By Jenny Manzer - 2005 Michener-Deacon Fellowship recipient (published December 2006)
Damage Control: It’s on the market, so now what?
Gulping a daily dose of statins to tame your cholesterol might lead
to amnesia. Taking a pill to cope with impotence could cause sudden
vision loss. Hormone therapy probably won’t help a woman’s heart,
but it might increase her risk of incontinence.
These are just some of the unexpected side-effects of popular drugs
that only came to light after they were on the market and being
taken by millions of people. While some of these effects are rare,
adverse drug reactions are as common as city smog. More than one in
three Canadians report having personally experienced an adverse drug
reaction, according to a 2003 Health Canada survey.
Estimates suggest half of all new drugs on the market end up having
side-effects that aren’t seen in the initial testing phase - and many
of them are serious. A 2002 U.S. study, published in the Journal of
the American Medical Association, estimated that one in five new
drugs will eventually receive a “black box” warning or be pulled
from the market altogether. No one knows for sure how many Canadians
die from drug reactions - studies have suggested anywhere from 1,400
up to 10,000 people a year - but it’s clearly a major health problem.
The clinical trials that test our medications are usually shorter
than real-life treatment and done in a select group of “healthy”
patients, so we must do a good job of tracking how drugs perform in
the real world. Unfortunately, by most accounts, we don’t. Critics
say a long history of under-funding has made post-marketing
surveillance the weakest arm of Canada’s drug safety system.
While there’s agreement that post-market monitoring needs an
overhaul, there are differing ideas about how to do it. Dr. Geoffrey
Anderson likens our post-market surveillance system to a stool that
needs three sturdy legs to function. In his analogy, one leg tracks
adverse drug reactions. The second does randomized controlled trials
after the drug is on the market, which involves assigning a group of
patients to receive the medication then comparing them to another
group, who receive a placebo. The third leg performs observational
studies, which simply follow patients who are already taking the
drug to see how they fare.
Dr. Anderson, a professor of Health Policy, Management and
Evaluation at the University of Toronto, says to date, Canada has
tended to focus post-market monitoring on adverse drug reporting.
“We seem to be putting a lot of investment into adverse drug
reporting, which is one very important part of the process and
certainly a good way to pick out rare, very serious idiosyncratic
side-effects,” he says, “but it doesn’t do a very good job of
identifying adverse effects that are more common. I guess a classic
example would be Vioxx and heart attacks.”
Other experts say Health Canada should keep drugs on a tighter leash
once they’re on the market. One way to do this would be through
conditional licensing. A drug would only be approved if the
manufacturer agrees to a certain set of conditions, such as
promising to do large, follow-up studies of its real-world use. That
way, the drug is still available promptly, the public gets
information about how it performs and Health Canada has a mechanism
to remove the drug if problems emerge.
Conditional, or probationary licensing, has its cheerleaders. The
House of Commons Standing Committee on Health, which issued a report
on prescription drugs in 2004, suggested our post-marketing
surveillance system needs major changes. The committee recommended
that Health Canada make licensing of new drugs probationary to
ensure that post-marketing surveillance is carried out diligently
after the drug is approved.
As it stands, Health Canada rarely issues a drug approval - called a
Notice of Compliance - with conditions. In fact, there were only 27
Notice of Compliance with Conditions issued from 1998 to 2005,
according to figures from an Access to Information request. Most of
the conditions given in those 27 approvals have yet to be fulfilled.
As of September 2005, only nine of these conditions had been
completed, according to documents from an Access to Information
request.
In practice, Health Canada is faced with a bit of a conundrum, says
Dr. Anderson. Regulators must deem a drug to be safe or not safe, so
these Notice of Compliance with Conditions are usually only given in
cases where the benefit of the drug could be big - which is not the
case with most new medications, he adds. Typically these types of
approvals are used for treatments involving life-threatening
conditions such as AIDS or cancer.
Dr. Supriya Sharma, associate director general of Health Canada’s
Therapeutic Products Directorate (TPD), says the Notice of
Compliance with Conditions is given in cases where a drug shows
promising efficacy for a serious condition, not when there are
safety concerns. But Dr. Sharma says the TPD is now studying the
entire regulatory framework and weighing whether it needs different
gradations of licensing to provide more leverage. “We’re really
looking at it to see what’s the best way to do ongoing evaluation. I
think in the previous system, we really thought about on the market,
off the market, but this is focusing on the continuum.”
