Can We Trust The Regulators?
By Meryl Nass, MD Redflagsweekly.com
Part 1 of 2 (Part
2)
Twenty years ago, as a newly
qualified doctor, I spent a lot of time in the library reading review
articles about my patients' diseases.
Twenty years later, my time
in the library is too often spent reading about problems and conflicts
of interest within the medical establishment. Here are a few
examples:
- Industry-funded research
results in a much higher proportion of studies showing positive results
for new drugs, compared to publicly-funded research.
- Flawed regulatory oversight
resulted in licensing, then withdrawal, of many dangerous drugs in the
past five years.
- Established protections
for human subjects in medical research, which did not prevent the deaths
of several subjects in high-profile cases recently, are being undermined.
Can Medical Research Findings
Be Trusted?
The education of my later years
has produced a doctor who is forced to fall back too often on anecdotal
evidence and personal experience, rather than trusting the "last
word" of the experts and our top medical journals.
Despite all the information
now at our fingertips, this loss of faith in the quality of the available
data pushes the practice of medicine backward, not forward.
Report after report confirms
that I would be foolish not to have serious misgivings regarding the results
of clinical trials, trepidation towards newly licensed drugs, and a lack
of trust in the so-called giants of my profession.
Too many of these giants would
enforce the practice of "evidence-based medicine" and "clinical
guidelines" on the rest of us: but the problem is, who
paid for the evidence and the guidelines?
JAMA recently
reported that a full nine out of ten doctors on committees that develop
clinical guidelines had financial ties to the industry whose products
they recommend.
Six of ten doctors had financial
ties to companies whose drugs were considered in the guidelines they wrote.
And pharmaceutical companies
paid for the development of 25 per cent of the guidelines.
If medical research is done
properly, with good controls and enough subjects for statistical validity,
why do so many studies yield answers that are in direct opposition to
each other?
It was widely reported this
week that mammograms do not save lives; the studies that had claimed they
did, were fatally flawed when they were (finally) carefully examined.
There is no question that use
of mammograms leads to earlier diagnosis of breast cancer than not using
mammograms. But this does not result in improved life expectancy. Does
it mean that we should stop seeking early detection for breast cancer
- that breast cancer is in some way different from all other cancers?
Are We Even Asking the
Right Question?
Is the problem the mammogram,
or is the problem that aggressive treatment of breast cancer could actually
decrease life expectancy in many cases, so that overall there is no treatment
benefit in this disease? I don't know the answer. Has anybody performed
solid research to answer the question?
Because there exists a multi-billion
dollar establishment that deals with breast cancer in a fairly monolithic
way, one is limited as to what questions are allowed to be asked. (You
can ask away, but who will fund your research?) Research funded by the
federal government is generally constrained to stay within the existing
boundaries of disease management, despite its public funding. It will
often mirror corporate-sponsored research.
When you don't ask the right
questions in clinical research, you can obtain answers that result in
worse patient care. Corporate sponsors of research are not going to spend
millions for a trial that could produce an answer in conflict with their
goals, if they can avoid it. (Unfortunately, their "wrong" answer
could have important clinical implications, but since the industry has
often tried to prevent publication of negative results, we may never learn
of these research findings.)
Since the drug manufacturer's
primary responsibility, whether funding research or in other matters,
is to the bottom line, we should not expect any other behavior.
However, the role of federal
agencies is oversight and regulation. Their job is to protect all those
with a stake in clinical research: the researchers, the subjects, and
the public, who may someday need the treatment in question. Federal agencies
should simply acknowledge that pharmaceutical companies have interests
that will not align with those of patients and physicians, and regulate
them accordingly.
Loosening Institutional
Protections
Over the last decade there
has been a shift backward by regulatory agencies charged with protecting
the public health. Although the shift at FDA has been blamed on the 1992
Prescription Drug User Fee charged to the manufacturer to review new drugs
and to expedite drug approval, the problems seem to me to be much more
profound.
Years ago, a new treatment
had to be proven safe before it could be used; during the past 8-10 years,
unless there was significant evidence of danger, new drugs were assumed
to be safe. In a 1998 survey, FDA's medical officers themselves reported
that standards for drug approval had declined.
