BAD MEDICINE

Four deaths have prompted the Food and Drug Administration to pull a
painkilling drug off the market. Is this a sign that the FDA is
moving too quickly and approving unsafe drugs for use? After a
background report, two medical experts debate the approval process of
the FDA.

SPENCER MICHELS: The withdrawal late yesterday of a new painkilling
drug by the Food and Drug Administration--after four deaths--has
renewed debate about the agency's drug approval process. The FDA has
primary authority to approve all new drugs and medications before they
can be prescribed to the public. Though the FDA has enjoyed a long
reputation for careful regulation, it has also endured continual
criticism from patient advocate groups, drug manufacturers, and some
members of congress who want drugs approved faster. Those critics have
argued that the agency is often too slow to make drugs available to
patients in urgent need.

In response, last November President Clinton signed into law a measure
to speed FDA approval of drugs and medical devices. The new measures
include: easier access to experimental drugs for severely ill
patients; and faster FDA review of medicines for aids, cancer and
other diseases. For their part, drug companies are required to study
the safety of so-called off-label uses of their drugs using a drug
originally intended to treat one disease for something else--and to
seek FDA approval for such uses within three years.

But recently, three highly publicized cases have once again set off
criticism of the approval process. But this time the issue is whether
the FDA is moving too quickly and allowing unsafe medicines to reach
patients before enough testing has been completed. Last fall, the
diet drugs Redux and Fenfluramine were removed from the market after
they were found to cause heart valve problems in a small number of
patients. Earlier this month, Posicor, a medication prescribed for
high blood pressure, was withdrawn when it was found to react
adversely with about two dozen other medications. At that time, the
FDA said it had received reports of 24 deaths associated with Posicor.
And yesterday, the painkiller Duract, was pulled from pharmacy shelves
after four patients died of liver failure and eight more required
liver transplants.

JIM LEHRER: More from Elizabeth Farnsworth.

ELIZABETH FARNSWORTH: Joining us now is the Acting Commissioner of the
FDA, Dr. Michael Friedman, and Dr. Sidney Wolfe, Director of the
Health Research Group of Public Citizen, a consumer advocacy
organization.

Dr. Friedman, is the FDA moving too quickly to approve drugs
now?

DR. MICHAEL FRIEDMAN, Acting Commissioner, FDA: I think the answer to
that is "no." It's a very considerable challenge for us to take all
the scientific information that we need to make a good decision. And
once a decision is made it's constantly re-examined. But I think in
these particular situations the answer is no.

ELIZABETH FARNSWORTH: What is the average review time now for a drug?
It was about 30 months in 1992, as I understand it.

Is the FDA moving to quickly to approve new drugs?.

DR. MICHAEL FRIEDMAN: The average review time is a little over one
year, but for the products that you've just been describing, for
example, for Duract, that product required 27 months, two and a third
years for review, and there was a study period of clinical trials of
about a decade from 1984 to 1994. So I think it's fair to say that
that period of time is fairly substantial and the 2,400 patients who
received the product were part of a very careful analysis and evaluation.

ELIZABETH FARNSWORTH: Dr. Sidney Wolfe, do you think the FDA is moving
too quickly?

DR. SIDNEY WOLFE, Public Citizen: For certain categories of drugs, like

drugs for cancer and AIDS and life-threatening illnesses, we applaud the
idea that the FDA is moving rapidly. Most drugs don't fall into that
category, and in the last couple of years the FDA has broken two records.
They've approved a record number of drugs, 92 drugs in 1996 and '97, more
than ever in any two-year period, and a record number of drugs has been
found so dangerous they had to be taken off the market. Most of these 92
drugs were not breakthrough drugs. There were another one of these-25th or
30th painkiller, and all of the drugs that came off the market were not for
any life saving purpose. So we think that in the last
couple of years, certainly under pressure from the Congress, the FDA has
been more reckless than they ever have been and the ducks are coming home
to roost, so to speak, because we are having one drug after another taken
off the market. The fact that it took such a long time for the drug that
came off the market yesterday to be looked at doesn't really mean anything,
because at the end of that time the answer should have been don't approve
it. It caused an extraordinary amount of liver damage in people. This was
known before approval, and there were many people in the FDA who did not
think it should be approved.

ELIZABETH FARNSWORTH: What about that, Dr. Friedman, how do you
explain the approval of Duract and then its withdrawal less than a
year later?

DR. MICHAEL FRIEDMAN: With all due respect, I believe the use of the
term "reckless" is in itself reckless, and I think it doesn't add to
the thoughtful debate that we're trying to have. I think that the
family of products that Duract is from, the non-steroidal
anti-inflammatory drugs, all have the side effect of irritating and
inflaming the liver. All can cause liver damage. Drugs that are over
the counter like Tylenol can do so, but many other drugs can as well.
If Duract is used as labeled for 10 days or less, the drug is
extremely safe. The incidence of serious side effects with liver
damage is perhaps one in 100,000 patients. Now, in order to study one
or two or three hundred thousand patients, decades would be required.
The side effects that were noted during the clinical trials were mild
elevations of liver enzyme abnormalities, mild liver abnormalities,
these are very frequently seen. And our responsibility is not to
approve one, two, or five drugs in a family. The legal requirement
that we have is as a new product is submitted to us to make the very
best scientific assessment that we can of that product.

ELIZABETH FARNSWORTH: Dr. Wolfe, yes, go ahead.

