551 total views, 3 views today
551 total views, 3 views today
Below is a the drug manufactures BEST GUESS as to how SSRI antidepressants work in your brain. They fully admit that they really don’t know how they work. However, we maintain that the positive effects that patients report come from the stimulant, amphetamine-like, nature of these mind-altering drugs.
What you need to know about serotonin-enhancing medications
Selective Serotonin Reuptake Inhibitors do exactly that: Inhibit the reuptake of serotonin, thus leaving excess serotonin which allows this stimulation to continue. It has long been known that inhibiting the reuptake of serotonin will produce depression, suicide, violence, psychosis, mania, cravings for alcohol and other drugs, reckless driving, etc. [See full list of reactions below]
The most popular drugs that produce this reuptake of serotonin are:
SSRI Antidepressants: Prozac, Serafem, Zoloft, Paxil, Luvox, Celexa, Lexapro
SNRI Antidepressants: Effexor, Remeron, Serzone, Cymbalta
Atypical Antipsychotics: Zyprexa, Geodon, Abilify, Seroquel, Risperdal
Weight Loss Medications: Fen-Phen, Redux, Meridia
Pain Killers: (Any opium or heroin derivative) Morphine, OxyContin, Ultram, Tramadol, Percocet, Percodan, Lortab, Demerol, Darvon or Darvocet, Codeine, Buprenex, Dilaudid, Talwin, Stadol, Vicodin, Duragesic Patches, Fentanyl Transdermal, Methadone, Dextromethorphan (commonly used in cough syrups), etc.
WARNING: Anesthetics can also fall into this group as well as drugs used for other purposes. Always check to see what the mechanism of action is in a drug before combining it with another serotonergic agent or using it soon after the use of a serotonergic agent because the combination of two can cause the potentially fatal reaction known as Serotonin Syndrome. As the main function of serotonin is constriction of smooth muscle tissue, Serotonin Syndrome produces death via multiple organ failure.
“Psychedelic agents mimic the effects of serotonin.”
The brain chemical these drugs increase, serotonin, is the same brain chemical that LSD, PCP and other psychedelic drugs mimic in order to produce their hallucinogenic effects. And remember that psychedelic agents are “a class of compounds with no demonstrated therapeutic use, a history of extensive abuse, and the ability to provoke psychosis. Yet many brain researchers value the psychedelic agents above any of the other psychoactive drugs” because “the research into psychedelic drugs has already enriched our understanding of how the brain regulates behavior.” (Dr. Solomon Snyder, DRUGS AND THE BRAIN). Just how much will these brain researchers learn from our experience with these drugs designed to specifically increase serotonin, the same brain chemical the psychedelic agents mimic to produce their effects?
We know that these drugs interfere with serotonin metabolism (demonstrated by levels of the serotonin metabolite 5HIAA). It is not serotonin that is low in these disorders, it is this by-product 5HIAA, which indicates the level of serotonin metabolism, that is low in depression, suicide, etc. Yet as serotonin (5HT) goes up serotonin metabolism (5HIAA) generally comes down. We already have studies demonstrating at what percentage each of these drugs increase 5HT and decrease 5HIAA. Here are the results of elevated levels of serotonin (5HT) and decreased levels of serotonin metabolism (5HIAA):
Elevated 5HT (serotonin) levels:
Lower 5HIAA (serotonin metabolism) levels:
All are exactly what patients and their families have continued to report to be their experience on these drugs since Prozac was introduced! These individuals are frantically searching for answers while this research sits right under our noses. Although this is a totally different picture than pharmaceutical marketing departments would have us believe, marketing claims and reality rarely have much in common.
Researchers tell us that five, ten or twenty years later it is not uncommon to find we have another thalidomide on our hands. Raising 5HT (serotonin) and lowering 5HIAA (serotonin metabolism) in such a high number of people can produce very serious, extensive and long term problems for all of society. Even more frightening for the future of our society is the rapidly rising and widely accepted practice of prescribing these drugs to small children and adolescents. This crucial medical research must be addressed openly, without delay, rather than remain buried in seldom read medical research documents as has been the case in the past with other mind-altering medications, once thought to be safe, which were subsequently prohibited by law.
[SOURCE: PROZAC: PANACEA OR PANDORA?, BY ANN BLAKE TRACY]
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How a New Policy Led to Seven Deadly Drugs
By DAVID WILLMAN
WASHINGTON–For most of its history, the United States Food and Drug Administration approved new prescription medicines at a grudging pace, paying daily homage to the physician’s creed, “First, do no harm.”
Then in the early 1990s, the demand for AIDS drugs changed the political climate. Congress told the FDA to work closely with pharmaceutical firms in getting new medicines to market more swiftly. President Clinton urged FDA leaders to trust industry as “partners, not adversaries.”
The FDA achieved its new goals, but now the human cost is becoming clear.
Seven drugs approved since 1993 have been withdrawn after reports of deaths and severe side effects. A two-year Los Angeles Times investigation has found that the FDA approved each of those drugs while disregarding danger signs or blunt warnings from its own specialists. Then, after receiving reports of significant harm to patients, the agency was slow to seek withdrawals.
According to “adverse-event” reports filed with the FDA, the seven drugs were cited as suspects in 1,002 deaths. Because the deaths are reported by doctors, hospitals and others on a voluntary basis, the true number of fatalities could be far higher, according to epidemiologists.
An adverse-event report does not prove that a drug caused a death; other factors, such as preexisting disease, could play a role. But the reports are regarded by public health officials as the most reliable early warnings of danger.
The FDA’s performance was tracked through an examination of thousands of pages of government documents, other data obtained under the Freedom of Information Act and interviews with more than 60 present and former agency officials.
The seven drugs were not needed to save lives. One was for heartburn. Another was a diet pill. A third was a painkiller. All told, six of the medicines were never proved to offer lifesaving benefits, and the seventh, an antibiotic, was ultimately judged unnecessary because other, safer antibiotics were available.
The seven are among hundreds of new drugs approved since 1993, a period during which the FDA has become known more for its speed than its caution. In 1988, only 4% of new drugs introduced into the world market were approved first by the FDA. In 1998, the FDA’s first-in-the-world approvals spiked to 66%.
The drug companies’ batting average in getting new drugs approved also climbed. By the end of the 1990s, the FDA was approving more than 80% of the industry’s applications for new products, compared with about 60% at the beginning of the decade.
And the companies have prospered: The seven unsuccessful drugs alone generated U.S. sales exceeding $5 billion before they were withdrawn.
Once the world’s unrivaled safety leader, the FDA was the last to withdraw several new drugs in the late 1990s that were banned by health authorities in Europe.
“This track record is totally unacceptable,” said Dr. Curt D. Furberg, a professor of public health sciences at Wake Forest University. “The patients are the ones paying the price. They’re the ones developing all the side effects, fatal and non-fatal. Someone has to speak up for them.”
