By Jenny Manzer – 2005 Michener-Deacon Fellowship recipient (published December 2006)
The parents of the little girl must have watched, horrified, as the days got darker and their daughter deteriorated. In December of 2000, she started taking the antidepressant Paxil.
During the months that followed the child experienced a Pandora’s box of side-effects: apathy, aggression, and insomnia. She developed skin discoloration and a personality disorder. On June 7, 2001, the girl had her last adverse reaction: suicide. Almost three years later, her death was reported to the database of the Canadian Adverse Drug Reaction Monitoring Program. The role of Paxil is listed as “suspected” and the outcome; “Died, drug may be contributory.” The girl was just 12 years old.
Report #167745 is one of several in Health Canada’s adverse drug reaction database concerning young people and Paxil, a top-selling antidepressant that was never officially licensed for children and teens but often prescribed for them. These kinds of drugs are seldom tested in children, so there is little data from large clinical trials, which scientists consider to be the “gold standard” in medical evidence. But pediatric patients still need medication, so clinicians might have to make do with what information is available and prescribe a drug as an unlicensed, or “off-label,” use.
But the case of Paxil is a bit different. There was more trial information available on the drug’s use in kids – it just wasn’t made public. In 2003, documents leaked to the media revealed that Paxil’s maker, GlaxoSmithKline, had evidence from two earlier trials showing the drug, part of a class called selective serotonin-reuptake inhibitors or SSRIs, did not benefit depressed children and teens. The trials had been done with the idea of expanding the drug’s market by applying to have it officially approved for use in pediatric depression.
The documents showed that, in 1998, the company intentionally withheld these negative results, knowing it could hurt its bottom line. As more trial evidence was revealed, it became apparent that the drug also could be harmful in some cases, doubling the rates of aggression and suicidal behaviour compared to patients taking placebo. It appeared Paxil did not help kids and for some it was highly dangerous.
Perhaps if the information about Paxil had been made available in 1998, the little girl in report # 167745 might have received another medication – or none at all.
After the media leak in 2003, Glaxo put the results of the trials in the public domain and information about the ineffectiveness of other newer antidepressants also came to light. By 2004, regulators in the United Kingdom and the U.S. had banned use of SSRIs in kids and Canada had issued a warning about them. “The disappointing reality is that antidepressant medications have minimal to no effectiveness in childhood depression beyond a placebo effect,” wrote Dr. Jane Garland, a professor of psychiatry at the University of British Columbia, in a 2004 editorial in the Canadian Medical Association Journal.
In the latest news, a comprehensive study done by scientists at the U.S. Food and Drug Administration (FDA) showed that antidepressant use also increases risk of suicidal thoughts and behaviour in young adults. The team found that young adults aged 18 to 25 years who took antidepressants were more than twice as likely to have suicidal behaviour than those given sugar pills. The analysis, released in December 2006, used pooled data from 372 antidepressant studies. It included 11 antidepressants and involved almost 100,000 participants. Researchers found no such increased risk in older adults using antidepressants.
One lesson emerges from the story of Paxil and pediatric depression: drug company goals are not always the same as public health goals. The incident also raises the question: should drug companies be calling the shots when it comes to testing new drugs?
It’s comforting to imagine a team of Canadian wunderkinds huddled in their publicly funded lab, comparing data and pouring over figures to ensure our drugs are safe before they march onto pharmacy shelves. But that’s a fantasy.
In the real world, a team of researchers handpicked by the drug company usually tests our pharmaceuticals. The sponsoring company funds the research, decides what questions about the drug need to be answered and often decides whether the results should be made public.
Since drug companies are in business to make a profit, they tend to fund studies that explore benefits, not potential harms. “There’s no rigorous study of drug interactions at all,” says Dr. Anne Holbrook, director of clinical pharmacology at McMaster University in Hamilton, Ont. “And yet if you ask physicians and patients what they worry about most, drug interactions are always in their top five.”
It’s hard to imagine a comparable situation in any other industry where human health and safety is at stake. Would we let airlines decide how high their planes should be flown during safety tests? Or allow them to test performance only when the aircraft is flying through sunny skies?
Dr. Joel Lexchin, a Toronto emergency room physician and drug industry critic, says the kind of safety problems we’ve seen with blockbuster drugs in recent years can be traced back to the limitations of the clinical trial.
“First of all, when drugs hit the market, they have only been tested in maybe 5,000 or 6,000 people, which means that any adverse reaction that occurs less than one in every 1,700 to 2,000 will not have been seen in those trials,” says Dr. Lexchin, a professor in York University’s School of Health Policy and Management. “Sometimes you only find out safety issues when drugs are more widely prescribed. And that’s one factor why you’ll have drugs being withdrawn.”
Dr. Lexchin estimates that drug companies finance about 75% of all clinical trials. Several studies have shown that trials sponsored by drug companies are between two and five times more likely to show their product in a favourable light, he adds.
