Who Is Protecting The Public Health?


Meryl Nass


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.

A recent
Journal of the American Medical Association
(JAMA) 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. Pharmaceutical companies paid for the development of 25 percent of
the guidelines.

If medical
research is being 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 recently 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? Is
anybody performing 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, 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.


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 be much more profound. Years
ago, a new treatment had to be proven safe before it could be used; during the
past eight to ten years, unless there was significant evidence of danger, new
drugs were assumed to be safe. In a 1998 survey, FDA’s medical officers reported
that standards for drug approval had declined. Last May, Richard Horton, editor
of the Lancet,  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.” The 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.

The Center for
Disease Control (CDC) recently sponsored a trial of post-exposure anthrax
vaccine use. The 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 percent
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.

But that wasn’t
the end of it. The FDA 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 the CDC and the FDA to experiment on human fetuses in the complete absence
of animal fertility data? These agencies have lost sight of their mandate to
protect 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 the CDC.

Additional moves
are afoot to weaken the protections for children in clinical research. 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. For many drugs, such as antibiotics, which
have demonstrated safety and efficacy over many millions of doses, this is not a
problem. 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
ten 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 “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.)

Using
Bioterrorism Fears


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.

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.

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. 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.


President Clinton
issued Presidential Order 13139 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.

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. “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. His June 2001 report recommended that the Army seek exemptions from
some regulatory approval processes to speed up the development of new medical
treatments.

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 Health and Human Services is giving the states a
blueprint to consolidate control over their citizens in the event of bioattack?

The 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?

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.

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.”

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.


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 Zoon’s role as a federal
regulator charged with protecting the public health.

The latest
episode in this saga concerns Congress’s 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
(HR 3448) and the Senate (Senate Amendment 2692) on the same day it was
introduced.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.

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 the 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, looks like it is about to be completely overturned.

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.

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
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.

Human safety
testing is not something we should allow to go by the board.
                      Z