The FDA’s faster and more lenient approach helped supply pharmacy shelves with scores of new remedies. But it has also yielded these fatal missteps, according to the documents and interviews:
1. Only 10 months ago, FDA administrators dismissed one of its medical officer’s emphatic warnings and approved Lotronex, a drug for treating irritable bowel syndrome. Lotronex has been linked to five deaths, the removal of a patient’s colon and other bowel surgeries. It was pulled off the market on Nov. 28.
2. The diet pill Redux, approved in April 1996 despite an advisory committee’s vote against it, was withdrawn in September 1997 after heart-valve damage was detected in patients put on the drug. The FDA later received reports identifying Redux as a suspect in 123 deaths.
3. The antibiotic Raxar was approved in November 1997 in the face of evidence that it may have caused several fatal heart-rhythm disruptions in clinical studies. FDA officials chose to exclude any mention of the deaths from the drug’s label. The maker of the pill withdrew it in October 1999. Raxar was cited as a suspect in the deaths of 13 patients.
4. The blood pressure medication Posicor was approved in June 1997 despite findings by FDA specialists that it might fatally disrupt heart rhythm and interact with certain other drugs, posing potentially severe risk. Posicor was withdrawn one year later; reports cited it as a suspect in 100 deaths.
5. The painkiller Duract was approved in July 1997 after FDA medical officers warned repeatedly of the drug’s liver toxicity. Senior officials sided with the manufacturer in softening the label’s warning of the liver threat. The drug was withdrawn 11 months later. By late 1998, the FDA had received voluntary reports citing Duract as a suspect in 68 deaths, including 17 that involved liver failure.
6. The diabetes drug Rezulin was approved in January 1997 over a medical officer’s detailed opposition and was withdrawn this March after the agency had linked 91 liver failures to the pill. Reports cite Rezulin as a suspect in 391 deaths.
7. The nighttime heartburn drug Propulsid was approved in 1993 despite evidence that it caused heart-rhythm disorders. The officials who approved the drug failed to consult the agency’s own cardiac specialists about the signs of danger. The drug was taken out of pharmacies in July after scores of confirmed heart-rhythm deaths. Overall, Propulsid has been cited as a suspect in 302 deaths.
The FDA’s handling of Propulsid put children at risk.
The agency never warned doctors not to administer the drug to infants or other children even though eight youngsters given Propulsid in clinical studies had died. Pediatricians prescribed it widely for infants afflicted with gastric reflux, a common digestive disorder.
Parents and their doctors had no way of knowing that the FDA, in August 1996, had found Propulsid to be “not approvable” for children.
“We never knew that,” said Jeffrey A. Englebrick, a heavy-equipment welder in Shawnee, Kan., whose 3-month-old son, Scott, died on Oct. 28, 1997, after taking Propulsid. “To me, that means they took my kid as a guinea pig to see if it would work.”
By the time the drug was pulled, the FDA had received reports of 24 deaths of children under age 6 who were given Propulsid. By then the drug had generated U.S. sales of $2.5 billion for Johnson & Johnson Co.
Questions also surround the recent approvals of other compounds that remain on the market, including a new flu drug called Relenza. In February of 1999, an FDA advisory committee concluded that Relenza had not been proved safe and effective. The agency nevertheless approved it. Following the deaths of seven patients, the FDA in January issued a “public health advisory” to doctors.
A ‘Lost Compass’
A total of 10 drugs have been pulled from the market in just the past three years for safety reasons, including three pills that were approved before the shift that took hold in 1993. Never before has the FDA overseen the withdrawals of so many drugs in such a short time. More than 22 million Americans–about 10% of the nation’s adult population–took those drugs.
With many of the drugs, the FDA used tiny-print warnings or recommendations in package labeling as a way to justify approvals or stave off withdrawals. In other instances, the agency has withheld safety information from labels that physicians say would call into question the use of the product.
Present and former FDA specialists said the regulatory decisions of senior officials have clashed with the agency’s central obligation, under law, to “protect the public health by ensuring . . . that drugs are safe and effective.”
“They’ve lost their compass and they forget who it is that they are ultimately serving,” said Dr. Lemuel A. Moye, a University of Texas School of Public Health physician who served from 1995 to 1999 on an FDA advisory committee. “Unfortunately the public pays for this, because the public believes that the FDA is watching the door, that they are the sentry.”
The FDA’s shift is felt directly in the private practice of medicine, said Dr. William L. Isley, a Kansas City, Mo., diabetes specialist. He implored the agency to reassess Rezulin three years ago after a patient he treated suffered liver failure taking the pill.
“FDA used to serve a purpose,” Isley said. “A doctor could feel sure that a drug he was prescribing was as safe as possible. Now you wonder what kind of evaluation has been done, and what’s been swept under the rug.”
FDA officials said that they have tried conscientiously to weigh benefits versus risks in deciding whether to approve new drugs. They noted that many doctors and patients complain when a drug is withdrawn. “All drugs have risks; most of them have serious risks,” said Dr. Janet Woodcock, director of the FDA’s drug review center. She added that some of the withdrawn drugs were “very valuable, even if not lifesaving, and their removal from the market represents a loss, even if a necessary one.” Once a drug is proved effective and safe, Woodcock said, the FDA depends on doctors “to take into account the risks, to read the label. . . . We have to rely on the practitioner community to be the learned intermediary. That’s why drugs are prescription drugs.”
In a May 12, 1999, article co-authored with FDA colleagues and published by the Journal of the American Medical Assn., Woodcock said, “The FDA and the community are willing to take greater safety risks due to the serious nature of the [illnesses] being treated.”
Compared to the volume of new drugs approved, they wrote, the number of recent withdrawals “is particularly reassuring.”
However, agency specialists point out that both approvals and withdrawals are controlled by Woodcock and her administrators. When they consider a withdrawal, they face the unpleasant prospect of repudiating their original decision to approve.
Woodcock, 52, received her medical degree at Northwestern University and is a board-certified internist. She alluded in a recent interview to the difficulty she feels in rejecting a proposed drug that might cost a company $150 million or more to develop. She also acknowledged the commercial pressures in a March 1997 article.
“Consumer protection advocates want to have drugs worked up well and thoroughly evaluated for safety and efficacy before getting on the market,” Woodcock wrote in the Food and Drug Law Journal. “On the other hand, there are economic pressures to get drugs on the market as soon as possible, and these are highly valid.”
But this summer–following the eighth and ninth drug withdrawals–Woodcock said the FDA cannot rely on labeling precautions, alone, to resolve safety concerns.
“As medical practice has changed . . . it’s just much more difficult for [doctors] to manage” the expanded drug supply, Woodcock said in an interview. “They rely upon us much more to make sure the drugs are safe.”
Another FDA administrator, Dr. Florence Houn, voiced similar concern in remarks six months ago to industry officials: “I think the lessons learned from the drug withdrawals make us leery.”
Yet the imperative to move swiftly, cooperatively, remains.
“We are now making decisions more quickly and more predictably while maintaining the same high standards for product safety and efficacy,” FDA Commissioner Jane E. Henney said in a National Press Club speech on Dec. 12.
