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March-April 2011

Why Canada’s drug-approval process isn’t as safe as you think

Elizabeth Wright

Bullets spilling from a pill container

Photo by Joanna Pecha

On March 18, 2000, Terence Young was at home catching up on the weekend paper when his 15-year-old daughter, Vanessa, came to ask his permission to go out with some friends that evening. Exhausted and not relishing the idea of another conversation about Vanessa’s curfew time, Young asked her to wait until after dinner. There was nothing remarkable about it.

But as Vanessa turned to leave, she suddenly went limp and collapsed, her head making a loud thump on the carpeted floor. Young ran to her, calling out to ask whether she was okay, thinking momentarily that it could be a joke, an overdramatic gesture by his teenage daughter. It wasn’t. As she lay motionless on the floor, Young frantically felt for a pulse, finding the spot on her neck where his first-aid training had taught him to press his fingers, but there was nothing. An ambulance rushed Vanessa to the hospital, and an exhausting, haunted night followed as the family kept vigil in intensive care. The next day, Vanessa Young died.

Her cause of death was later determined to be cardiac arrest, caused by the effects of Vanessa’s bulimia nervosa and possibly an undiagnosed underlying heart defect. But there was another factor: Vanessa had been prescribed a drug called Cisapride—better known by its trade name, Prepulsid—to assist her digestion and prevent vomiting. Terence Young was later to learn the drug had been linked to irregular heartbeats and other cardiac problems. In July 2000, Janssen-Pharmaceutica Inc., a subsidiary of drug giant Johnson & Johnson, voluntarily pulled Prepulsid from U.S. pharmacy shelves. In August 2000, Health Canada pulled it from the Canadian market. On April 24, 2001, a coroner’s jury concluded that Vanessa Young’s arrhythmia and cardiac arrest resulted “from the effects of bulimia nervosa in conjunction with Cisapride toxicity and possibly an unknown cofactor such as congenital cardiac defect.”

The potential danger of Prepulsid was known, but key information about the drug didn’t make it to the right people at the right time. Eventually the right decision was made—but it was too late for Vanessa Young.

Canada’s drug-approval process suffers some serious flaws. The proceedings lack transparency; scientific data often goes fully or partially unpublished; once on the market, approved drugs seldom receive long-term monitoring for adverse effects; compared to other countries, drug labelling is less rigorous; and the whole process is paid for, in large part, by the same companies it is supposed to be regulating.

To be fair, Health Canada, the ministry responsible for approving pharmaceuticals, is often in a difficult position: patients and doctors want effective treatments made available quickly, but the department’s job is to thoroughly test drugs for safety, which takes time. Speeding drugs to market and protecting public health are two mutually exclusive goals, afflicted at every stage by interests that are often financially, and sometimes emotionally, vested. And at every stage, the pharmaceutical companies themselves are there, embedded in the approval process.

The result is a system with conflicting loyalties, bizarre blind spots, and, sometimes, dangerous outcomes. Why is it that Canada lags so far behind in providing an open, accessible drug-approval process? I sought out some of Canada’s leading experts on health policy and drug safety to try and understand what in our drugapproval system is broken—and how we can fix it.

Part of the problem of understanding Canada’s drug-approval process is that so much of it takes place behind closed doors.

“The way that we deal with drug approvals is actually quite different than the U.S., in that theirs is a much more open process,” says Dr. Barbara Mintzes, assistant professor in the department of anesthesiology, pharmacology and therapeutics at the University of British Columbia. When the U.S. Food and Drug Administration, for instance, approves a drug for the market, the full review report is published online. Expert advisory committee meetings are open to anyone and transcripts are published on the FDA’s website. The public is invited to submit input, and scientific reviewers’ comments are also made public. Almost none of that happens in Canada.

Dr. Joel Lexchin, a professor at the School of Health Policy and Management at York University in Toronto, agrees that lack of transparency is a problem.

“The FDA demands that drug companies submit the raw, clinical data,” says Lexchin. “Then they will do their own reanalysis of the data to make sure that the way the companies analyzed it is appropriate.” Drug trials in the U.S. are also catalogued with redacted information in an online registry. “Not only do you know what trials were started but you’ll be able to see what the results of those trials are,” says Lexchin. “Health Canada doesn’t require the posting of trial results.” In contrast, the comments of Health Canada researchers reviewing drug company applications are never made public. In fact, the public may not even find out that a drug is under review.

