By Jenny Manzer – 2005 Michener-Deacon Fellowship recipient (published December 2006)
I was climbing a flight of stairs to a hotel room in Playa Langosta – Lobster Beach – on the Pacific coast of Costa Rica. It was December 2001, and my husband and I were escaping the grim funnel of Toronto winter. I was sunburned, as red as the beach’s namesake, but content.
As I ascended, I noticed two things. One was a black spider, the size of a gardening glove, lurking on the landing. The second was a pain along my Achilles tendon, like a thread being yanked from a sweater. The spider parachuted onto my ankle.
“It’s on you, it’s on you!” crowed my husband, clearly amused.
I flailed my ankle like a mixmaster. The spider scurried off, but the tendon pain clung on. I’d been having leg pain throughout our trip, limping after my husband as he slogged through rainforests or charged at buffet tables. I thought I’d been running too much.
I was also battling a sinus infection. I had been plagued with them for months, each infection slamming into the next like a five o’clock pile-up. Thinking she was doing me a favour, my family doctor had tried me on a course of a new and powerful antibiotic called Levaquin, part of a group of drugs known as quinolones. I’d been getting sinus infections for years and had tried all the older, cheaper road-tested drugs. Levaquin provided new hope for relief.
We returned to Canadian winter. My sunburn faded, but the sinus infection persisted. At my behest, my doctor prescribed a second round of Levaquin. My calf pain dragged on, so I stopped jogging. Late for a play one night, I tried to dash for a subway car, but was smacked down by pain. Tears streamed down my face throughout the performance. By then, I could barely walk.
One day at my job as a medical reporter, I decided to take a closer look at Levaquin, and cracked open the 2001 Compendium of Pharmaceuticals and Specialties, a tome with text the size of ant tracks that lists information about drugs available in Canada. It’s a bible for doctors and pharmacists, but seldom consulted by the public.
Buried amid technical information was a list of more than 30 serious adverse reactions reported after the drug hit the market, ranging from amnesia to liver failure. My jaw dropped when I saw two words: tendon rupture.
The product monograph warned that ruptures of the shoulder, hand and Achilles tendon had been reported in patients taking quinolones and that people who experience pain should stop Levaquin and refrain from exercise. I was floored. How could an antibiotic cause tendon pain?
I was lucky. I went off the drug before my tendons ruptured, an occurrence that would have been, as my doctor put it, “a disaster.” Still, it took weeks before I could walk without pain. Having just cracked my 30s, I wondered if I would ever run again. I did, but it took time.
I had become one of the thousands of Canadians that experience an adverse drug reaction. In fact, more than one in three Canadians report having had an adverse drug reaction, according to a Health Canada survey. Like most patients, I never filed an adverse drug reaction report, nor, I suspect, did my overworked family physician. Is it any wonder so many of these side-effects are considered rare?
By Health Canada’s estimates fewer than 10% of all adverse drug reactions are reported, though other research suggests the number may be as low as 1% or 2%. Given those figures, it’s astonishing that Health Canada received more than 10,000 reports of suspected adverse drug reactions in 2005, up slightly from 2004. Close to 70% of these were classified as “serious,” which means the reaction required hospitalization, caused congenital malformation, significant disability, was life-threatening or resulted in death.
A search of the database of the Canadian Adverse Drug Reaction Monitoring Program reveals more than 330 reports concerning Levaquin alone, including a possible role in 19 deaths. Many of the suspected reactions appeared in elderly patients, who, along with women, are more likely report side-effects, in part because they tend to take more drugs. From Levaquin’s introduction in 1997 to December 2005, Health Canada received 40 reports of people having tendon-related problems, including rupture, after taking the drug.
While I experienced the potential dangers of medication first-hand, the rest of the world was reminded in the summer of 2002 when findings from the Women’s Health Initiative blindsided women around the globe. Data from the large, randomized trial confirmed that, contrary to what previous, less rigorous studies had suggested, hormone replacement therapy did not protect women against events such as heart attacks and breast cancer, but actually raised the risk of some of these outcomes.
Fuelled by a diet of drug company promotion, there had been high hopes that hormone therapy would both treat menopause symptoms and bring a goody basket of other health benefits. At one point, it was practically considered malpractice for a physician not to prescribe hormone therapy.