Motivated by AIDS
The impetus for change at the FDA emerged in 1988, when AIDS activists paralyzed operations for a day at the agency’s 18-story headquarters in Rockville, Md. They demanded immediate approval of experimental drugs that offered at least a ray of hope to those otherwise facing death.
The FDA often was taking more than two years to review new drug applications. The pharmaceutical industry saw a chance to loosen the regulatory brakes and expedite an array of new products to market. The companies and their Capitol Hill lobbyists pressed for advantage: If unshackled, they said, the companies could invent and develop more remedies faster.
The political pressure mounted, and the FDA began to bow. By 1991, agency officials told Congress they were making significant progress in speeding the approval process.
The emboldened companies pushed for more. They proposed that drugs intended for either life-threatening or “serious” disorders receive a quicker review.
“The pharmaceutical companies came back and lobbied the agency and the Hill for that word, ‘serious,’ ” recalled Jeffrey A. Nesbit, who in 1991 was chief of staff to FDA Commissioner David A. Kessler. “Their argument was, ‘Well, OK, there’s AIDS and cancer. But there are drugs [being developed] for Alzheimer’s. And that’s a serious illness.’ They started naming other diseases. They began to push that envelope.”
The wielding of this single, flexible adjective–“serious”–swung wide the regulatory door knocked ajar by the AIDS crisis.
New Order Takes Hold
In 1992, Kessler issued regulations giving the FDA discretion to “accelerate approval of certain new drugs” for serious or life-threatening conditions. That same year a Democrat-controlled Congress approved and President Bush signed the Prescription Drug User Fee Act. It established goals that call for the FDA to review drugs within six months or a year; the pharmaceutical companies pay a user fee to the FDA, now $309,647, with the filing of each new drug application.
The newly elected Clinton administration climbed aboard with its “reinventing government” project. Headed by Vice President Al Gore, the project called for the FDA, by January 2000, to reduce “by an average of one year the time required to bring important new drugs to the American public.” As Clinton put it in a speech on March 16, 1995, the objective was to “get rid of yesterday’s government.”
For the FDA’s medical reviewers–the physicians, pharmacologists, chemists and biostatisticians who scrutinize the safety and effectiveness of emerging drugs–a new order had taken hold.
The reviewers work out of public view in secure office buildings clustered along Maryland’s Route 355. At the jet-black headquarters building, the decor is institutional, the corridors and third-floor cafeteria without windows. The reviewers examine truckloads of scientific documents. They are well-educated; some are highly motivated to do their best for a nation of patients who unknowingly count on their expertise.
One of these reviewers was Michael Elashoff, a biostatistician who arrived at the FDA in 1995 after earning degrees from UC Berkeley and the Harvard School of Public Health.
“From the first drug I reviewed, I really got the sense that I was doing something worthwhile. I saw what a difference a single reviewer can make,” said Elashoff, the son and grandson of statisticians.
Last year he was assigned to review Relenza, the new flu drug developed by Glaxo Wellcome. He recommended against approval.
“The drug has no proven efficacy for the treatment of influenza in the U.S. population, no proven effect on reducing person-to-person transmissibility, and no proven impact on preventing influenza,” Elashoff wrote, adding that many patients would be exposed to risks “while deriving no benefit.”
An agency advisory committee agreed and on Feb. 24 voted 13 to 4 against approving Relenza. After the vote, senior FDA officials upbraided Elashoff. They stripped him of his review of another flu drug. They told him he would no longer make presentations to the advisory committee. And they approved Relenza as a safe and effective flu drug.
Lost Faith in the System
Elashoff and other FDA reviewers discern a powerful message.
“People are aware that turning something down is going to cause problems with [officials] higher up in FDA, maybe more problems than it’s worth,” he said. “Before I came to the FDA I guess I always assumed things were done properly. I’ve lost a lot of faith in taking a prescription medicine.”
Elashoff left the FDA four months ago.
“Either you play games or you’re going to be put off limits . . . a pariah,” said Dr. John L. Gueriguian, a 19-year FDA medical officer who opposed the approval of Rezulin, the ill-fated diabetes drug. “The people in charge don’t say, ‘Should we approve this drug?’ They say, ‘Hey, how can we get this drug approved?’ ”
Said Dr. Rudolph M. Widmark, who retired in 1997 after 11 years as a medical officer: “If you raise concern about a drug, it triggers a whole internal process that is difficult and painful. You have to defend why you are holding up the drug to your bosses. . . . You cannot imagine how much pressure is put on the reviewers.”
The pressure is such that when a union representative negotiated a new employment contract for the reviewers last year, one of his top priorities was to defend what he called the “scientific integrity” of their work.
“People feel swamped. People are pressured to go along with what the agency wants,” said Dr. Robert S.K. Young, an FDA medical officer who in 1998 formed a union chapter to represent the reviewers. “You’re paying for these highly educated, trained people, and they’re not being allowed to do their job.”
Each new drug application is accompanied by voluminous medical data, enough at times to fill 1,000 or more phone books. The reviewers must master this material in less than six months or a year, while juggling other tasks.
“The devil is in the details, and detail is something we no longer have the time to go into,” said Gurston D. Turner, a veteran pharmacologist with the FDA’s scientific investigations division who retired this year. “If you know you must have your report done by a certain date, you get something done. That’s what they [top FDA officials] count, that’s all they count. And that is really, to me, a worrisome thing.”
The FDA did spur reviewers to move at record speed.
In 1994, the FDA’s goal was to finish 55% of its new drug reviews on time; the agency achieved 95%. In 1995, the goal was 70%; the FDA achieved 98%. In 1996, the goal was 80%; the FDA achieved 100%. In both 1997 and 1998, the goal was 90% and the FDA achieved 100%.
From 1993 to 1999 the agency approved 232 drugs regarded as “new molecular entities,” compared with 163 during the previous seven years, a 42% increase.
The time-limit goals quickly were treated as deadlines within the FDA–imposing relentless pressure on reviewers and their bosses to quickly conclude their work and approve the drugs.
“The goals were to be taken seriously. I don’t think anybody expected the agency to make them all,” said William B. Schultz, a deputy FDA commissioner from 1995 to 1999.
Schultz, who helped craft the 1992 user-fee act as a congressional staff lawyer, added: “You can meet the goal by either approving the drug or denying the approval. But there are some who argue that what Congress really wanted was not just decisions, but approvals. That is what really gets dangerous.”
Indeed, the FDA drug center’s 1999 annual report referred to the review goals as “the law’s deadlines.” And, Dr. Woodcock, the center director, elaborated in a subsequent agency newsletter:
“In exchange [for the user fees], FDA makes a commitment to meet certain goals for review times. [The agency] has exceeded almost all of the goals, and it expects to continue to exceed them. Basically, the number of new approved drugs has doubled, and the review times have been cut in half.”