“The drug-approval process in Canada is secret,” says Mintzes, “in that when a drug is being considered for approval, there’s no announcement to the public by Health Canada to say that’s happening. It’s up to the company whether or not they want to publish the clinical trials [they submit] and often they will decide to publish only a subset of their studies.”

Health Canada’s approval process, then, is a kind of black box: drugs go in one end, and some emerge at the other, but what exactly transpires inside to influence that decision is unclear. (Health Canada’s only response to interview requests for this story was to refer me to its website.)

Many critics say that money exerts too big an influence on approvals. The biggest culprit is user fees, in which pharmaceutical companies pay the government to fund the approval process. User fees were introduced in 1995, partly in response to federal budget cuts, based on the idea that, because they benefit from having their drugs for sale, drug companies should shoulder some of the cost of approving them.

“I think this is a mistake,” says Lexchin. By 1999, the Therapeutic Products Directorate, the Health Canada department responsible for assessing drugs’ safety and efficacy, got close to 70 percent of its budget from the companies it was supposed to be regulating. Today, Lexchin claims, it’s about a third, though recently proposed regulations from Health Canada aim to cover 50 percent of TPD’s budget with user fees. At that level, critics question who’s actually setting the agenda—the pharma companies or the public interest?

“User fees are totally inappropriate,” says Terence Young, Vanessa’s father, who is also a Conservative MP in Oakville, Ontario, and founder of the advocacy and research group Drug Safety Canada. “They create a situation where a drug reviewer feels that the company is like a client, that they should be working fast to get this drug approved because these companies are paying up to 50 percent of the cost of having drugs reviewed for approval. That is an inappropriate relationship.”

After the death of his daughter, Young became a fierce critic of the pharmaceutical industry and wrote about the civil and classaction lawsuits subsequent to Vanessa’s death in his book Death by Prescription. He echoes the sentiment—common enough to have become cliché—that drug companies have put profits above patients.

“Big Pharma’s profits are multiples, in most cases, of other industries,” says Young. “You cannot overstate their influence on modern medicine. We spend more money on pharmaceuticals, both prescription and non-prescription, than we do on doctors.”

In Canada, the effect of user fees is not just that it makes the drug companies clients of Health Canada, expecting value for money; the user-fee structure also influences approval deadlines. The 2004 User Fees Act gives Health Canada a set timeline to approve new drugs; if the agency misses its deadline, there are financial penalties: user fees for the following year are cut. “If you go, say, 20 percent over deadline, then next year the user fees are going to be cut by 20 percent,” says Lexchin.

That pressure to approve, says Young, inevitably influences the decisions of Health Canada reviewers. “Drug reviewers should not feel that their job depends on, in any way, approving a drug,” he says. “You approve a drug when you believe it’s effective and safe,” he says. “You don’t approve it by any given date. And if it’s doubtful, you don’t approve it.”

Lexchin and Young both argue for the elimination of user fees, to make the whole process publicly funded and cut down on industry influence. Young proposes a mandatory levy on pharmaceutical companies so they still fund the process, but without the strings attached.

Once a drug is on the market, additional problems crop up: follow-up research on drugs is relatively rare, and drug labelling is inconsistent.

With few exceptions, once a drug reaches the market and is being prescribed routinely by doctors, there is no system evaluating the long-term effects or adverse reactions for prescription drugs.

“Health Canada, at this point, doesn’t have the ability to require companies to undertake post-market trials; all they can do is ask companies to do it,” says Lexchin. He draws attention to a Health Canada policy called Notice of Compliance with Conditions that approves the drug but requires further testing. “They will approve it on the requirement that companies undertake additional trials to show that what looks promising actually is promising.”

But there’s no reporting on the progress of meeting those conditions. “You have drugs that were approved nine years ago under this policy that still haven’t met their conditions, and you can’t find out why because it’s considered confidential,” says Lexchin. “With the cancer drug Iressa, the trials showed it didn’t work, but Health Canada still left it on the market.”

