- Twenty years ago, as a newly qualified
doctor, I spent a lot of time in the library reading review articles about
my patients' diseases.
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- 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:
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- Industry-funded research results in a
much higher proportion of studies showing positive results for new drugs,
compared to publicly-funded research.
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- Flawed regulatory oversight resulted
in licensing, then withdrawal, of many dangerous drugs in the past five
years.
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- 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.
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- Can Medical Research Findings Be Trusted?
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- 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.
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- 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?
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- This week's Journal of the American Medical
Association 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.
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- 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?
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- 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.
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- 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?
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- 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?
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- 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.
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- 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.)
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- 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.
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- 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.
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- Loosening Institutional Protections
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- 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.
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- 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.
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- A move to weaken human subject protections
in clinical research has occurred parallel to this weakening of drug oversight.
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- 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.
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- Isn't it unethical to offer a vaccine
to pregnant women that might cause birth defects, and one that was not
necessary? 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.
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- What logic led both CDC and FDA to experiment
on human fetuses in the complete absence of animal fertility data? How
could pregnant females be used as guinea pigs, before any 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.
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- 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.
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- 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.
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- 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.
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- 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.
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- 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.
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- 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?
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- When a family is paid for a child's participation
in research, the parent joins the researcher in assuming a conflict of
interest.
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- Unless there is a clear potential benefit
to the child, let's keep our children out of the laboratory.
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- Employing Bioterrorism Fears to Weaken
Regulatory Oversight
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- You cannot compel people to become experimental
subjects: that is the legacy of Nuremberg. If a drug or vaccine is not
fully-licensed, it cannot be forced on anyone.
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- But it is desirable to have drugs ready
to counteract a chemical or biological attack If the illnesses anticipated
from an attack do not occur naturally in the population, one cannot test
the new drugs for effectiveness. It would be unethical to expose people
to a chemical or disease just to test whether the new drug is truly protective.
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- That results in a conundrum: if you have
to prove effectiveness in human trials to license a drug, but you can't
do the trial, then you can't license the drug. If the drug is not licensed,
it can be used with informed consent, but you cannot force people to take
it.
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- The Defense Department was not satisfied
with that. There is no provision for informed consent on the battlefield,
and a soldier who refuses an experimental treatment could endanger the
lives of his colleagues, so they said.
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- Presidential Order 13139 was issued by
President Clinton to deal with this situation. It allowed the President,
in consultation with the Secretary of Defense and the FDA Commissioner,
to require that troops take experimental drugs or vaccines in special circumstances.
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- That should have been adequate to take
care of the situation, but the federal authorities were still not satisfied.
The National Research Council (of the National Academies of Science) was
contracted to report on protecting troops from bioterroism.
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- "How can we ensure safety of troops
if we have to go through an onerous two or five years of certification
[for new drug approval]?" asked Robert Love, the study director.
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- His June 2001 report recommended that
the Army seek exemptions from some regulatory approval processes to speed
up the development of new medical treatments.
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- CDC did its part by contracting with
Laurence Gostin, a law professor at Georgetown University and professor
of public health at Johns Hopkins University, to create a "Model Law"
that the states would be encouraged to use. It would give state officials
the authority to involuntarily quarantine and vaccinate citizens, among
other things. Does it seem odd that HHS is giving the states a blueprint
to consolidate control over their citizens in the event of bioattack?
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- FDA had already embraced the new regulatory
culture. How better to both speed up drug approvals, and save the President
the political cost of contravening the Nuremberg Convention than by weakening
the current requirements for drug licensing?
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- After acknowledging that the effectiveness
of bioterrorism drugs could not be tested in humans, and therefore animal
efficacy tests should be used instead, FDA prepared to throw out the baby
with the bathwater. In 1999, hints that human safety testing would be jettisoned
as a requirement for licensure began to appear.
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- The 1999 Annual Report for FDA's Center
for Biologics said: "A research program to produce vaccines, therapeutics
and drugs to treat [bioterrorism] outbreaks faces the challenge of not
being able to proceed with Phase III efficacy clinical trials. Given ethical
and safety concerns that would rule out infecting human subjects with a
deadly organism in order to test a vaccine or therapeutic for efficacy,
trials with humans cannot be undertaken. Therefore, the regulatory process
for approval of treatments must be modified to permit the emergency use
of antibiotics, therapeutics and vaccines that have been shown to be safe
and effective in animal models."
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- Wait just one minute. Nobody needs to
be infected with anything to test drug or vaccine safety. All you do is
administer the drug or vaccine, and watch the recipient for possible adverse
effects. Could this leap of faith in animal models have been a mistake?
After all, it is universally acknowledged that human adverse effects cannot
be extrapolated from animal tests. Each species responds uniquely to a
drug or vaccine. Vaccines that are safe in some species can be fatal in
other species, and this cannot be accurately predicted ahead of time.
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- Unfortunately, it looks like there is
no mistake. The director of FDA's Center for Biologics, Kathryn Zoon, published
a paper in "Emerging Infectious Diseases" in which she reiterated
the call to fully license drugs for bioterrorism in the absence of any
human testing. She said that once licensed, the safety of the drugs can
be assessed. It is hard to reconcile this philosophy with Dr. Zoon's role
as a federal regulator charged with protecting the public health.