The user fees have enabled the FDA to hire more medical reviewers. Last year, 236 medical officers examined new drugs compared with 162 officers on duty in 1992, the year before the user fees took effect.
Even so, Woodcock acknowledged in an FDA publication this fall that the workloads and tight performance goals “create a sweatshop environment that’s causing high staffing turnover.”
An FDA progress report in 1998, describing the work of agency chemists, said that “too many reviews are coming ‘down to the wire’ against the goal date. . . . This suggests a system in stress.”
Said Nesbit, the former aide to Commissioner Kessler: “The clock is always running, whereas before the clock was never running. And that changes people’s behavior.”
Dozens of officials interviewed by The Times made similar observations.
“The pressure to meet deadlines is enormous,” said Dr. Solomon Sobel, 65, director of the FDA’s metabolic and endocrine drugs division throughout the 1990s. And the pressure is not merely to complete the reviews, he said. “The basic message is to approve.”
Over the last seven years, “there has been a huge shift,” said Kathleen Holcombe, a former FDA legislative affairs staffer and congressional aide who now is a drug industry consultant. “FDA, historically, had an approach of, ‘Regulate, be tough, enforce the law [and] don’t let one thing go wrong,’ ” Holcombe said, adding that now, “the FDA sees itself much more in a cooperative role.”
How Deaths Were Calculated
Reports of adverse drug reactions to the Food and Drug Administration are considered by public health officials to be the most reliable early warnings of a product’s danger. The reports are filed to the FDA by health professionals, consumers and drug manufacturers. The Los Angeles Times inspected all reports filed in connection with seven drugs that were approved and withdrawn since 1993. By hand and by computer, The Times counted 1,002 deaths in which the filer identified the drug as the leading suspect. Since fall 1997, this top category has been termed “primary suspect.” The Times did not count any death in which the drug was identified as the “secondary suspect” or less. The methodology and results were reviewed by Sheila R. Weiss, a former FDA epidemiologist who is an assistant professor at the University of Maryland’s department of pharmacy practice and sciences.
The perception of coziness with drug makers is perpetuated by potential conflicts of interest within the FDA’s 18 advisory committees, the influential panels that recommend which drugs deserve approval or should remain on the market. The FDA allows some appointees to double as consultants or researchers for the same companies whose products they are evaluating on the public’s behalf. Such was the case during committee appraisals of several of the recently withdrawn drugs, including Lotronex and Posicor, The Times found.
Few doubt the $100-billion pharmaceutical industry’s clout. Over the last decade, the drug companies have steered $44 million in contributions to the major political parties and to candidates for the White House and both houses of Congress.
The FDA reviewers said they and their bosses fear that unless the new drugs are approved, companies will erupt and Congress will retaliate by refusing to renew the user fees. This would cripple FDA operations–and jeopardize jobs.
The companies’ money now covers about 50% of the FDA’s costs for reviewing proposed drugs–and agency officials say that persuading Congress to renew the user fees into 2007 is now a top priority.
Yet even if the user fees remain, the FDA is prohibited from spending the revenue for anything other than reviewing new drugs. So while the budget for pre-approval reviews has soared, the agency has gotten no similar increase of resources to evaluate the safety of the drugs after they are prescribed.
“It’s shocking,” said Dr. Brian L. Strom, chairman of epidemiology at the University of Pennsylvania. “How can you say, ‘Release drugs to the market sooner,’ and not know if they’re killing people? . . . It really is a dramatic statement of public priorities.”
More than 250,000 side effects linked to prescription drugs, including injuries and deaths, are reported each year. And those “adverse-event” reports by doctors and others are only filed voluntarily. Experts, including Strom, believe the reports represent as few as 1% to 10% of all such events. “There’s no incentive at all for a physician to report [an adverse drug reaction],” said Strom, who has documented the phenomenon. “The underreporting is vast.”
Even when deaths are reported, records and interviews show that companies consistently dispute that their product has caused a given death by pointing to other factors, including preexisting disease or use of another medicine.
To be sure, a chain of events affects the safe use of a prescription drug: The companies’ conduct of clinical studies; the FDA’s regulatory actions; the doctor’s decision to prescribe; the pharmacist’s filling of a handwritten prescription; the patient’s ability to take the drug as directed. A lapse at any link could prove fatal.
And once a pill is approved by the FDA, the manufacturer often spends heavily on promotion to seize the largest possible market share. This can exacerbate the risk to public health, according to experts.
“Aggressive promotion increases exposure–and doesn’t give you the time to find the problem before patients get hurt,” said Dr. Raymond L. Woosley, pharmacology department chairman at Georgetown University and a former FDA advisory committee member.
When serious side effects emerge, the FDA officials have championed using package labeling as a way to, in their words, “manage” risks. Yet the agency typically has no way to know if the labeling precautions–dense, lengthy and in tiny print–are read or followed by doctors and their patients.
The FDA often addresses unresolved safety questions by asking companies to conduct studies after the product is approved. But the research frequently is not performed–prompting the inspector general of the Department of Health and Human Services to say in 1996 that “FDA can move to withdraw drugs from the market if the post-marketing studies are not completed with due diligence.”
Since that report was issued, the FDA has not withdrawn any drug due to a company’s failure to complete a post-approval safety study. Officials conceded this week that they still do not know how often the studies are performed.
One consequence is that greater risk is shifted to doctors and patients.
For example, Woodcock and her senior aides allowed Rezulin to remain on the U.S. market nearly 2 years after it was withdrawn in Britain in December 1997. The FDA recommended frequent laboratory testing of patients using the drug but had no scientific assurance that the tests would prevent Rezulin-induced liver failure.
“They kept increasing the number of liver-function tests you should have,” noted Dr. Alastair J.J. Wood, a former FDA advisory committee member who is a professor of medicine at Vanderbilt University. “That was clearly designed to protect the FDA, to protect the manufacturer, and to dump the responsibility on the patient and the physician. If the patient developed liver disease and he hadn’t had his [tests] done, somebody was to blame and it wasn’t the manufacturer and it wasn’t the FDA.”
Leading industry officials say Americans have nothing to fear from the wave of drug approvals.
“Do unsafe drugs enter and remain in the marketplace? Absolutely not,” said Dr. Bert A. Spilker, senior vice president for scientific and regulatory affairs for the Pharmaceutical Research and Manufacturers of America, in remarks last year to industry and FDA scientists.
But during interviews over the last two years, current and former FDA specialists cited repeated instances when drugs were approved with less than compelling evidence of safety or effectiveness. They also said that important information has been excluded from the labels on some medications.
Elashoff, for instance, was surprised at the labeling for a drug called Prograf, approved in 1997 to prevent rejection of transplanted kidneys. The drug first had been approved in 1994 for use among liver-transplant patients.
The new label notes that Prograf was proved effective in a study of 412 U.S. kidney transplant patients. But no mention is made of the company’s 448-patient European study, in which 7% of the patients who took Prograf died–double the 3.5% death rate among those who received a different anti-rejection drug, documents show.