One problem with conditional licensing is that drug companies have a
poor track record of following through with the promised trials. A
2000 study by the U.S. lobbying group Public Citizen looked at all
the new drugs the U.S. Food and Drug Administration (FDA) approved
from 1990 to 1999 that required some kind of post-market commitment
from the company.
Public Citizen found that only 13% of the study commitments made for
drugs approved from 1990 to 1994 had been fulfilled. None of the
promised studies for drugs approved from 1995 to 1999 had been done.
Worse, Public Citizen found the FDA has no power to ensure these
promises are kept. The finding was confirmed by the FDA’s own
researchers last year, who found that manufacturer compliance in
fulfilling post-market studies was poor, with results overdue years
after they were required.
The idea that both the U.S. and the Canadian systems lack the teeth
to compel drug companies to complete required studies leads some
experts to support another school of thought: gaining leverage at
the formulary level, when we decide if our public plans will pay for
it.
The drug enters the market, but will be only be added to the public
formulary - or list of medications our healthcare system will
fund - under certain terms and conditions. For example, the public
payers could call for a well-designed observational study or a large
randomized trial once the drug is on the market. These types of
studies could be done by the drug company, or by the public sector,
as was the case with the Women’s Health Initiative, the large U.S.
study that revealed the risks of hormone therapy in 2002.
Boosters of this approach, such as Dr. Anderson, say that trying to
change the system at the licensing level would be a logistical
migraine, especially since it would draw in legal baggage from other
countries because of various rules and statutes. A better,
made-in-Canada solution, he insists, would be to reassess the drugs
once they are being considered for the public formulary, or even for
inclusion into private insurer plans. The provinces could give a
drug a provisional listing, he argues. If the drug didn’t perform
well in the real world, the provinces could simply stop paying for
it. “So my sense is that the real area where we have traction is not
the federal level, but rather at the provincial level,” he says.
Dr. Anne Holbrook, director of clinical pharmacology at McMaster
University in Hamilton, agrees that changing the system at the
licensing level would be odious. Given the influx of expensive
medications on the market, she can envision a system in which
approval by Health Canada is only the first step in the public
reckoning of a new drug. If a company wanted the drug included on
the formulary, it would have to go through more hoops.
Health Canada doesn’t seem to have much power once a drug is on the
market, but there is hope for the formulary, says Dr. Holbrook, who
sits on the Canadian Expert Drug Advisory Committee, an independent
board that makes recommendations to publicly funded drug plans. “The
way things are going at least, the provinces and the feds are
beginning to work more collaboratively to have a kind of a common
front.”
Dr. Holbrook says researchers had hoped that the Notice of
Compliance with Conditions would be a useful tool to retain some
control over drugs on the market and offset faster approval times.
Unfortunately, this kind of conditional licensing hasn’t panned out
the way many of her colleagues had expected, she says.
Experts say inadequate funding for post-market surveillance is part
of the problem. While the problem of slow drug approval times has
received a lot of attention from Health Canada—and a big chunk of
cash—post-market monitoring is still sitting in coach class by
comparison.
In 2006, the budget for the Therapeutic Products Directorate, which
handles new drug submissions, was $42 million a year. The Marketed
Health Products Directorate (MHPD), which monitors the safety of
drugs on the market, received only $13 million a year. The MHPD
receives no industry funding, while the TPD gets more than half of
its budget from industry user fees.
Mary Wiktorowicz, chair of York University’s School of Health Policy
and Management, says chronic under-funding over the years has led
Health Canada to its current tight relationship with industry.
“I think that’s part of the weakness with Health Canada and why they
tend to rely on industry so much, because they haven’t had the
resources. They’ve had to find other ways to work with industry, get
industry to comply with their standards because they are
under-resourced.”
Colleen Fuller, co-founder of the Vancouver-based consumer group
PharmaWatch, says post-market monitoring has long been hungry for
cash. “Within Health Canada, within the whole area of Therapeutic
Products, it is the poor cousin within the entire chain,” says
Fuller.
“From my point of view, it’s basically because there is no interest
in it from the drug industry itself and the job of Health Canada is
to secure the investment environment. This is what it boils down to.