Richard Horton, editor of The
Lancet, last May described the FDA's process for the re-licensing of a
drug that had earlier been taken off the market. He explained, step by
step, how the FDA had a "two track process, one official and transparent,
one unofficial and covert."
FDA controlled the composition
of its advisory committee, and its agenda, so the committee would not
overturn the agreement already made between senior FDA staff and industry
executives.
Clearly, there is a big
problem at FDA.
A move to weaken human subject
protections in clinical research has occurred parallel to this weakening
of drug oversight.
CDC recently sponsored a trial
of post-exposure anthrax vaccine use. FDA approved the trial. The study's
consent form acknowledged that preliminary data showed anthrax vaccine
could cause birth defects.
Since for the preceding two
months antibiotic treatment had been 100 per cent successful at preventing
anthrax in those exposed, it was not at all obvious that vaccination offered
any additional benefit. Yet pregnant women were invited to enroll as subjects.
Isn't it unethical to offer
a vaccine to pregnant women that might cause birth defects, and was unlikely
to provide them with clinical benefit? But that wasn't the end of it.
FDA just approved the license
for anthrax vaccine, and approved a new anthrax vaccine label, which became
public five weeks after the CDC study began. The new label clearly states
that no animal experiments have ever been performed to determine the vaccine's
effect on pregnancy.
What logic led both CDC and
FDA to experiment on human fetuses in the complete absence of animal fertility
data? How could pregnant humans be used as guinea pigs, before any pregnant
guinea pigs or mice were studied?
These Agencies Have Lost
Sight Of Their Mandate To Protect The Public Health.
Their lack of ethics might
have been influenced by the Defense Department's contribution to their
budgets, which amounted to $2.5 billion last year for CDC.
Additional moves are afoot
to weaken the protections for children in clinical research. Children
cannot provide informed consent; therefore, how can you ethically use
them as experimental subjects? Until now, there had to be a very good
reason to use a child. For example, the child had to have a disease that
would benefit from a new treatment.
The Jesse Gelsinger case, in
which a teenager died from participation in a gene therapy experiment
from which no personal benefit was expected, demonstrated that fully informed
consent is often missing in clinical trials.
Informed consent is presented
to potential participants by the researcher, who has a vested interest
in signing up subjects. Its oversight by institutional review boards tends
to be cursory. In the Gelsinger case, the principal investigator, along
with the University of Pennsylvania, had a large financial stake in the
outcome of the experiment.
Perhaps half the drugs used
in children have never been licensed for pediatric use. They are prescribed
"off-label" by clinicians. Is this a problem? Not for most drugs,
such as antibiotics, which have demonstrated safety and efficacy over
many millions of doses. Both patients and doctors are perfectly satisfied
using such drugs in the pediatric population, on or off label.
But in the case of other drugs,
such as psychotropic medications, many doctors are loathe to prescribe
for children without adequate pediatric testing. Drugs that are given
indefinitely are better moneymakers than antibiotics, which are only used
for 10 days at a time. So expanding approvals for chronic drug use into
the pediatric age group could yield handsome rewards.
Perhaps as a result, the rules
for using children in clinical research are being undermined. No longer
would a child need to clearly demonstrate potential benefit from a new
treatment before being enrolled in a trial; proposed rules would allow
a child who is simply "at risk of" the condition to be used
as a subject. But most of us are "at risk of" most diseases.
Furthermore, new consent forms
have been developed that allow adolescents to provide a modicum of "informed
consent." (They were used in CDC's recent anthrax vaccine trial.)
Treating a child like a small adult for the purpose of obtaining research
subjects weakens the authority of the parent to protect his child. When
it is nearly impossible for an adult to understand the legal implications
of the consent form he signs, what must it be like for a child?
When a family is paid for a
child's participation in research, the parent joins the researcher in
assuming a conflict of interest.
Unless there is a clear potential
benefit to the child, let's keep our children out of the laboratory.
Continued
in Part 2
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