Contributors to this Report
Design director: Joe Hutchinson
Photographer: Brian Walski
Photo editor: Steve Stroud
Graphics: Rebecca Perry
Graphics editor: Chris Erskine
Researchers: Janet Lundblad, Sunny Kaplan
Editors: Roger Smith, Nan Williams, Steve Devol, Bobbi Olson, Kathie Bozanich
Web site Editors: Sarah D. Wright, Clare Sup
An auditor from the FDA’s scientific investigations unit, Antoine El-Hage, examined the European study results and concluded the “data are reliable.” Elashoff agreed in his review.
Yet the only way for doctors or patients to find that data is to search the medical literature or seek the FDA’s review documents.
Excluding the European study from the Prograf label, Elashoff said, “was just a total whitewash. . . . I think any rational person would reconsider taking this drug if they knew what happened in Europe.”
A spokesman for the manufacturer of Prograf said the company had no objection to including the European study results in the labeling. William E. Fitzsimmons, a vice president of drug development for Fujisawa Healthcare Inc., said the decision to exclude the results was entirely the FDA’s.
“We submitted that data,” he said. “It came down to what the FDA was comfortable putting in the label. We certainly have no interest in trying to hide that information. We presented it at major meetings on transplantation. . . . We’re comfortable with that information being out in the public domain.”
But if the FDA had included the European results in the label, it would have impugned the agency’s basis for approving the new, expanded use for Prograf, according to Elashoff and others.
Asked why the agency excluded the information, Woodcock said the European results were “unreliable and could be potentially misleading to doctors and patients in the U.S. if these were included in the label.”
Copyright 2000 Los Angeles Times
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Taper off very, very, very slowly!!!!!!!!!!!!!!
Dropping “cold turkey” off any medication, most especially mind altering medications, can often be MORE DANGEROUS than staying on the drugs. With antidepressants the FDA has now warned that any abrupt change in dose, whether increasing or decreasing the dose, can produce suicide, hostility, or psychosis – generally a manic psychosis when you then get your diagnosis for Bipolar Disorder. Of course drug-induced Bipolar is temporary so you need to learn more about that if it has already happened to you. We have a DVD on explaining this and how to recover from it: “Bipolar? Are You Really Bipolar or Misdiagnosed Due to the Use of or Abrupt Discontinuation of an Antidepressant”: https://store.drugawareness.org/product/bipolar-disorder-streaming/
The most dangerous and yet the most common mistake someone coming off any antidepressant, atypical antipsychotic, or benzodiazaphine makes is coming off these drugs too rapidly. Tapering off VERY, VERY, VERY SLOWLY–OVER MONTHS OR YEARS (The general rule of thumb for those on antidepressants (ANY antidepressant, not just the current antidepressant – add up all time on any of them) for less than a year is to take half the amount of time on them to wean off and for long-term users for each 5 years on psychiatric drugs of any kind the general rule of thumb is at least a year or more.), NOT JUST WEEKS OR MONTHS!—has proven the safest and most effective method of withdrawal from these types of medications. Thus the body is given the time it needs to readjust its own chemical levels. Patients must be warned to come very slowly off these drugs by shaving minuscule amounts off their pills each day, as opposed to cutting them.
WARNING: The practice of taking a pill every other day throws you into withdrawal every other day and can be very dangerous when you consider the FDA warnings on abrupt changes in dose.
This cannot be stressed strongly enough! This information on EXTREMELY gradual withdrawal is the most critical piece of information that someone facing withdrawal from these drugs needs to have.
A REMINDER: IT IS EASIER TO GET DOWN OFF A MOUNTAINTOP ONE GUARDED STEP AT A TIME THAN TO JUMP FROM THE TOP TO THE BOTTOM.
No matter how few or how many side effects you have had on these antidepressants, withdrawal is a whole new world. The worst part of rapid withdrawal can be delayed for several months AFTER you quit. So even if you think you are doing okay you quickly find that it becomes much worse. If you do not come off correctly and rebuild your body as you do, you risk:
Although my book, Prozac: Panacea or Pandora? Our Serotonin Nightmare!, contains massive amounts of information you can find nowhere else on these drugs, it does not have the extensive amount of information contained in the CD focusing mainly on withdrawal issues. The CD contains newer and updated information on safe withdrawal from these drugs. It details over an hour and a half the safest ways found over the past 30 years to withdraw from antidepressants and the drugs so often prescribed with them – the atypical antipsychotics and benzodiazapenes. And it explains why it is safest to withdraw tiny amounts from all of the medications at the same time rather than withdrawing only one at a time.
It also lists many safe alternative treatments that can assist you in getting though the withdrawal and lists other alternatives to avoid which are not safe after using antidepressants. And it contains information on how to rebuild your health after you have had it destroyed by these drugs so that you never end up feeling a need to be on these drugs again.
The CD is very inexpensive and will save you thousands in medical bills which far too many end up spending trying to do it on your own without this information. (One woman who decided she was okay coming down twice as fast as recommended paid a terrible price. After withdrawing she suffered the REM Sleep Disorder early one morning and attacked her husband with a baseball bat (for which she has no memory) and which ended their lifelong courtship and marriage. And cost her $30,000 to be in a psychiatric facility where they put her on five more drugs plus the antidepressant she had just withdrawn from! You can see why many have lamented that they wished they would have had the information on this CD before attempting withdrawal.
To order Ann Blake-Tracy’s book go to: https://store.drugawareness.org/product/prozac-panacea-or-pandora-our-serotonin-nightmare-2014-ebook-download/
To order the CD, “Help! I Can’t Get Off My Antidepressant!” go to: http://store.drugawareness.org/product/help-i-cant-get-off-my-antidepressant-mp3-download/
This is a CD doctors can also benefit from when attempting to withdraw their patients from these drugs which the World Health Organization has now told us are addictive and produce withdrawal. And doctors have begun to recommend the CD to their patients.
In 2005 the FDA issued strong warnings about changes in dose for antidepressants. They warned that ANY abrupt change in dose of an antidepressant, whether increasing or decreasing the dose….so that would include switching antidepressants, starting or stopping antidepressants, forgetting to take a pill, skipping doses, taking a pill one day & not the next, etc…. can cause suicide, hostility, and/or psychosis – generally a manic psychosis which is why so many are given a diagnosis for Bipolar Disorder after this withdrawal reaction that can so severely impair sleep leading to a psychotic break.
Clearly coming down too rapidly can be very, very dangerous. We encourage you to arm yourself with knowledge by downloading our CD on safe withdrawal.
WARNING: In sharing this information about adverse reactions to antidepressants I always recommend that you also give reference to my CD on safe withdrawal, Help! I Can’t Get Off My Antidepressant!, so that we do not have more people dropping off these drugs too quickly – a move which I have warned from the beginning can be even more dangerous than staying on the drugs!
