I
have been a consumer advocate for nearly 30 years, writing
about medical research and critically appraising clinical
trials. I'm still surprised that I could have been at
it so long without fully understanding-until about two
years ago-that it is not unusual for drug company-sponsored
trials to withhold data about adverse drug reactions.
I am referring to trials published in high-profile medical
journals.
I
learned this while writing about the cholesterol-lowering
drugs, statins, when I was putting together a poster for
the Cochrane Collaboration's 2003 conference. My work
has long focused on the selling of drugs to healthy people-drugs
to reduce a risk factor, drugs that healthy people will
take for the rest of their lives. I have always been interested
in the way we Americans have come to accept the idea that
a risk factor should be treated as if it were a disease.
Bisphosphonate drugs for bone loss, postmenopausal estrogen
to improve lipid profiles-that sort of thing. The emphasis-when
selling healthy people the idea of lifelong preventive
drug therapy-is on the benefits. We don't hear much about
the drugs' risks.
For
my Cochrane Poster, I summarized the proven benefits of
statins for people who do not have heart disease-just
a few risk factors like high cholesterol. I found only
one review of the five major mostly primary prevention
trials that had compared a statin drug with a placebo.
All five were drug company-sponsored and published in
leading medical journals. Here's what jumped out at me.
The authors of that review, who are based at the University
of British Columbia , wrote in their on-line publication,
Therapeutics Initiative, that only two of the five trials
had reported their serious adverse events (SAE). The UBC
authors reported that they had asked the investigators
from other three trials for their SAE data and were refused.
Working with what they had (data from only two of the
trials), the UBC authors found that the benefit of statins
was far more modest than doctors and the general public
have been led to believe. There was approximately a 1.8%
lower rate of non-fatal heart attacks in the male study
participants, but this was offset by the 1.4% increase
in SAE among the statin users. SAE were defined
as "any untoward occurrence that results in death, is
life-threatening, requires hospitalization or results
in prolonged hospitalization, or significant disability."
[1]
It
troubled me to see that statins aren't anywhere near the
lifesaving medications they're purported to be. In fact,
this review showed that for primary prevention, only middle-aged
men under 70 benefited from these drugs. Not only was
the benefit small, it was canceled by the risks. But it
was far more alarming to learn that we do not have the
full story on the safety of statins because three of the
trials had refused to release all their SAE data [2]
.so it is quite possible that the risks could considerably
outweigh the benefits. But we simply do not know. Keep
that in mind the next time you see a doctor quoted in
the media, telling us that statins are safer than aspirin.
I would learn later that this withholding of data is not
unusual. In fact, sometimes the lead investigator has
received only incomplete data on the drug.
I
have since relayed my "revelation" to other experienced
consumer advocates and every one of them said that they
never heard that published drug trials often provide incomplete
data about safety. I have also reported this to physicians
and researchers who also say that they never heard of
this withholding of SAE data. In fact, most deny that
it is so.
How
can healthy people who are on lifelong drug therapy make
an informed decision about their medications when drug
companies are allowed to withhold such important information?
To go beyond statins for a moment, I've found that it
is not unusual for anti-hypertensive drug trials to show
that the cardiovascular death rate is reduced by the drug.
But the overall death rate is no different from
that of placebo group. Often this finding goes unexplored.
How
prevalent is the non-reporting of SAE? A study by Ioannidis
and Lau surveyed the safety reporting of new medications
in 192 randomized drug trials, which altogether included
over 130,000 participants. Only 46% of these trials reported
or specified the drugs' SAE. Overall, the researchers
found the space allocated to safety results was equal
to the amount of space devoted to contributor names and
affiliations. The conclusion: "The quality and quantity
of safety reporting vary across medical areas, study designs,
and settings, but they are largely inadequate." 3
I hope that the IOM report will shine a light on this
issue and related questions like:
Why
do medical journal editors let the trial sponsors get
away this these glaring omissions of important data? Why
aren't these omissions "redflagged" in the abstract of
every published trial that fails to provide complete safety
data? Why do these editors allow drug company-sponsored
trials to express their results in relative risk reduction
terms and omit the more-understandable-to-consumers absolute
risk reduction? Is it any wonder that many consumers overestimate
the effectiveness of their prescription drugs?
We
must find a better way to quickly detect SAE once drugs
are on the market.
I
urge the IOM to encourage more government-funding of epidemiological
studies like the one announced last year by Kaiser Permanente.
It found a greater incidence of heart attacks and sudden
deaths among the enrollees who had been taking higher
than normal doses of Vioxx. Everything should be done
to encourage Center for Medicare and Medicaid Services
to continue using its database to determine the safety
and effectiveness of drugs prescribed to people on Medicare
and Medicaid. And registries should be established for
all clinical trials from their onset to prevent drug companies
from hiding the existence of clinical trials that show
negative results and from withholding SAE data from their
trials [see related article].
I
thank this committee for taking on this important issue
and giving me the opportunity to present my perspective.
[1]
Therapeutics Initiative Evidence Based Drug Therapy.
Do statins have a role in primary prevention? University
of British Columbia . Vancouver , April-May-June 2003.
www.ti.ubc.ca
The reviewers attempted to answer the question:
What is the overall health
impact when statins are prescribed for primary prevention?
" In the 2 trials where serious adverse events
are reported, the 1.8% absolute reduction in myocardial
infarction and stroke should be reflected by a similar
absolute reduction in total serious adverse events; myocardial
infarction and stroke are, by definition, serious adverse
events. However, this is not the case; serious adverse
events are similar in the statin group, 44.2%, and the
control group, 43.9% . This is consistent with the possibility
that unrecognized serious adverse events are increased
by statin therapy and that the magnitude of the increase
is similar to the magnitude of the reduction in cardiovascular
serious adverse events in these populations."
[2]
Walsh J and Pignone M. Drug treatment of hyperlipidemia
in women. JAMA, May 12, 2004. "For women without cardiovascular
disease, lipid lowering does not affect total or CHD mortality.
Lipid lowering may reduce CHD events, but current evidence
is insufficient to determine this conclusively.".. The
risk for total mortality was not lower in women treated
with lipid-lowering drugs, regardless of whether they
had prior cardiovascular disease or not. In the primary
prevention studies, there was no reduction in either CHD
or total mortality. This may be because lipid lowering
does not affect total mortality in women or because there
were few deaths in the small, relatively healthy cohorts
of women studied, even after summarizing study findings.
In most of the studies, the length of follow-up was only
2.8 to 6 years. It is possible that a reduction in total
mortality might have been observed with a longer duration
of follow-up. For secondary prevention, CHD mortality
is reduced, but total mortality is not. Possible explanations
include chance, the limitation that not all studies reported
both CHD and total mortality, or not all studies could
be included in each summary estimate. Another potential
explanation might be an increase in a competing cause
of mortality, for example, an increase in hemorrhagic
stroke with lipid-lowering therapy. However, information
on the causes of non-CHD mortality is not available for
all the trials, so this possibility cannot be proven.
Publication of cause-specific mortality for
many of the larger trials could help to clarify the association
between lipid-lowering therapy and total mortality."
3
Ioannidis JME, Lau J. Completeness of safety reporting
in randomized trials of seven medical areas. JAMA 2001,
Jan 24-31.