And if the drug industry isn’t interested, then nor is Health
Canada.”
Still, both the budget and staff at the MHPD are growing, as its
director, Dr. Marc Berthiaume, is quick to emphasize. In 2006, his
department had about 120 staff, up from just 63 in 2003. Although
the directorate had only 15 people reviewing adverse drug reactions
for pharmaceuticals, that number is also on the rise. Asked if 15
are enough, Dr. Berthiaume says they’re moving in the right
direction.
“I don’t think we could grow faster than that. You need to train
these people. You need to develop the work process around them, and
pharmacovigilance or regulatory medicine is not something that you
can have at university as a course, so basically part of it is
training at work.”
The 2006 numbers seem scrawny, however, compared to the 182
assessment officers who worked on drug reviews at the TPD, which had
a total staff of about 525 people.
In the 2004 report, the Standing Committee on Health expressed
concern over the lack of staff to address adverse drug reaction
reports and called for additional resources to assess reports and
convey the findings back to consumers.
Dr. Joel Lexchin says we have to make it clear to the public that
reporting adverse drug reactions is important, and to make it easier
to do so. We also have to give feedback to patients who file
reports. “You have to be seen to be doing something with the
information that you’re getting, so people don’t feel it’s
disappearing down a black hole.”
It’s not enough to sit and wait for good or bad news, insists Dr.
Lexchin, a professor at York University’s School of Health Policy
and Management. He says we need to set up a system of active
monitoring for certain drugs, particularly those used by high-risk
groups. “So you can set up a database whereby you record the names
and birth dates of, say, the first 50,000 people who get a drug and
you can link with things like hospital visits or hospitalizations or
death or cancer or doctor’s visits using other databases, and you
can see whether or not these drugs are presenting certain problems.”
Drug safety experts seem to agree that linked databases are the way
to go. Canada has a rich vein of data sources to mine, thanks to our
public healthcare system. In B.C., for example, every time a
prescription is filled, an electronic record is created that leaves
the patients anonymous, but tells us what drug they took and in what
dose. The information can then be linked to other data such as
hospitalization records, physician visits or mortality to determine
how people who took a given drug fared compared to those who did
not.
“I think Health Canada’s approach has been very narrow,” comments
Mary Wiktorowicz. Basic science has changed in areas such as biotech
products and so has health services research, she points out. We now
have access to databases that weren’t available a decade ago. “So in
terms of being able to monitor products when they’re on the market,
we have some powerful resources and a powerful research community
that is available to do that kind of monitoring that is not being
used.”
“Canada could be a leader in this area in terms of innovative
post-marketing surveillance,” she says, a refrain echoed by many
researchers.
These databases are being used sporadically. For example, the team
at the Institute for Clinical Evaluative Sciences (ICES) in Toronto
has done several studies of elderly patients using Ontario drug plan
data—but the information could be used to far greater advantage. Dr.
Anderson says the FDA tends to work strategically with
university-based researchers on observational studies and it also
has a large in-house scientific team, both of which Canada lacks.
Dr. Andreas Laupacis and colleagues from ICES have floated a new
approach to drug evaluation in Canada. Their idea, outlined in a
2003 Canadian Medical Association Journal (CMAJ) article, places
more emphasis on using the drug’s performance in the marketplace to
decide if provincial governments should add it to the public drug
plan. The group wants to see “centres of excellence in
pharmacosurveillance” set up across the country. Large, head-to-head
randomized trials could be done after the drug has been approved,
the team says. This will help determine the “relative benefits and
risks of competing medications in regular practice,” they write.
These centres of excellence could provide a badly needed network to
share data between provinces and detect trends in side-effects.
While we must do a better job tracking drugs, we also need to boost
adverse drug reaction reporting. By Health Canada’s own estimates,
as few as 10% of side-effects are currently being reported, though
other estimates suggest it may be as low as one percent.
Various parties have supported the idea of making adverse drug
reaction reporting mandatory, including former Health Minister Ujjal
Dosanjh and the 2001 coroner’s jury that made recommendations
following the death of teenager Vanessa Young, who had been taking
the stomach drug Prepulsid.