The FDA also now warns that any abrupt change in dose of an antidepressant can produce suicide, hostility or psychosis. And these reactions can either come on very rapidly or even be delayed for months depending upon the adverse effects upon sleep patterns when the withdrawal is rapid! You can find the CD on safe and effective withdrawal helps here: http://store.drugawareness.org/
Ann Blake Tracy, Executive Director,
International Coalition for Drug Awareness
www.drugawareness.org & http://ssristories.drugawareness.org
Author: ”Prozac: Panacea or Pandora? – Our Serotonin Nightmare – The Complete Truth of the Full Impact of Antidepressants Upon Us & Our World” & Withdrawal CD “Help! I Can’t Get Off My Antidepressant!”
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Candace Pert, the discoverer of the opiate binding process that made Serotonin Reuptake Inhibitors possible, is an internationally recognized pharmacologist who has published over 250 scientific articles. She received her Ph.D. in pharmacology from Johns Hopkins University School of Medicine, served as Chief of the Section on Brain Biochemistry of the Clinical Neuroscience Branch of the National Institute of Mental Health (NIMH), held a Research Professorship in the Department of Physiology and Biophysics at Georgetown University School of Medicine in Washington, DC, and is currently working in a private company developing an AIDS vaccine in addition to treatments for other diseases.
Dr. Pert appeared in the feature film What the Bleep Do We Know!?? and Bill Moyer’s TV program Healing and the Mind. She is the author of the book Molecules of Emotion: The Scientific Basis Behind Mind-Body Medicine (Scribner, 1997), Everything You Need to Know to Feel Go(o)d (Hay House, 2006), and the musical guided imagery CD Psychosomatic Wellness: Healing your Body-Mind.
Dr. Pert publicly came out against Serotonin Reuptake Inhibitors in October of 1997 in TIME magazine. She boldly stated: “I am alarmed at the monster that Johns Hopkins neuroscientist Solomon Snyder and I created when we discovered the simple binding assay for drug receptors 25 years ago . . . following is the full quote from Dr. Candace Pert’s TIME magazine letter to the editor:
“I am alarmed at the monster that Johns Hopkins neuroscientist Solomon Snyder and I created when we discovered the simple binding assay for drug receptors 25 years ago. Prozac and other antidepressant serotonin-receptor-active compounds may also cause cardiovascular problems in some susceptible people after long-term use, which has become common practice despite the lack of safety studies.
“The public is being misinformed about the precision of these selective serotonin-uptake inhibitors when the medical profession oversimplifies their action in the brain and ignores the body as if it exists merely to carry the head around! In short, these molecules of emotion regulate every aspect of our physiology. A new paradigm has evolved, with implications that life-style changes such as diet and exercise can offer profound, safe and natural mood elevation.”
Dr. Candace B. Pert
Letter to the Editor of TIME Magazine, October 20, 1997, page 8.
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Paragraph 10 reads: “Concerns about the ethics of clinical trials do not exist merely in the realm of speculation. The GVK exposés are not unusual. An increasing number of reports are coming to light of unethical and illegal practices that exploit people’s social and economic vulnerability, subject them to serious risks without their knowledge and consent, and do not even assure them of access to the drugs developed from the trials. Certain types of trials depend on paid volunteers who desperately need money. In Gujarat, unemployed diamond workers and migrants from Uttar Pradesh and Bihar get paid between INR 5000 and INR 20,000 to take part in bioequivalence trials – sums large enough for them to put money over personal safety. Indeed, trial participants may be both financially and socially vulnerable. It is reported that Surender, who died in the Hyderabad felodipine trial, was one of a number of Dalit students being recruited for clinical trials in that city. Likewise, some years ago, a 22-year-old Adivasi youth died in a bioequivalence trial of the antidepressant citalopram [Celexa] by the Sun Pharma Advanced Research Centre in Vadodara. ”
Bodies for hire; The outsourcing of clinical trials August 2009
By: Sandhya Srinivasan
Medical testing by Western countries is having a staggering impact on India, if only we were to care to pay attention. And the government’s own policies are encouraging this.
In November 2008, the Hindustan Times’ LiveMint broke the story of an infant in Bangalore having died after being administered a vaccine in a drugs trial. The Drugs Controller-General of India (DCGI), Dr Surinder Singh, halted the testing, reportedly the first time that the office of the DCGI had taken such action. The trial, for a new pneumonia vaccine, was being conducted by a Hyderabad-based contracted research organisation, GVK Biotech, for the US-based multinational Wyeth Pharmaceuticals. The infant had been recruited from St. John’s Medical College, a reputed private medical institution in Bangalore.
GVK’s spokesperson claimed that the vaccine had nothing to do with the death, as the child had received an approved and widely used vaccine – not the experimental product. However, the DCGI’s investigation revealed that the infant had a heart condition, and that the trial had been meant to be conducted only on healthy babies. According to C M Gulhati, editor of the Monthly Index of Medical Specialities, India and a Delhi-based expert on clinical-trial regulations, the investigation revealed a number of other irregularities as well: the informed-consent document had not been signed before the child was recruited; and the St John’s ethics committee had not been properly constituted, as it was not chaired by an external member to ensure independent functioning.
Yet the infant’s death was not an aberration. In December 2008, 25-year-old K Surender, of Hyderabad, died in a ‘bioequivalence’ trial of a blood-pressure drug, felodipine. Bioequivalence trials test generic versions of drugs to ensure that they are as effective as the original, and involve administering the drug and then monitoring the individual through blood tests and other investigations. These tests are conducted on healthy people who are paid for their participation. The Hyderabad trial also happened to be run by GVK Biotech, which subsequently issued a statement that Surender had simultaneously been part of many bioequivalence studies, with GVK as well as other contracted research organisations. This multiple trial participation could have accounted for his death, argued the company.
Such an explanation is unconvincing. If Surender had taken part in many trials, it would only have been for the money, which would amount to an inducement according to national and international ethical guidelines for research – an inducement that might have made him overlook the risks of the trials. And, in any case, why did the company let him take part in the felodipine trial when it was aware that he had taken part in many others? The answer to this question lies in the compulsions of the global pharmaceutical industry. The GVK trials are among the increasing number of international clinical trials that are taking place in India – and the concerns that they raise will come up increasingly frequently in the future. The reports of various government and private bodies put the potential of the clinical-trial industry into billions of dollars, though the method of calculating these numbers is not available. One market-research company, Frost and Sullivan, reportedly estimates a USD two billion turnover by 2010.
The growth of the outsourced clinical-trial industry in India followed changes in the law in January 2005 that encourage clinical research in India. The most important of these was an amendment to the Drugs and Cosmetics Rules, permitting clinical trials in India to be carried out at the same time that they are done in other countries, rather than waiting until the results of drug trials in other countries were made public. Previously, this ‘phase lag’ had ensured that India was of no interest to big pharmaceutical companies to test their drugs. At that time, Phase II trials were permitted in India only after the results of a Phase III trial abroad were declared. And Phase I trials of foreign drugs were simply not permitted. (Phase I or safety trials are done on healthy ‘volunteers’, Phase II trials look at the drug’s safety and effectiveness on patients, and Phase III trials also look at safety and effectiveness, but in large numbers of patients.) It should be noted, though, that an exception was made for drugs deemed of importance to India. While the Drugs and Cosmetics Rules do not specify, such drugs would probably include the HIV vaccine.