One of the challenges with making trials relevant to the real world is that drug companies tend to select “healthy” patients for their studies. They want to show their drug is effective in as many people as possible, so they include patients without multiple diseases and who are not taking other medications. In some cases, this decision might mean the drug will not be tested in the patients most likely to use it. For example, Viagra was never tested in men with certain heart conditions, even though these patients are among those most likely to suffer from erectile dysfunction.
For years, researchers like Muhammad Mamdani have appealed for clinical trials to be designed to apply to the patients in waiting rooms.
“What happens when you get a homogenous group of people, you exclude a ton of other people,” says Mamdani, a former senior scientist at the Institute for Clinical Evaluative Sciences in Toronto who now works for the drug company Pfizer in New York.
In a lot of trials it’s not rare to exclude over 80% of patients you would normally see in practice. In many clinical trials that’s fairly typical,” says Mamdani.
Trials are pricey. Rather than waiting years to complete one, companies often choose to study drug effects over six to eight weeks – shorter than the average course of treatment for many chronic conditions. The researchers might also look at “surrogate endpoints,” which can be seen faster, such as studying patient cholesterol levels, rather than waiting to see if a drug actually reduces the risk of heart attack or death.
Findings in these trials may also be skewed by the fact that patients are meticulously monitored, with far more surveillance than the real world allows. Mamdani suggests all these factors in the testing phase – the homogenous patient groups, the limited time frame, the surrogate endpoints and the extra monitoring – help set the stage for the warnings and withdrawals we see with blockbuster drugs.
Drug companies may also choose inappropriate comparators or less than optimal doses to achieve favourable results. In general, studies are not usually designed to look at safety – just whether it works. They often don’t even have the numbers to try and examine safety issues. And all you need to get a drug on the market in Canada are positive results from two clinical trials.
“All you have to do to get a drug approved is have two positive studies. And it doesn’t matter whether there are also six negative studies, as long as you’ve got two positive studies, you can get the drug approved,” says Dr. Lexchin. “But nobody ever knows about the negative studies because chances that they’ll be published are very small.”
If a drug company decides they want to try and expand the market for one for their drugs, they are free to do the necessary studies and then file an application. If the studies don’t turn out as they had hoped, they could just drop the idea and never file the application. The regulator might never see these negative results – as happened in the case of Paxil and pediatric depression.
Adding fuel to the criticism of drug trials is the way that negative results can be manipulated and obscured by industry. And even if Health Canada is aware of negative results, the agency is legally bound to keep the findings confidential.
Dr. Holbrook says that when conducting studies in-house, it’s easy for industry to tinker with statistics to show good results, or selectively report outcomes. Companies can simply “dredge the data” until they come up with results that favour the product, she says. This pattern is evident from viewing data disclosed by the FDA, which is not bound by the same confidentiality clauses as Health Canada, she adds.
While industry-led trials tend to produce favourable results, there’s also evidence that researchers cherry-pick results from their studies, often changing their game plan along the way. Dr. An-Wen Chan and colleagues from Oxford University looked at 100 study protocols and compared the published trials to see whether the main outcomes changed. They found that more than 60% of the trials had something changed, added or omitted by study’s end. For example, the research team might have started out saying they were going to report how the drug affected blood pressure, but changed their minds along the way.
Dr. Chan, now a scientist with the University of Toronto, says his team knew there was bias in the reporting of research, but didn’t expect it would be so prevalent. “I think we were all quite shocked to find the majority of studies actually altered the primary aim of their study, the primary measure of whether their intervention worked or not.”
Worse still, Dr. Chan showed in a follow-up study published in the Canadian Medical Association Journal that even researchers receiving public funds from the Canadian Institutes of Health Research (CIHR) strayed from their original study blueprint.
Why are researchers doctoring results? It could be the “publish or perish” pressures of academe. Medical journals are far more likely to print positive findings than ones with negative ones or no effect. Dr. Chan’s findings suggest that, if we are basing our evidence-based medicine on data from these types of tidied-up trials – we’ve got a problem.
In light of Dr. Chan’s study, the CIHR now requires all trials funded by them to be registered and has become an international cheerleader for full registration. Infamous cases like Dr. Nancy Olivieri’s clash with the generic drug giant Apotex over the right to disclose research findings have also had an impact. In the wake of such well-known debacles, editors representing the world’s top medical journals have taken steps to preserve their integrity.
These days, all researchers submitting papers for publication in journals must show proof they retained control of their right to publish data. The International Committee of Medical Journal Editors has also demanded that all trial data submitted to them for publication must have been registered at the outset, a move intended to reduce the chances of data being omitted or altered by researchers, whether in self-interest or at the behest of the drug’s sponsor.
Critics fear that drug companies will resist full registration, but industry insiders insist there is a willingness to increase transparency. In September 2005, the International Federation of Pharmaceutical Manufacturers and Associations launched a clinical trials search engine to improve public access to information on industry-funded trials. The portal links to online information about ongoing and completed trials around the world and now indexes close to 90,000 individual pages, according to the federation. It can be reached atwww.canadapharma.org/ClinicalTrials/index_e.htmll
Participation in the portal is voluntary, but representatives of Canada’s Research-Based Pharmaceutical Companies (Rx&D) say most companies are on board. “We’ve come a long way on this issue,” says Rav Kumar, vice-chair of the regulatory affairs committee for Rx&D.
