Can Drug Clinical Trials Be Trusted?
Drug Safety, Drug Efficacy, and Clinical Trials: Your Frequently Asked Questions
By
Daniel J. DeNoon
WebMD Health News
Reviewed By
Louise Chang, MD
April 15, 2008 — Clinical trials are the gold standard for judging the
benefits and risks of new drugs. But new revelations suggest this gold standard is sometimes adulterated.
Today's issue of The Journal of the American Medical Association
suggests that a major sponsor of clinical trials, the drug company Merck,
may have used misleading statistics to downplay the risks Vioxx might pose
to people with Alzheimer's disease. Another
article in The Journal of the American Medical Association suggests that
clinical-trial and review articles about Vioxx often were written by
company-hired ghostwriters and later signed by researchers who had little
to do with the actual study or review.
Don't scapegoat Merck — other pharmaceutical companies do the same thing, suggest Catherine D.
DeAngelis, MD, MPH, and Phil B. Fontanarosa, MD, MBA. DeAngelis is
editor-in-chief of The Journal of the American Medical Association;
Fontanarosa is the executive deputy editor.
"Make no mistake — the manipulation of study results, authors, editors,
and reviewers is not the sole purview of one company," they write in a
scathing editorial.
Can we still trust clinical trials? Are the drugs we're now taking safe?
Here's WebMD's FAQ.
What do clinical trials test?
When a drug finally makes it through clinical trials and FDA approval,
here's what we know about it:
- The new drug, in combination with
standard treatment, is more helpful than standard treatment alone.
- If the trial tested one drug against another, the new drug is at least as
good as the other.
- Benefits of the new drug — for narrowly defined groups of patients — outweigh the drug's risks.
But there are a lot of important things clinical trials usually don't tell
us:
- Clinical trials don't tell whether a new drug works better than existing
drugs — unless the trial compared one drug to another.
- Clinical trials don't show that a drug is risk-free.
- Clinical trials usually don't show whether a drug is safe to take in
combination with other drugs, vitamins, or supplements.
- Clinical trials don't show whether a drug might have unexpected long-term
side effects.
- Clinical trials don't show how well a drug might work in people, such as pregnant or breastfeeding women, who weren't included in the study.
How are clinical trials supposed to work?
The clinical trial system is designed first to look at whether a drug is
safe enough for further testing (phase I clinical trials), then to look at
whether a drug seems both safe and effective (phase II clinical trials), and
then to compare the drug to an inactive placebo or standard treatment to see
whether the drug is both safe and at least minimally effective (phase III
clinical trials).
After a drug is shown to be safe and effective in phase III clinical trials,
the drugmaker may ask the FDA for approval. The new drug does not have to be
more effective than existing drugs, just more effective than placebo in defined
patient groups. FDA approval, if granted, sets the conditions under which the
drug can be sold.
In 2007, Congress passed a law (the Food and Drug Administration Amendments
Act) allowing the FDA to make drug approval contingent on agreement to perform
a post-approval clinical trial (sometimes called a phase IV clinical
trial). This is done to evaluate
possible long-term side effects. And, as before, all drugmakers must
collect and send to the FDA patient and doctor reports of adverse events
possibly related to taking the drug.
Phase III trials are the crux of the system. These trials can make or break
a new drug. Virtually all of these extremely expensive trials are paid for by
the companies that make the drug.
"The vast, vast, vast majority of clinical trials in this country are
performed by pharmaceutical companies that must do these studies to get FDA
approval," DeAngelis tells WebMD. "The government doesn't pay for them.
That is not what NIH [National Institutes of Health] money is used for. Until
we decide that it is worth it in this country to put many billions of dollars
into clinical trials, then the drug companies will have to do it. And there is
nothing wrong with that."
Drug companies don't just pay for clinical trials. User fees paid by drug
and device manufacturers — largely dedicated to speeding the approval process — account for about 25% of the FDA's annual budget.
What roles do drug companies play in clinical trials?
Advocates of this system say it's only fair that companies that stand to
benefit from sales of new drugs should underwrite the cost of testing them — and of approving them in a timely manner.
Many of the most helpful medicines now in routine use emerged from
drug-company-sponsored clinical trials. Drug companies "are committed"
to making information from these trials available to patients and their
doctors, says Ken Johnson, senior vice president of the Pharmaceutical Research
and Manufacturers of America (PhRMA), the lobbying group that represents the
drug industry.
"It is patently unfair to suggest that a manufacturer-sponsored clinical
trial is inherently biased," Johnson says in a news release sent in
response to the articles in The Journal of the American Medical
Association. "PhRMA and its member companies believe that protecting
the integrity of clinical research is paramount to patient safety."
Critics of the system say the drug industry's money has a corrupting
influence on the clinical trial process. DeAngelis agrees with Johnson that
there's nothing inherently wrong with drug companies paying for clinical
trials. But she notes that companies focus more on maximizing profits than on
maximizing public health.
"Fifteen years ago or so, pharmaceutical companies transferred most of
their resources and emphasis into their marketing divisions rather than their
science divisions," DeAngelis says. "There are relatively few new drugs
or devices in the pipeline. Most of what they are doing now is testing drugs
that are already out there to get approval for people who don't really need
them."
Far worse, DeAngelis says, is companies sometimes put marketing ahead of
science when reporting clinical trial results. Merck's apparent
misrepresentation of data about deaths among Vioxx patients is just one
example, she says.