The reports dashed women’s trust in their physicians and gave drug company execs night sweats. More alarming news came in September 2004, when Canadians learned that the arthritis drug Vioxx was being voluntarily pulled from the market. A study had found that the painkiller led to an increased risk of heart attack and stroke when taken over the long term. One whistle-blower later estimated the drug could have caused more than 88,000 heart attacks in the U.S. alone.
Over the five years the drug was sold here Canadians filled more than 15 million prescriptions for it, according to IMS Health Canada, a company that tracks pharmaceutical sales. The public later found out that Merck, the makers of Vioxx, may have downplayed evidence of safety concerns to protect sales. Health Canada later warned healthcare providers that Bextra and Celebrex, COX-2 cousins to Vioxx, also appeared to increase risk of cardiovascular events. Bextra is now off the Canadian market and Celebrex is saddled with more warnings.
The bad news from Health Canada about big drugs continued in 2005. The cholesterol-lowering statin Crestor can cause dangerous muscle problems. The birth control method Depo-Provera is linked with bone loss. The attention-deficit/hyperactivity disorder drug Strattera might make kids want to hurt themselves. It’s enough to make you clear out your medicine cabinet.
While a Health Canada expert panel has since recommended that Vioxx be reintroduced, its maker, Merck Frosst Canada has not yet applied for this status. In November of 2006, Quebec became the first jurisdiction in North America to authorize a consumer class-action lawsuit against Merck over Vioxx. The Quebec court ruled that Quebec residents who alleged they were injured by the drug could join the action.
As patients around the country await the fate of their Vioxx class action lawsuits, there is much we can learn about our drug safety system by the Vioxx story. Some of the symptoms:
Drug trials are short, but illness is long
The cardiovascular side-effects associated with Vioxx were only seen after 18 months of treatment. Initial drug company studies submitted to have the drug approved didn’t last longer than 18 months, Merck stated in its recall notice to pharmacists.
Similarly, drug trials tend to be far shorter than a usual course of treatment. It is not unreasonable to expect that a patient taking an arthritis drug, or an antidepressant, might be on it for several years, yet drug trials tend to last a matter of weeks.
Drug trials are also typically designed to show efficacy of a drug, so they use relatively healthy patients with only one illness. “Real world” patients usually suffer from many conditions and may be on several medications at once.
Overhyping benefits, downplaying harms
When Vioxx came on the scene doctors embraced it for its lower risk of the gastrointestinal side-effects that had been seen with older non-steroidal anti-inflammatory drugs (NSAIDs). It was widely prescribed for all walks of life, reaching far beyond its target group of patients who were at risk of gastrointestinal problems.
The pursuit of a new use – and more sales – of Vioxx – helped unmask the cardiovascular risks associated with the drug. Vioxx and other COX-2 inhibitors came under scrutiny after early results from the APPROVe study, a trial designed to test Vioxx as a possible treatment for colon cancer, revealed in 2004 that it doubled the risk of heart attack and stroke compared to placebo when taken for longer than 18 months.
The VIGOR trial, published in 2000, had suggested a higher risk of heart problems in patients taking Vioxx compared to naproxen, an older NSAID. Merck speculated, however, that these results could be because naproxen was protective against heart problems.
Dr. Andreas Laupacis, who chaired Health Canada’s expert panel on COX-2 inhibitors, says a key lesson we can learn from Vioxx is that we must study harms as carefully as benefits. Enthusiasm about its slightly lower risk of gastro-intestinal side-effects compared to the older drugs led to a massive increase in NSAID use without potential harms being carefully considered, he says.
“One advantage of old drugs is that they’ve been around for a long time we generally have a pretty good idea of what their side-effects are, number one.”
There’s also the question of how data are interpreted, says James McCormack, a professor with the faculty of pharmaceutical sciences at the University of British Columbia. For example, the FDA has described the risk of Vioxx as very low, even though it’s comparable to the magnitude of the benefits reported in taking the widely prescribed statins. “In fact the benefit of the statins is less than the harm associated with Vioxx. Yet you never hear anyone when they’re reporting the cholesterol trials as saying the magnitude was very low or little.”