Some observers remain skeptical about the new drive for transparency. The drug industry is protective of their competitive interests and has a track record of taking aim at those who question their products. Canadian companies are no exception.
In 1997, the Canadian Coordinating Office for Health Technology Assessment (CCHOTA) was slapped with a lawsuit by Bristol-Myers Squibb in an attempt to block a scientific report on statins, which the company said threatened sales of the drug Pravachol. CCHOTA, a non-profit, publicly funded group, stood its ground and the drug company eventually lost in court.
Dr. Holbrook also earned drug company ire when she was part of an advisory group helping to draft treatment guidelines on a group of ulcer drugs for the Ontario health ministry, which funded the exercise. Industry often likes to fund these kinds of initiatives, but this time the team declined to let pharmaceutical companies get involved at all.
The group came up with guidelines for a class of popular ulcer drugs called “proton pump inhibitors” and concluded that if used at a proper dose, all the drugs could be used interchangeably. The conclusion didn’t sit well with AstraZeneca, makers of Losec, a drug that has brought them a hefty profit but was slightly more expensive then a couple of the alternatives. Dr. Holbrook received a warning letter from the company’s law firm. In the end, the letter delayed publication of the guidelines, which, Dr. Holbrook notes, allowed the company to keep reaping the rewards of the drug during that time.
Registering is an obvious first step towards transparency and optimizing information about our drugs, but researchers also want changes to the ways trials are funded and designed.
Mamdani makes an appeal for large trials to be done with the real world in mind, preferably before the drug hits the market. He noted there were more than 200 trials looking at the class of COX-2 inhibitors such as Vioxx and most were virtually useless, focusing on the same outcomes again and again. The money would have been better spent on one, large pragmatic trial, he argues. “Those are the trials that change practice.”
James McCormack has another solution. McCormack, a professor with the Faculty of Pharmaceutical Sciences at the University of British Columbia, says we should require all trials to answer a basic set of questions, which could be determined by a group of experts. These questions would address what patients really want to know about a drug, such as whether it will reduce their chance of death from a certain disease. Other areas could touch on adverse events and the drug’s effect on quality of life – key factors that McCormack says are almost never addressed.
The result would be consistent information about the endpoints that are valuable to patients and clinicians and it would allow for meaningful comparisons, he says.
Of course, the question of trial design is inextricably linked to who pays for the trial. Some experts say that if Canada is going to build a reliable drug safety system we must fund pre-market testing – a daunting thought. According to Rx&D it costs an average of $1.3 billion to bring a new drug onto the market and takes an average of 12 years.
Others, like Arthur Schafer, say drug companies could continue to fund the work, but pass on the funds to a third, independent party.
“It could be that we would want to make the drug companies pay for the research, but pay the money to an independent body which would assign the project based on peer review to a competent researcher or a team of competent researchers, with no drug company involvement in the selection process and that would sever the need to please drug companies,” says Schafer, director of the University of Manitoba Centre for Professional and Applied Ethics.
Schafer suggests we could also recoup the cost of trials through taxation. A drug company would pay later to gain access to research done by publicly funded scientists. He insists that the public is already paying a huge price for corporate-funded research.
“We don’t pay it in taxes, we pay it in the loss of objective truth-seeking science. If we want to increase knowledge in the public interest, it’s going to have to be paid for with public tax dollars. That doesn’t mean that most, or all of this expenditure can’t be recaptured by the companies that will eventually commercialize this research.”
Rav Kumar of Rx&D says it’s important to understand that trials are already strictly regulated. The government is closely involved in trials, and companies must report data to Health Canada throughout the process at each stage. The checks and balances already exist; he argues, right down to the ethics review boards, independent bodies that must approve trials before they begin. Kumar also says that having a third party managing the trial would not result in a stronger system, since industry boasts experts who may have spent 10 or 15 years in their fields – and are the best ones to oversee these trials.
Kumar says greater harmonization with the rest of the world would be a step in the right direction, allowing regulators and industry to draw more trial information from a bigger patient pool. “I think a better approach is to come at it from a global basis and see where Canada can fit into that, as opposed to having a Canadian invented-only concept. At the end of the day, Canada represents a pretty small percentage in terms of the global patient population,” he says, adding that industry and regulators from around the world should work together to improve global standards.
Some critics might be skeptical of such collaboration. They insist that drug companies, as corporations, have different goals for clinical trials than the public healthcare system. “It’s an economic goal,” says Dr. Lexchin. “It’s the ability to market the drug and to market it to as wide a population as possible, which is not necessarily a public health goal.”
Schafer says the reformist measures that have been proposed, such as registering trials, are potentially helpful, but aren’t enough. “If our judges were paid by litigants and our police were paid by individual firms, we wouldn’t get the kind of policing or judging we want,” he says.” He who pays the piper calls the tune.” We still can use drug company money, he says, but we need to set up a way to avoid pitfalls of influence. “I just don’t see that a conflict of interest that wouldn’t be tolerated in our judicial system should be tolerated in science.”