its supplemental licensing request to the FDA. The request was submitted based entirely on the results of HIVNET, as published in The Lancet. Since Boehringer had not originally intended to use this study for licensing purposes, it decided to perform its own inspection before the FDA arrived. Boehringer's team arrived in Kampala and did a sample audit. They were the first to discover what a shambles the study was. According to Boehringer's preinspection report, " serious non-compliance with FDA Regulations was found " in the specific requirements of reporting serious adverse events. Problems also were found in the management of the trial drug and in informed-consent procedures. DAIDS then hired a private contractor, a company named Westat, to go to Uganda and do another preinspection. This time the findings were even more alarming. One of the main problems was a " loss of critical records. " One of two master logs that included follow-up data on adverse events, including deaths, was said to be missing as the result of a flood. The records failed to make clear which mothers had gotten which drug, when they'd gotten it, or even whether they were still alive at various followup points after the study. Drugs were given to the wrong babies, documents were altered, and there was infrequent follow-up, even though one third of the mothers were marked " abnormal " in their charts at discharge. The infants that did receive follow-up care were in many cases small and underweight for their age. " It was thought to be likely that some, perhaps many, of these infants had serious health problems. " The Westat auditors looked at a sample of forty-three such infants, and all forty-three had " adverse events " at twelve months. Of these, only eleven were said to be HIV positive. " The HIVNET team had essentially downgraded all serious adverse events several notches on a scale it had created to adapt to " local " standards. That downgrade meant, among other things, that even seemingly " life-threatening " events were logged as not serious. Deaths, unless they occurred within a certain time frame at the beginning of the study, were not reported or were listed as " serious adverse events " rather than deaths. In one case, " a still birth was reported as a Grade 3 adverse event for the mother. " As a defense, the HIVNET team often cited ignorance. They told the Westat monitors that they were unaware of safety-reporting regulations, that they'd had no training in Good Clinical Practice, and that they had " never attempted a Phase III trial. " The principal investigators and sub-investigators " all acknowledged the fin dings [of the audit] as generally correct, " the Westat report said. " Dr. Guay and Dr. Jackson noted that many ('thousands') of unreported AE's and SAE's occurred. . . .They acknowledged their use of their own interpretation of 'serious' and of severity. " " All agreed " that the principal and subinvestigators " had generally not seen the trial patients, " and " all agreed " that in evaluating adverse and serious adverse events " they had relied almost entirely on second or third hand summaries . . . without attempting to verify accuracy. " Westat also discovered that half the HIVpositive infants were also enrolled in a vitamin A trial, which effectively invalidates any data associated with them. In light of the Westat report, DAIDS and Boehringer asked the FDA for a postponement of its inspection visit. The FDA responded by demanding to see the report immediately. On March 14, 2002, the FDA called a meeting with DAIDS, Boehringer, and the trial investigators. " They reprimanded the whole gang, " says Fishbein. Then they said to Boehringer: Withdraw your application for extended approval, if you want to avoid a public rejection. " Boehringer complied with the FDA ' s demand, though statements put out by NIAID made it sound as if the company had withdrawn the application for FDA approval in a spirit of profound concern for protocol. In South Africa, a few months later, the news focused on the angry chorus of AIDS experts and activists, speaking as one....cut .... FAIR USE NOTICE: This may contain copyrighted (© ) material the use of which has not always been specifically authorized by the copyright owner. Such material is made available for educational purposes, to advance understanding of human rights, democracy, scientific, moral, ethical, and social justice issues, etc. It is believed that this constitutes a 'fair use' of any such copyrighted material as provided for in Title 17 U.S.C. section 107 of the US Copyright Law. This material is distributed without profit. Quote Link to comment Share on other sites More sharing options...
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