Pharmaceutical companies "are doing their darndest to hide the side
effects of the drugs they are developing," DeAngelis says. Everybody who
uses a drug has to judge its cost — not just the financial cost but cost in
terms of side effects — to understand its benefits. But you can't do that
unless you have the data. Some of them are trying to suppress the data on side
effects."
What roles do independent scientists play in clinical trials?
Drug companies employ many eminent scientists. But the companies usually ask
outside scientists to serve as "principal investigators" for clinical
trials. These scientists are responsible for conducting the trial in a
scientific manner and for guaranteeing that the sponsor has not exerted undue
influence either in conducting the trial or in reporting its results.
These outside scientists usually are prominent experts in their fields. For
performing this work, sponsoring drug companies pay the university or
institution with which the scientist is affiliated, says Margaret Dale, JD,
dean for faculty and research integrity at Harvard Medical School.
"We do not accept contract language that restricts publication of study
findings," Dale tells WebMD. "We have policies that relate to whether
that investigator can have any financial interest in the sponsoring company,
and their obligation to disclose it."
In addition, these experts often are paid to discuss the study findings at
scientific meetings, symposia, advisory-board meetings, and
drug-company-sponsored events. Dale says Harvard restricts investigators to
$20,000 in such consulting fees — and requires them to disclose this support
in publications and scientific presentations.
Most journals require study authors to declare that they have received such
payments. Dale says that journals are becoming more and more insistent that
scientists disclose all consulting fees.
Troubled by the appearance of conflict of interest, a few prominent
researchers have recently announced they will no longer accept payment for
these services.
When clinical trials are over, the results appear as official reports in
peer-reviewed medical journals. These journals have their own rules to ensure
that the studies are scientific. The Journal of the American Medical
Association even requires the statistical analysis of the study findings to
be done by someone who does not work for the sponsor and who has an academic
appointment.
When clinical trial studies are submitted to a journal, they undergo a
process called peer review. During this process, draft versions of the
manuscripts are sent — anonymously — to experts who were not involved in the
study. These experts tell the journal whether, in their opinion, the study
meets acceptable scientific standards. They often suggest changes or ask for
more information and do not deem the manuscript acceptable until their
questions are answered.
The peer review process seems to have failed to detect the statistical sleight of hand chronicled by
The Journal of the American Medical Association. And, as the journal's
studies suggest, journal editors permitted publication of study reports
and review articles written by drug company employees and contractors that were
signed by independent scientists who actually had little to do with the study's
research or writing. Moreover, some of the company hires who worked on the
study were not listed as investigators or authors.
"Drug companies shouldn't be paying people to ghostwrite a paper and
then find an author who would prostitute him or herself — that is the proper
word, I believe — to put their name and reputation on a paper for which they
had very little to do," DeAngelis says.
Dale notes that Harvard forbids its scientists from being listed as study
investigators unless they made substantial contributions to the work. And she
says the school also insists that everyone who made substantial contributions
to a study must be listed as authors.
Richard Bookman, PhD, executive dean for research at the University of
Miami, says many medical schools and academic research institutions are
tightening their policies so that potential conflicts of interest always are
declared.
What's wrong with the clinical trial process?
Today's studies in The Journal of the American Medical Association
suggest — not for the first time — that not all clinical trials are designed,
conducted, analyzed, or reported ethically.
DeAngelis says it's wrong to blame the drug companies. The misdeeds
suggested by the report "could not occur without the cooperation (active
and tacit) of clinical researchers, other authors, journal editors, peer
reviewers, and the FDA," DeAngelis and Fontanarosa write.
Directly asked about this allegation by WebMD, the FDA chose not to
respond.
How can the process be fixed? DeAngelis and Fontanarosa detail an 11-point
program they say is a starting point. Their recommendations include:
- There should be a registry for all clinical trials that clearly shows — before patients enter the study — the names of the principal
investigators.
- The statistician who analyzes study results should not be employed by a
for-profit company.
- All study investigators should fully disclose all pertinent relationships
with for-profit companies.
- All of the investigators listed as study authors should make substantial
contributions to the work — and all investigators who make substantial
contributions should be acknowledged.
The medical research community already is taking action, Bookman says.
"It is absolutely clear that in academic medicine, awareness of these
issues has mushroomed over the last five years," Bookman tells WebMD.
"The pendulum has swung too far one way, but it is already returning. It is
clear that the academic medical community has waked to the fact they have to
look at this more carefully. Academic medicine in five years will be
transformed with much more complete conflict-of-interest disclosure policies
and much more management capability to avoid conflict of interest."
SOURCES: DeAngelis, C.D. The Journal of the American Medical Association,
April 16, 2008; vol 299: pp 1833-1835. Ross, J.S. TheJournal of the American Medical Association, April 16,
2008; vol 299: pp 1800-1813. Psaty, B.M. and Kronmal, R.A. The Journal of the American Medical
Association, April 16, 2008; vol 299: pp 1813-1817. Memorandum, "Food and Drug Administration Act Amendments Act of
2007," Hyman, Phelps & McNamara, P.C., Oct. 11, 2007; accessed April
14, 2008. News release, Pharmaceutical Research and Manufacturers of America, April
14, 2008. Catherine D. DeAngelis, MD, MPH, editor-in-chief, The Journal of the
American Medical Association. Margaret Dale, JD, dean for faculty and research integrity, Harvard Medical
School. Richard Bookman, PhD, executive dean for research, University of Miami.
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