Who is Protecting the Public's Health?

February 16, 2002

http://www.redflagsweekly.com/nasspubhlth.html

WHO IS PROTECTING THE PUBLIC HEALTH?

CAN WE TRUST THE REGULATORS?

By Meryl Nass, MD

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?

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.

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.

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 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.

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.

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 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.

Employing Bioterrorism Fears to Weaken Regulatory Oversight

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.

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.

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 bio-terrorism.

" 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 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 ce Gostin, a law professor at

town University and professor of public health at s 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?

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, 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.

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.

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.

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 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.

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

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