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- The latest episode in this saga concerns
Congress' role in bioterrorism prevention. A bill designed to fund federal
bioterrorism efforts, called the "Public Health Security and Bioterrorism
Response Act of 2001" was passed in December by both the House (H.R.
3448) and the Senate (Senate Amendment 2692) on the same day it was introduced
in both houses. Both the House and Senate versions of the bill contain
a provision mandating that FDA finalize and implement a 1999 Notice of
Proposed Rulemaking. This action would allow animal efficacy tests to be
sufficient to fully license drugs and vaccines intended for bioterrorism.
Although safety testing is not explicitly addressed in the bill, given
the statements made by FDA above, it appears that safety testing in humans
may be waived as well, as a requirement for licensure.
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- Another way to look at this bill's provision
is as a way of getting around the absolute requirement for informed consent.
As was pointed out earlier, people are allowed to use experimental drugs
and vaccines, as long as FDA has approved the experimental use and the
patient or subject has provided informed consent. By licensing what would
previously have remained an experimental drug, one opens up the possibility
of forced use, with no need for informed consent. The Nuremberg Convention,
first nibbled at by mandating use of experimental drugs in the Gulf War
theater, looks like it is about to be completely overturned.
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- This bill is now in conference committee.
Congress should be informed that despite having undergone human safety
and efficacy tests to be licensed, many drugs and vaccines have still had
to be withdrawn from use due to severe side effects, including death. These
side effects were usually not discovered until the drugs were given to
large numbers of people.
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- In the case of drugs and vaccines for
bioterrorism, it is likely that, following an attack, the entire country
will receive a drug or vaccine in a crash program, over days or at most
weeks. This leaves no time to assess the adverse event profile of the drug
in smaller numbers of people, before it is given to the entire population.
If the "Model Law" is used, forced acceptance of drugs or vaccines
that have never been tested in a single human could be demanded of the
entire U.S. population. One poor choice of a drug or vaccine that is later
found to be dangerous could have a dire effect on a very large number of
people.
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- Human safety testing is not something
we should allow to go by the board.
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- RECOMMENDED READING
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- JAMA 2002;287:612-617 http://jama.ama-assn.org/issues/current/abs/joc11772.html
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- Horton R. Commentary. Lotronex and the
FDA: A fatal erosion of integrity. The Lancet 2001; 357: 1544-5.
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- Drug After Drug, Warnings Ignored. With
Study Results Ignored, Nation Got Another Blood Pressure Drug. LA Times
2000.
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- Landow L. FDA Approves Drugs Even Wh
en Experts on its Advisory Panels Raise Safety Questions. BMJ 1999; 318:
944.
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- Friedman MA et al. The Safety of Newly
Approved Medicines: Do recent market removals mean there is a problem?
JAMA 1999; 281:1728-34.
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- Wood AJJ. The Safety of New Medicines:
The importance of asking the right questions. JAMA 1999: 281: 1753-4.
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- Lurie P et al. Safety of FDA-Approved
Drugs (Letter and reply). JAMA 1999: 282
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- Angell M and Relman AS. Prescription
for Profit. Washington Post, 6/20/2001, A27
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- Wood AJJ and Woosley R. Making Medicines
SaferÛThe Need for an Independent Drug Safety Board. NEJM 1998; 339:
1851-4.
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- Bodenheimer T. Uneasy Alliance: Clinical
Investigators and the Pharmaceutical Industry. NEJM 2000: 342: 1539-44.
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- Brennan TA. Buying Editorials. NEJM 1994:
331: 673-5.
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- Mucklow JC. Reporting Drug Safety in
Clinical Trials: Getting the Emphasis Right. The Lancet 2001; 357: 1384.
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- Chalmers I. Underreporting Research is
Scientific Misconduct. JAMA 1990; 263: 1405-8.
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- Rochon PA et al. A Study of Manufacter-Supported
Trials of Nonsteroidal Anti-Inflammatory Drugs in the Treatment of Arthritis.
Achives of Internal Medicine 1994; 154: 157-63. [Conclusion: The manufacturer-associated
NSAID is almost always reported as being equal or superior in efficacy
and toxicity to the comparison drug. These claims of superiority, especially
in regard to side effect profiles, are often not supported by trial data.
These data raise concerns about selective publication or biased interpretation
of results in manufacturer-associated trials.]
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- Ionnidis JPA and Lau J. Completeness
of Safety Reporting in Randomized Trials. JAMA 2001; 285: 437-43.
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- Woodward B. Challenges to Human Subject
Protections in US Medical Reseaerch. JAMA 1999: 282: 1947-52. [Conclusion:
Nationally and internationally, there are new pressures to subordinate
the interests of the subjects to those of science and society. The National
Bioethics Advisory Commission, which is about to undertake a comprehensive
review of the US system of human subject protections, faces a daunting
task.]
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- Zoon KC. Vaccines, pharmaceutical products,
and bioterrorism: Challenges for the US Food and Drug Administration. Emerging
Infectious Diseases 1999;5:534-536.
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- http://www.redflagsweekly.com/nasspubhlth.html
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