Outsourced side effects; Perils of foreign clinical trials
By Tom Blackwell
3 June 2009
National Post
Canadian researchers studying the effects of a heart drug two years ago tried to expedite the experiment by farming out much of their clinical-trial work to developing countries, where suitable human subjects are easy to find and costs rock-bottom low.
But when they looked into some suspicious data coming out of a trial site in Iran, the scientists made a startling discovery. The study results there turned out to be largely fraudulent, to the point where one patient listed by the Iranian researchers as dead was still very much alive.
“It was bad, so bad we thought the data was not salvageable,” said Dr. Gordon Guyatt, part of the research group at McMaster University in Hamilton. “It’s a different culture, a culture with a lack, perhaps, of a long-standing research tradition dedicated to high standards and integrity.”
The incident underlined the little-discussed pitfalls of a dramatically new era in human drug research. Clinical trials –as studies on people are called–are crucial to determining whether medicines or medical devices are licensed for widespread use or not, and an important way to gauge the safety or efficacy of products already on the market.
Yet statistics show increasing numbers of trials are being outsourced to emerging economies such as India, China and Eastern Europe to limit expense and avoid what some researchers call stifling red tape in Canada and other jurisdictions with highly sophisticated medical systems. The trend is sparking debate about the quality and applicability of some of the research, and the treatment of vulnerable subjects in poor nations.
Health Canada said recently it had unearthed problems in a number of developing-world trials submitted by companies trying to get drugs approved here. Key information on side effects and other potential shortcomings had been left out, either deliberately or because of misunderstanding.
The problems “bring into question the reliability of the data and whether or not the trials were conducted to acceptable … standards,” a Health Canada official is quoted as saying within minutes of a January meeting with a pharmaceutical trade group.
The regulator is drafting a warning to pharmaceutical companies to ensure that quality is maintained in clinical trials in lower-income countries, and has launched a study to determine if more action is required, said Alastair Sinclair, a Health Canada spokesman. It is also offering direct guidance to India, which has experienced a boom in clinical research lately.
“Clinical trials have always been global to some extent. What we have seen is a huge expansion … to a whole set of new countries: Easternbloc countries, India and China,” said Kevin Schulman, a medical professor at Duke University in North Carolina, who co-authored a commentary on the topic published recently in the New England Journal of Medicine. “There’s no reason not to take advantage of lower costs … but I don’t think what we want is lower ethical standards.”
There is also concern that Canadian scientists will have fewer opportunities for clinical research as the trend progresses, and Canadian patients less access to investigational drugs. Still, Dr. Guyatt and other scientists who run clinical trials say outsourcing to emerging-economy countries is a fact of life and has clear benefits, such as improving research expertise and availability of medicine in poorer countries. What is needed, some say, is to step up monitoring of outsourced trials and bring regulators in those places up to Western standards.
There is no question that a dramatic shift is underway. Canada still had the fourth-largest number of trial sites in the world in 2007, but its relative number had dropped 12% from the year before, according to a paper published last year in the journal Nature Reviews Drug Discovery. Meanwhile, India’s total had jumped 20%, China’s 47% and Argentina’s 27%.
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Ironically, though, one of the chief reasons trials are moving to jurisdictions with questionable regulatory oversight is that the process here has become bogged down, according to critics, by an overly restrictive ethics system.
When patients are recruited at several universities and hospitals across Canada, for instance, researchers must apply to ethics committees at each institution, and the panels typically have different rules and can take months to decide, scientists say. “There is a huge amount of bureaucracy,” said Dr. Ian Tannock, a cancer researcher at the University of Toronto. “I think it’s gone overboard.”
The result is a prolonged process that is convincing many pharmaceutical CEOs, amongst others, to send trials elsewhere, said Russell Williams, head of Canada’s Researchbased Pharmaceutical Companies, the main industry association.
As trials started moving to developing countries, one of the first issues to emerge was the treatment of the patients recruited as subjects. A 1996 trial by Pfizer of an antibiotic in Nigeria, for instance, was allegedly conducted without the patients’ consent and resulted in the deaths of 11 children. Pfizer has denied wrongdoing and said the subjects died from a meningitis outbreak.
But less light has been shone on the quality and nature of data coming out of the trials in such countries. One problem is that factors on the ground in those jurisdictions, such as higher rates of infectious disease and less-developed health-care systems, can skew how a drug affects someone.
There is also evidence that genetic differences sometimes alter results. Dr. Schulman said researchers told him recently about an Alzheimer’s drug they were testing in China, only to discover that no one there had the specific genetic makeup that responds to the medication.
“Someone of southeast Asian ancestry may react one way to a drug, versus someone who is of African American or European background,” said Dr. David Klein of St. Michael’s Hospital in Toronto. “Just because you can prove something in a large population in south Asia, that doesn’t necessarily mean you’re learning all the lessons you need to learn about how the drug might act in a North American population.”
Dr. Guyatt, though, downplays the issue, saying drugs that work differently on different ethnic groups are extremely rare. Then there is the question of research quality. In a January meeting with the Canadian Generic Pharmaceutical Association, Health Canada outlined problems it discovered in out-sourced trial results submitted with applications for various generic versions of medicines.
Some showed fewer adverse reactions than would be anticipated, given evidence that has already been published on the same drugs. Some reports also failed to note deviations in both the trial’s protocol and the timing of blood and urine sampling, anomolies the regulators would expect to see, according to the minutes.
Dr. Guyatt maintains that the standard of research is adequate in most of the lower-income countries he has dealt with, but says particular care is needed to pick the right colleagues in those nations. His team’s trial initially involved 10,000 patients in 21 countries, both industrialized and lower-income.
Called POISE and headed by Dr. P. J. Devereaux, a McMaster colleague, the study was published in the journal Lancet last year, suggesting that patients given beta-blocker heart drugs before undergoing noncardiac surgery are at increased risk of stroke or death. The final results did not include those from Iran, or from one research assistant in Colombia whose data was also considered fraudulent.
The Iranian team was enrolling people not eligible for the trial and it was unclear if any patients were even getting the study drug, said Dr. Guyatt. When perceived problems first arose, Dr. Devereaux flew to the middle-eastern country to get to the bottom of things, earning the nickname Sherlock from his colleagues. “He was brilliant,” recalls Dr. Guyatt with a laugh. “He got there and says, ‘I’m going to find out what really happened’ and he picks out a chart. ‘It says this person is dead. I want to call the relatives and find out.’ So, lo and behold, the person is alive.”