This changed in January 2005, and India is now prominently on the radar screen of the international pharmaceutical industry in terms of clinical trials, given its vast population of potential trial subjects. As of today, the bulk of clinical trials are still located in rich countries. To illustrate, as of 19 July 2009, the US government clinical-trial database lists a total of 76,018 trials, of which 44,758 have sites in North America and 17,878 have sites in Europe – accounting for the bulk of trials. In contrast, only 1021 clinical trials have sites in India, in addition to 122 in Pakistan, 61 in Bangladesh and 12 each in Nepal and Sri Lanka.
However, the number of trials in India is growing fast. Figures given by the DCGI’s office show that the number of newly approved trials every year went from 100 in 2005, when the new rules kicked in, to about 500 in 2008. What is of concern here is that many of the trials that come to countries such as India are likely to be those rejected as unethical in Western countries. As trials shift to countries such as India, there has been an international debate on ethical concerns of the outsourcing boom. This debate has been partly responsible for amendments in the World Medical Association’s Declaration of Helsinki, “Ethical Principles for Medical Research Involving Human Subjects” in 1996, 2000 and in October 2008. Drug regulators in Europe and the US require that clinical trials submitted to them adhere to the Declaration.
Some of these changes have dealt with placebos or ‘sugar pills’. The October 2008 revision took a strong stance against the use of a placebo in a trial when a treatment exists. Clinical trials compare the effect of an experimental drug to an existing drug. If there is no drug for the condition, the experimental drug may be compared to a placebo. Using a placebo when a treatment exists deprives the trial participant of effective treatment. The ethical guidelines of the Indian Council of Medical Research and the World Medical Association’s Declaration of Helsinki both forbid the use of a placebo when an effective treatment exists, with certain specific exceptions. While both of these documents have been a bit ambiguous in the past, the 2008 revision of the Helsinki Declaration is clear: placebos can be used only when absolutely methodologically necessary, and when the risk to the participant is low. This revision was reportedly preceded by behind-the-scenes lobbying by the drug industry to permit greater use of placebo controls.
In the same month that the revised Declaration was announced, the US Food and Drug Administration (FDA) amended its own requirements for clinical trials. While placebos are rarely necessary, regulatory bodies such as the FDA require placebo-controlled trials to give marketing approval to new drugs. Yet as of October 2008, trials conducted for FDA approval no longer had to adhere to the Declaration of Helsinki – an internationally accepted document, but not binding unless incorporated into national regulations. The FDA would continue to require placebo controls, and no one was going to tell them otherwise.
Concerns about the ethics of clinical trials do not exist merely in the realm of speculation. The GVK exposés are not unusual. An increasing number of reports are coming to light of unethical and illegal practices that exploit people’s social and economic vulnerability, subject them to serious risks without their knowledge and consent, and do not even assure them of access to the drugs developed from the trials. Certain types of trials depend on paid volunteers who desperately need money. In Gujarat, unemployed diamond workers and migrants from Uttar Pradesh and Bihar get paid between INR 5000 and INR 20,000 to take part in bioequivalence trials – sums large enough for them to put money over personal safety. Indeed, trial participants may be both financially and socially vulnerable. It is reported that Surender, who died in the Hyderabad felodipine trial, was one of a number of Dalit students being recruited for clinical trials in that city. Likewise, some years ago, a 22-year-old Adivasi youth died in a bioequivalence trial of the antidepressant citalopram by the Sun Pharma Advanced Research Centre in Vadodara.
Certain types of trials are more likely to be conducted in India and other countries where regulatory and monitoring mechanisms are weak, or regulators are too willing to please drug companies. The use of placebos is a good example, as it is not difficult to conduct placebo trials in India. In 2005-06, Indian patients with schizophrenia were taken off their regular medication and given either a new, ‘extended-release’ formulation of an approved drug (quetiapine, marketed by AstraZeneca) or a placebo, to compare the time it took for people in each group to have a relapse attack of schizophrenia. The trial was conducted by a Contract Research Organisation (CRO) called Quintiles, in India as well as a number of countries in Eastern Europe. One patient (not in India) who was on the placebo committed suicide. Experts are unanimous in their view that a placebo was methodologically unnecessary in that trial, as the new formulation could have been compared to the existing ‘immediate-release’ drug. But the European regulators required a placebo-controlled trial, noted Irene Schipper and Francis Weyzig of the Dutch research organisation Centre for Research on Multinational Corporations, in a 2008 report. They also argued that placebo-controlled trials for severe conditions, which put the participants at greater risk, are more likely to be conducted in developing countries.
Trials in government hospitals in India can also be of special concern. In one trial, 290 people who had been hospitalised because they were having a severe attack of acute mania were given either a drug (risperidone, marketed by Johnson & Johnson) or a placebo. The idea, of course, was to examine how many people recovered with the drug, and how many with the placebo. This subjected seriously ill people to harm. The majority of patients in this India-only trial, also conducted by Quintiles, were recruited from government hospitals where, according to the principal investigator of the trial, the most seriously ill patients could be found. It is also where patients can be recruited easily, because trial participation ensures a hospital bed and free, quality treatment.
Another concern about trials in government hospitals is that they are conducted on poor people who may have no access to the drugs tested on them after the trial is over. In August 2008, the media reported that 49 children died in 42 clinical trials that were conducted over two and a half years in the Department of Paediatrics at the All India Institute of Medical Sciences (AIIMS) in Delhi. An investigation ordered by the National Human Rights Commission concluded that the trials were conducted properly: the children in the trials were seriously ill, and all the deaths occurred because of the serious illnesses, not the treatments. However, the committee’s report left many questions unanswered. What, for instance, was the purpose of these trials? Would they help other poor children in India?
One of these trials tested the blood-pressure drug valsartan, supplied by its manufacturer Novartis. Paediatric hypertension is indeed a serious condition, but companies conduct paediatric trials for various reasons, including to get information for the benefit of doctors who prescribe the drug to children. Another reason is because the US FDA extends a drug’s exclusive marketing rights when it is tested on children; this provision is meant to encourage research on children who are otherwise prescribed drugs based on the results of research on adults. However, companies also use this clause to maximise their profits. Another trial was linked to gene-activated human glucocerebrosidase, a treatment for Gaucher’s disease, a serious genetic condition in which a fatty substance (lipid) gets deposited in cells and specific organs. The drug for this trial was provided by the US-based Shire Human Genetic Therapies. Will the drug be made available in India once it is proved effective? Both the Helsinki Declaration and the ICMR’s guidelines emphasise that a community on which a drug is tested should have access to the drugs, if proven effective, once the trial is over. Unfortunately, this is rarely the case. Although all of the new drugs being tested in India will indeed be available in India, this will be at prices unaffordable to the very people who agree to have them tested on their bodies.