At the moment, Health Canada is still consulting on mandatory
reporting, according to Dr. Marc Berthiaume. Some drug safety
advocates are outraged that adverse reaction reporting is still
voluntary. Physicians are less keen on the idea. A Health Canada
survey showed that 45% of doctors oppose mandatory reporting.
Clinicians may regard reporting as a hassle, but some researchers
also doubt mandatory reporting will result in a better system.
Critics of mandatory reporting say it will be easy for physicians to
dismiss patient symptoms as not being drug-related. They also
question how all the data that flood into Health Canada will be
analyzed to produce meaningful information.
Dr. Andreas Laupacis of ICES says he suspects such a system would
result in an avalanche of minor adverse drug reaction reports. He
hasn’t filed a single report in his more than 20 years of practice.
He’s not alone. Only a small fraction of health professionals say
they have reported an adverse drug reaction in the past year - and
more than a third of doctors say they don’t even know how to file
one.
While Dr. Lexchin also doubts mandatory reporting will be a big
improvement, he stands by the importance of having the public make
reports. In a commentary in the CMAJ, he argues that these kinds of
reports capture problems, trends and nuances that can be missed by
only relying on formal studies, and suggests several ways to improve
the reporting system.
One interesting idea he notes is the British example of flagging new
drugs with black inverted triangles. The triangle symbol appears
beside the drug name in the formulary and reinforces the need for
physicians to report any suspected adverse reactions. In the U.K.,
these black triangle drugs undergo close monitoring for two years,
and the symbol stays until safety is established. This system could
be adapted for Canada, Dr. Lexchin argues, with symbols appearing in
our listings of drugs.
While adverse drug reaction reporting is still voluntary for health
professionals, drug companies must meet certain post-market
obligations under the Food and Drug Regulations. For example,
companies must forward any adverse drug reaction reports they
receive to Health Canada within 15 days. In 2004, Health Canada
started doing inspections of Canada’s health product manufacturers
and distributors to determine how well companies were complying with
post-market obligations. Health Canada completed 45 inspections from
September 2004 to August 2005, then another 18 from September 2005
to December 2005. The Health Canada department that does these
inspections draws more than 60% of its budget from user fees paid by
drug companies.
All of the businesses, which included both over-the-counter and
prescription drug companies, received a rating of “C.” This grade
indicated that they were found to be compliant with their regulatory
requirements with no observed “objectionable practices.”
Still, more than half of the companies who underwent these initial
inspections had “observations” noted which required some kind of
corrective measure. There were 35 observations noted, of which 12
were “major” - one level down from the most serious rating of
“critical.”
A company could receive a “major” rating for not reporting adverse
drug reactions within the 15-day time limit, or for not turning
their records of unusual failure of new drugs over to Health Canada
within 72 hours.
There are new initiatives underway, such as these post-market
inspections, and other innovative ideas in waiting in the wings. In
November 2006, Health Canada announced that it has awarded a
contract to supply a new computerized system for monitoring adverse
reactions to health products. Health Canada says the new system,
expected to be up and running in October 2007, will bolster their
ability to detect safety problems and allow for better analysis,
such as being able to track products over their entire life-cycle.
Still, advocates fear progress on post-market surveillance will
fizzle.
Several measures brought forward under the Liberal regime in the
wake of the Vioxx media flare have been delayed with the change of
government, including mandatory reporting and the creation of a
Health Products Safety Board. The board, announced in February of
2005, was intended to ensure transparency and encourage public input
into regulatory decision-making. A post-market surveillance strategy
was supposed to be finalized and implemented in 2005, but that has
also yet to happen, although there’s a draft document on the go,
according to Dr. Berthiaume.
Some drug safety advocates fear the political will to change the
system is gone - at least until the next major crisis. Unfortunately,
many experts also agree, there will be one. It’s just a question of
when.
“If you look at the history of adverse drug report monitoring in
Canada, it’s all been crisis-driven. It was set up in the shadow of
thalidomide,” reflects Colleen Fuller from PharmaWatch, referring to
the infamous drug that caused severe birth defects. It was pulled
from the Canadian market in 1962. “Nothing’s changed as far as I can
tell,” she says. “So right now the only thing that will get it going
is another crisis.”
Series Continues:
| The Painful Truth |
Trial Under Fire |
Taking Care of Business |
Damage
Control | Message in a Bottle |