Lexchin believes it’s probably still on the market because some cancer doctors think that, although it doesn’t work statistically, it might work on individuals. “We’re always dealing with statistics,” he says.

Monitoring of adverse drug reactions across the country is largely confidential. Young says it’s meaningless: “Health Canada never insists follow-up studies be done; they don’t even call the drug company back and say, ‘Did you do those studies?’ Because they get approval, and it’s open season.”

Pharmaceutical labels are notoriously difficult to read, and potential side effects or drug interactions get lost in a sea of technical and legal language. “They’ll say, ‘See look, here on page 19, right near the bottom it says you shouldn’t take it with grapefruit juice, so don’t say we didn’t warn you!’” says Young. “The labels are written by lawyers, for lawyers, to confuse. They should issue effective safety warnings in plain language so patients and doctors will know when a drug is safe.”

To try and reform some of the problems he and many doctors see with the Health Canada drug-approval regime, Young has tabled a private member’s motion to create an independent drug agency that focuses purely on safety. “If Air Canada had a crash of one of their planes, you wouldn’t ask Air Canada to investigate the crash. So when a drug company has a crash of its drug, like Prepulsid, why would we ask them to investigate their own crash?” he asks. “Prescription drugs used as prescribed in hospitals with no error are the fourth leading cause of death in our society. That’s why everybody has an interest in this.”

While the picture is troubling at the federal level, experts say provincial drug-review bodies do a better job of sorting pharmaceuticals by safety and efficacy. Because the provinces bear most of the cost of providing health care through provincial health plans, they have traditionally done a better job of prioritizing drugs that actually work well, since they don’t want to pay for ineffective treatments. Even so, the provincial bodies suffer some of the same problems of transparency and accountability.

Once Health Canada has approved a drug, the second level of screening is the Common Drug Review, a body funded jointly by the federal government and the provinces. There, a group of experts examines new drugs coming to the market. The provinces, though their processes vary, are responsible for deciding what drugs will go on pharmacy shelves, how much they will cost, and how to best use provincial dollars to pay for them.

“What they will do is look at that drug and compare it to other treatments in its class. They will determine whether the drug is costeffective to be used by the provinces,” says Alan Cassels, a drug policy researcher at the University of Victoria’s faculty of human and social development.

“Health Canada might review a dozen cancer drugs and say they’re all safe and efficacious. But that doesn’t help the provinces decide if they should fund it or not,” says Cassels. “And that’s really the information the provinces need in order to make decisions about whether they should be covered.”

“Health Canada’s standard of efficacy is so low that all you have to do, because of so-called commercial rights, is prove that your new drug works slightly better, even one percent better, than placebo and you can get it approved based on efficacy,” says Young. “The provinces, on the other hand, because they’re concerned with money and the cost of the drug, they actually demand a higher standard of efficacy than Health Canada.”

Two projects are trying to address some of these problems, to make at least part of Canada’s drug-approval process more transparent and open to the public.

Set to launch this spring, the pan-Canadian Oncology Drug Review, or PCODR, is a national review board specifically for cancer drugs. Funded by the provinces (except Quebec, which opted out) PCODR will make recommendations to the provinces on which cancer treatments would be most effective to fund. Notably, the PCODR review process will be much more open and transparent than the current structure.

“I’m very pleased that PCODR is going to include patient representatives,” says Dr. Chuck Blanke, head of medical oncology at the B.C. Cancer Agency and PCODR steering committee co-chair. “Everything is going to be as transparent as possible. Reviews will be posted on the website and there will be invited commentary from pharmaceutical companies, but also from patients and patient-advocacy groups.”

The Therapeutics Initiative is another example of an effort to pry open the approvals process. The initiative acts as an independent drug bulletin. Researchers look at the clinical trial evidence of safety and effectiveness of drugs after they’ve been approved for marketing, and the “independent” part is what’s key. “With independent drug bulletins, there’s a commitment not to have any financing or advertising from pharmaceutical manufacturers,” says Mintzes, who does research for the group.