More generally, but of no less concern, AIIMS has stated that the trials did not “target” children from poor backgrounds. But there is no need to target poor people at AIIMS – they constitute the majority of patients at this government referral hospital. The simple fact is that the vast majority of people seeking care at the AIIMS centre would be there because they cannot afford treatment elsewhere.
The pharmaceutical industry depends on constantly getting new drugs into the market. New drugs include new uses for old drugs (a cancer drug that can also be used for infertility?) or ‘improved’ or ‘me-too’ versions of older drugs (all those antacids, blood-pressure and cholesterol-lowering drugs, anti-depressants or antibiotics). These drugs must be tested on human beings before they can go into the market. Permission has to be obtained, patients have to be recruited, trials carried out and the results filed – all at top speed, because time is money.
This is where the Contract Research Organisation – the CRO, such as GVK Biotech referred to earlier – steps in. The CRO undertakes all aspects of the process involved in getting regulatory clearance: getting the necessary permissions, tying up with doctors and hospitals to recruit patients on whom the drugs are to be tested, analysing the data that emerges from the trials, monitoring the trial to make sure that the information collected meets standards, putting together reports and even ghostwriting articles for publication in medical journals. Of course, the most important aspects of all this is the recruitment of patients. The best place to recruit patients for, say, a diabetes-drug trial, is a country with a large diabetic population. And diabetics who have not received treatment make better trial subjects, as the results of drugs tested on them will not be ‘contaminated’ with the results of drugs that they have already used.
Clinical trials in developing countries depend not only on physical infrastructure – hospitals and laboratories – and trained human power. They also depend on drug companies getting access to bodies on which they can test their drugs. So, CROs in India market Indian bodies. In a 2006 advertisement on their website (which has since been removed), a CRO named Igate advertised the ‘India advantage’ as “40 million asthmatics, about 34 million diabetics, 8-10 million people HIV positive, 8 million epileptic patients, 3 million cancer patients.”
CROs in India all claim to have ‘access’ to patients with various health problems for which drugs can be tested. For instance, a research group called Veeda claims to have “access to vast patient populations and has specific expertise in recruiting patients with cardiovascular disease, oncology, diabetes, renal disease”. The CRO Quintiles India once boasted that, for a paediatric-flu-vaccine trial, it recruited 201 one- to three-year-olds from three sites in India in just six days. What kind of network does Quintiles have, and what kind of influence does it have with the medical profession, that it can round up 200 children and convince their parents to let them get an experimental flu shot – all in just six days flat?
It seems that at least some of this is able to take place through wilful misinformation. Spectrum Clinical Research specialises in recruiting patients, collecting patients through networks of private clinics, hospitals, specialists and family physicians. It also runs ‘awareness campaigns’ – for instance, a “white ribbon initiative” on osteoporosis, co-organised with the women’s magazine Femina of the Times of India stable, collected data on 2000 patients with osteoporosis. Another campaign, this time to “defeat diabetes”, collected data on 1000 patients with diabetes. In these ways, people who think they are joining patient-support groups are actually being tracked so they can potentially be put on a trial.
Behind a veil
Other than the boasts of CROs, there is little information available on the hundreds of clinical trials being conducted in India. This is despite the evidence that many of these trials are conducted for the benefit of international drug companies, at unacceptable cost to the local population; that trial subjects could be put at risk; that subjects often have not given their informed consent to participate; that they might be provided care that is of lower quality than if they had been recruited for a trial in the West; that injuries during a trial might not be investigated thoroughly, and that those injured may not receive treatment of the highest standard, or even compensation; and that drugs that are tested are often too expensive for people who need them in India.
The only institution to have direct power over the conduct of a trial is the ethics committee (EC). Research institutions appoint their own institutional ethics committee to conduct an ethics review of all research proposals from within the institution. Independent or freelance ethics committees undertake ethics review for a fee, from anyone who applies – usually the CRO or drug company who coordinates the trial at a number of small nursing homes or private clinics, which don’t have their own ethics committee. The EC is a collection of specialists from various fields who review trial documents, including the trial design, the manner in which subjects are recruited, the patient information sheet and the informed-consent form, and approve or reject the application. These committees also have the authority to investigate a trial, and even to stop it if they feel that something is not right.
Ethicist Amar Jesani points out that ethics committees have a lot of power, as the DCGI requires that all trials be passed by such an appointed group. In fact, the DCGI only requires approval by an ethics committee, since it does not monitor the actual conduct of the trial – it does not check that informed consent is taken, that the investigators do their job correctly, that subjects are not harmed, and so on. Thus, says Jesani, it is the ethics committee, not the DCGI, that is the real regulator of clinical trials.
Yet the effectiveness of an ethics committee depends entirely on the setting in which it functions. Important factors, for instance, include the institution that funds the committee’s work or that determines its level of independence, the training of its members, and their competence in terms of doing a proper ethics review. Likewise ‘independent’ or freelance ethics committees are more accountable to the companies that pay for their services. Even the patient information sheet and informed-consent document are treated as confidential documents by the ethics committee – and, of course, the trial’s sponsor. These contain the information on the purpose of the trial, its risks and benefits, and an assurance that a patient’s treatment will not be jeopardised by refusal to participate, or withdrawal from a trial. There is nothing here of proprietary value – on the contrary, everything in these documents is of public interest, and they should be available to the public. Ethics committees are also often poorly educated in their responsibilities.
The reports of people dying in trials are likely to be merely the tip of the proverbial iceberg. And many more are likely to suffer an injury related to the trial drug, injuries that require treatment and that could result in temporary or permanent disability. Indian guidelines require that trial participants be compensated for injuries suffered during research. However, a study by Urmila Thatte and others in a 2009 issue of the UK-based Journal of Medical Ethics found that many trial investigators as well as ethics committee members are not even aware of this requirement. The guidelines of trial sponsors – such as drug companies – provide for medical treatment of any participant who suffers a trial-related injury, or reimbursement of their medical costs. However, Thatte and her colleagues found that none of the companies sponsoring trials, or ethics committees reviewing their trials, had a policy of compensation for trial-related disability or death. Yet for ethics committees to be a law unto themselves is hardly surprising, given the overall environment of lax regulation and monitoring.
Now, the FDA’s decision to do away with the Declaration of Helsinki will create a dilemma for the DCGI. If CROs in India are to follow the FDA requirements – such as using a placebo even when it is not absolutely necessary, and when it might put subjects at risk – they will be violating Indian regulations, which require that the Declaration of Helsinki be followed. The latest revision of the Declaration is quite clear that the placebo may be used in very few circumstances. At the moment, however, the DCGI’s record – permitting a number of unethical trials – suggests that his office places greater value on the potential financial returns of clinical trial outsourcing than on protecting the people who take part in drug trials in India.
Sandhya Srinivasan is a Bombay-based journalist specialising in public health and development issues. She is executive editor of the Indian Journal of Medical Ethics.
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