The belief that newer is better
Vioxx was heavily prescribed and heavily marketed. Both physicians and patients (particularly in the U.S., where broader direct-to-consumer marketing is legal) bought into the idea that the newer COX-2 inhibitors, such as Vioxx, are superior to older, cheaper painkillers such as ibuprofen or aspirin. Yet the COX-2 drugs are not better at relieving pain than these older drugs. The idea that “newer is better” when it comes to drugs may boost industry profits, but it results in less-than-optimal drug use and skews the research agenda.
Many of the drugs coming down the pipeline are known as “me toos” – drugs that show little advantage in effectiveness or safety over existing competitors. In fact, Canada’s Patented Medicine Prices Review Board has estimated only about 6% of new drugs offer substantial improvement over existing treatments. So drug companies must be creative in convincing physicians to prescribe a new drug – and it’s working. Research from the Centre for Health Services and Policy Research at the University of British Columbia shows that in 2003, the province devoted more than 60% of their prescription drug expenditures to these “me too” drugs compared to just 10% spent on “breakthrough” medications. Vioxx itself might even be considered a “me-too,” since the COX-2 inhibitor Celebrex had already been approved.
McCormack says we shouldn’t blame regulators or drug companies for less-than-optimal prescribing habits. “It’s the system that we’re in. Our clinicians are not asked or have the skills to appraise things very well. If you are of a skeptical ilk, you probably wouldn’t have prescribed (Vioxx). If you are of a ‘newer is better’ ilk, you probably would have.”
Dr. John Hoey, former editor of the Canadian Medical Association Journal, notes that it costs hundreds of millions to introduce yet another statin or antidepressant. “Every class of drugs has companies trying to produce me-too drugs to get in the market, and then spending huge amounts advertising them to doctors. And the advantage of one over the other is probably very trivial if it exists at all,” he says, adding these expenditures are supposedly in the interest of patients – but aren’t.
Merck could have initiated a trial to investigate the link between Vioxx and cardiovascular deaths, but they’d never do that, insists Dr. Hoey. “They’re not answering questions that are really important to patients and doctors. And yet they would spend a large amount of money looking for other uses for Vioxx, preventing colon cancer and whatever. The research agenda gets heavily skewed in the direction of me-too drugs and in the direction of not answering the really important questions around the adverse events.”
Regulatory systems failed
Public regulators in Canada and the U.S. failed to identify the true cardiovascular risks of using Vioxx over the long term. Why did post-approval monitoring not discover this problem?
Unfortunately, our current system of adverse drug reaction reporting is best at picking up “idiosyncratic” events, such as a dramatic skin rash, but poor at flagging more common events, such as the heart attacks seen in Vioxx patients. Few physicians would be suspicious if a sixty-something patient with multiple health problems had a heart attack. Experts say that’s why we need a more active monitoring system, so when a “signal” of a problem is picked up, targeted studies can be done to get to the bottom of the issue.
In a scathing editorial published in January 2005, the Canadian Medical Association Journal questioned why it took Health Canada and the U.S. Food and Drug Administration (FDA) four years to identify the problems with Vioxx that should have been apparent as early as 2000. “Using an active surveillance system that targeted serious adverse events would have sounded the alarm much earlier,” the editors wrote. “Both the FDA and Canada have failed miserably in carrying out this important aspect of their public mandate. Their current emphasis on partnerships with industry and rapid drug approval conflicts with the public’s expectation that these agencies exist to protect them by restricting approval to drugs that have been thoroughly tested and are likely to be free of serious risks.”
In September 2006, a long-awaited report from the U.S. Institute of Medicine, part of the National Academies that advise Congress, called for a major shake-up in the way the FDA approves and monitors drugs.
Recommendations included putting symbols on the package labels of all new drugs to warn consumers that the product has no track record. The experts also suggest that every new drug should undergo a mandatory re-evaluation five years after hitting the market. The report stipulated that the funding boost needed to make these changes should come from the public purse, not user fees.
Editors of the influential Harvard Health Letter listed these findings as one of the Top 10 health stories of 2006, noting that calls for FDA reform are getting “louder and clearer.” Drug safety advocates here are clamouring for a similar overhaul of Health Canada.