Mintzes agrees that the provinces generally have a more transparent, better-informed drug-approval process. The Common Drug Review, she says, has improved the situation because provinces can share the cost of research, eliminating expensive duplication. “I think it’s been a big advance, and useful particularly for the smaller provinces, not having to review the same scientific data separately. Recommendations are posted on the Common Drug Review website, so it creates a situation of greater trust.”

Time constraints remain a problem, however. “Clinical reviewers are being asked to do a full systematic review within a short time frame of six weeks,” says Mintzes. “That’s a pretty short period of time for the depth of the report being expected. They get the same pressure from industry in terms of drug approval for marketing—pressure for the decisions to be made very quickly.”

And like at the federal level, technical details are still bound by confidentiality agreements. “Which is crazy,” says Mintzes, “if you think that this is evidence of potential for benefit or harm of a pill or medicine that a person is actually going to take. Those people, and the doctor who is recommending it, and the whole community, should have access to the full body of scientific evidence.”

Pharma companies generally come across as the villain in these stories, and for good reason: these are large, multinational corporations that reap huge profits exploiting government-aided monopolies on life-saving drugs. Stories abound of Big Pharma wining and dining doctors to cajole them into prescribing more. Of flying them to Caribbean resorts for what in the industry are called “continuing medical education” sessions, but which are actually just marketing junkets. Of drug-company sales representatives quietly persuading doctors to prescribe “off-label,” for conditions the drug wasn’t originally intended.

But experts say that what the pharma companies don’t do can be just as harmful to patients.

Fewer than 10 percent of new drugs are considered “breakthroughs” that substantially improve efficacy or attack a disease with a novel approach. The rest of the business consists of making slight tweaks to already-successful compounds. “It’s always these ‘me too’ drugs,” says Cassels. “You have a product, and if you modify a few molecules you can come up with your own version that’s almost the same but different enough so that you can get your own patent. ‘Me too’ drugs … are much less expensive to develop.”

“There are lots of diseases out there that we just don’t understand enough about,” says Lexchin, “and putting all your money into looking for drugs that are actually going to cure something—when you’re dealing with processes that are not well understood—is a big gamble that drug companies don’t want to take. So they’re going to go for, in general, the easy processes for new drugs, rather than looking for these real major breakthroughs.”

Frustratingly, there have been breakthroughs in Canada that, because they aren’t patented—and therefore are unlikely to be highly profitable—struggle to find funding even to finish clinical trials.

For example: dichloroacetate, or DCA, an inexpensive substance that has been used for decades to treat metabolic disorders. Researchers at the University of Alberta believe it could be used as an effective treatment for many forms of cancer, too. Research has shown that DCA can cause regression in several cancers, including lung, breast, and brain tumors. The next step is to run clinical trials on human cancer patients. But these trials may have to be funded by charities, universities and government. Drug companies aren’t interested, because without a patent, there’s little money to be made.

“Because drugs tend to be developed by for-profit companies, they’re only interested in products where they’ll have a monopoly for whatever the patent period turns out to be,” says Lexchin. “If they’re going to put all this money into it, then they’re going to want to be sure that nobody else can make that drug for whatever that patent period is. These things tend to be orphans.”

As Cassels confirms, “So much of what drives drug discovery is the ability to patent stuff. If they discovered that apple seeds cured cancer, no one would ever hear about it. Sad, but true.”

It doesn’t have to be this way. Despite the seemingly insurmountable obstacles facing those who would like to see a more open, transparent drug-approval process, the more engaged the public is through knowledge and dialogue, the better chance we have in creating a fully accountable process.

The experts concur that a more transparent, independent drug-approval process would raise Canada’s drug-approval system to levels already attained by many European countries and the U.S. One thing is for certain: an approvals process funded largely by the pharmaceutical industry itself is unacceptable and represents a threat to patient safety.

Prioritizing efficacy and thorough, truly independent safety testing will help create a situation of greater trust. Research focused on developing better drugs through patent reform is not an outlandish gamble, and should be recognized as inherent to the pharmaceutical business model and supported by government regulation. Safe, effective drugs are an integral part of our health-care system. But the current approval process is needlessly secretive, incomplete, and vulnerable to private interests. What’s at stake is not simply the public’s right to know, or wasted government spending, but the health and well-being of millions.

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