DR. SIDNEY WOLFE:I agree with that plan, but internal FDA documents
show that one of the physicians at the FDA thought that this drug
before approval was more dangerous than any of the other drugs, the
non-steroidal and non-inflammatory drugs. And it was originally
studied to be used for longer periods of time, so lots of patients and
lots of doctors used this drug for months and months and months when
it was studied for arthritis. And it was so dangerous that they had to
decide that it should not be used for more than 10 days. The drug
caused an enormous amount of liver damage in animals known even before
clinical trials on people were exposed. So this drug was really unique
in its liver toxicity, and it is because of this it came off the
market. The idea of some FDA spokesperson yesterday it shows the
system works because we picked up these things after approval is
itself a really irresponsible statement, because if the system worked,
this drug never would have come on the market, and all the people who
have died or had liver transplants or have had near misses in terms of
liver toxicity would be spared.

ELIZABETH FARNSWORTH: Dr. Friedman.

Were people recklessly exposed to dangerous drugs?

DR. SIDNEY WOLFE: And it's not the only one. The same is true of a
couple of the other drugs. Evidence known at the time of approval and
recommendations by several FDA advisers were that this heart-blood

pressure drug, Posicor, shouldn't be approved until the results of a
study, ongoing then, came out. And when the results of that study came
out, it was taken off the market a couple of weeks ago. Two hundred
thousand people were needlessly exposed to that drug, and many of them
died.

ELIZABETH FARNSWORTH: Dr. Friedman.

DR. MICHAEL FRIEDMAN: Well, I disagree strongly with many of the
assertions that Dr. Wolfe is making. There's always a vigorous
internal debate within the agency amongst our scientists as to how
best to review and approve a product. I think the balance here is
between having perfect information and having sufficient information.
We all recognize that there's no product that's perfectly safe or
perfectly effective, and so we don't ask for that. What we do ask for
is a sufficiency of information so it can be properly used by a health
care provider and that there's proper information for a patient to
utilize that. With all respect, I think what's expected is to provide
that good information. Many times, in fact, in the large majority of
cases, that information becomes more evident, both for benefits and
for toxic side effects, after a product is on the market. Our
responsibility is an ongoing one, and again respectfully, I disagree
with Dr. Wolfe. I think the system worked very well in this case.

ELIZABETH FARNSWORTH: I'd like to move this on to products that have
been on the market a while, and that's the case, for example, with the
Fen-Phen diet drug, and then it's discovered that they have adverse
reactions with other drugs. How is the system, Dr. Friedman, for
monitoring drugs that have been on the market for a long time? Because
the Journal of the American Medical Association reported that 100,000
Americans die each year from adverse reactions.

DR. MICHAEL FRIEDMAN: Well, that article in the Journal of the
American Medical Association says that those patients die from known
side effects of medicines used quite properly. Their point is that
these are deaths which are in a sense unavoidable. I'm more concerned
about deaths that are avoidable and new toxicities that have never
previously been described. For example, with the diet products that
you've been mentioning, Fenfluramine was a product that was first
approved in 1963. The product has been used in tens of thousands of
individuals for decades. The side effects that were seen-the subtle
new heart valve toxicity-was very rare, very subtle, and required the
greatest scrutiny in order to observe it. In fact, I think it's safe
to say that there are many products which cause side effects that we
don't properly appreciate. The challenge to us to try and have the
most vigilant, the most dynamic, the most proactive system for
tracking side effects, and then having an agency that's prepared to
revisit decisions and to make re-evaluations whenever that's possible.

The challenge: to be vigilant in decisions and reevaluations.

DR. SIDNEY WOLFE: That's a theory which I couldn't agree with more.
The problem is that these drugs, Posicor, the blood pressure drug that
came off the market two weeks ago and the drug Duract, the painkiller
that came off yesterday, never would have been approved 10 years ago.
Ten years ago the FDA was much more careful, much more vigilant, and
when a serious question-I mean, Dr. Friedman said you can't have
perfect evidence, I agree with that. You have to have sufficient
amount of information. But if there's a sufficient amount of
information to raise serious questions about the safety of a drug, 10
years ago they would have said, no, we're not going to approve it. We
did a study a few years ago showing then that many more drugs came on
the market in France, Germany, and the United Kingdom and then had to
be banned because of safety reasons. Then was the case in the United
States. That gap, then an advantage to Americans, is narrowing
significantly with the kinds of reckless approvals and now safety
withdrawals that are occurring. I would bet that there are going to be

another two or three of these record number of 92 drugs approved in
1996 and '97 that are going to have to come off the market.
Unfortunately, instead of having good congressional oversight that
says can we learn something from this, can we do a post mortem, not
avoid that, the FDA is pummeled by the drug industry and its
indentured service in Congress, who hold hearings to actually weaken
the FDA, not to approve it.

ELIZABETH FARNSWORTH: I need to get back to Dr. Friedman. Here, we
just have a little time left, Dr. Friedman, for a response.

DR. MICHAEL FRIEDMAN: Please. I think the rhetoric, again, is
unfortunate. This is hardly reckless. These are scientists who
evaluate things so carefully and take the responsibility so seriously.
Dr. Wolfe speaks of pressures that are on the agency, and I think he's
quite correct. There are important expectations layered upon the
agency by the public. There are important expectations laid on by
Congress as the voice of the public, by industry, by health care
providers, by advocacy groups and others. But I submit that the
biggest pressures, the most intense pressures felt by the agency, are
those from within each of the staff reviewers. They take so seriously
their responsibility to act in a speedy fashion but to act responsibly
and carefully. Scientists may disagree about certain scientific
information, but I think it's irresponsible to speak of the decisions
that the agency goes through as being reckless or ill considered-quite
the contrary.

ELIZABETH FARNSWORTH: Thank you both very much for being with
us.

DR. MICHAEL FRIEDMAN: Thank you.

Checked-by: (trikydik)