Information was available, but not disclosed
Drug companies are also often less than forthcoming about problems with their drugs, as was the case with Vioxx. As drug safety advocate Dr. Joel Lexchin says, there were two theories about the initial VIGOR study: that Vioxx was causing problems or that the other drug, naproxen, was protective. “Merck chose to push the latter and was not willing to investigate the possibility that Vioxx may be harmful,” says Dr. Lexchin, a professor in the School of Health Policy and Management at Toronto’s York University. “So this is an example of companies choosing profit over health.”
Drug companies can also be fierce in their pride about their medications, and will resist all attempts to criticize them, says Barbara Martinez, who spent years as a drug company salesperson. “When a drug company has a pill, it’s like their baby and they protect it as fiercely as a mother would protect her child,” says Martinez, who now works for a benefits consulting firm in Toronto. “These drug company people, we all love our pills and we believe in them.”
Indeed, it appears that Merck was aware of the cardiac effects of Vioxx for years before the drug was withdrawn, but fought to keep those safety concerns from dampening sales.
After the recall, Dr. David Graham, a scientist at the FDA, said he had alerted his employers to the pattern of cardiovascular risk, but his concerns were ignored. The move typifies a documented reluctance on the part of FDA staff to acknowledge that a drug their scientists worked to approve could be flawed.
Both the FDA and Health Canada take their lumps for having what critics regard as a too-cozy relationship with industry. In Canada, critics maintain that Health Canada’s current emphasis on partnership with industry compromises its ability to do its main job – protecting the public from unsafe drugs.
Drugs are pushed beyond their indications
According to the Archives of Internal Medicine report, Merck spent close to $161 million US on direct-to-consumer advertising in 2000. Just as Hollywood has a “blockbuster” mentality for their films, so does the drug industry with their fledgling medications. The end result is that new drugs like Vioxx are greased with advertising dollars. The drugs end up being taken by millions of people before we have any evidence of how they will perform in the real world.
Vioxx was supposed to be used by people who were at risk of the stomach problems that the older medications could cause. After the drug was recalled, a study published in the Archives of Internal Medicine showed that 73% of the patients in a U.S. database were at very low or low risk of developing gastrointestinal bleeding from NSAIDS. Doctors term this phenomenon, in which drugs are used beyond its targeted group, “therapeutic creep,” and it is seen in many other new drugs. Denis Piquette, president of Ogilvy Healthworld Montreal, a healthcare communications firm, notes a trend towards drugs being mass marketed just after the launch, when there’s a lot we don’t know about them. He asks: Would you fly in a plane whose captain pushed it beyond its tested performance range? Piquette, a veteran of the drug industry, says companies need to stop withholding information, just so they can try and sell to a wider market. “These drugs will still be blockbusters,” he says. “They’re still going to sell billions of dollars, but let’s provide factual, honest information so people can make an honest decision. To me the marketplace does not lie.”
In all the debates about our drug safety system, many critics say we simply have too many. As it stands, a drug doesn’t have to be better than existing drugs to get on the market, it just has to be better than placebo. Drug industry watchers like Dr. Lexchin speak wistfully about Norway in the mid-1990s. Up until 1996 when Norway harmonized its drug approval process with the European Union, there was a “medical need” clause. If a drug couldn’t be shown to be better, safer, or more convenient than some existing product, it could be turned down for approval.
But, of course, Canadians clamour for the latest medications, and I, with my throbbing headaches, was no exception. These days, I am blessedly free of sinus infections. After years of allergy shots, antibiotics and nasal sprays, the infections just disappeared one day.
I am more vigilant about medications and study pharmacy handouts carefully. As drug safety advocates say, consider any new reaction you experience after starting a drug to be the result of the medication until proven otherwise.
Real world treatment means that responses will vary from individual to individual. When I discovered my reaction to Levaquin, I donated my unopened – and expensive – refill to my doctor for a patient without a drug plan to use. It doesn’t take a biostatistician to see that what harms one person could cure another.
“I know people who, if a drug reduced the chance of a heart attack by one percent, they would take it,” says James McCormack. “And I know a lot of people who wouldn’t. Neither is wrong.” But he needs to know the true risk, he adds. “I need complete information.”