DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

PART 15 HEARING

RISK MANAGEMENT FOR PRESCRIPTION DRUGS

Wednesday, May 22, 2002

8:10 a.m.

National Transportation Safety Board

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Welcome, Introductions & Ground Rules

for Part 15 Hearing

Dr. Steven Galson, FDA 4

National Center for Policy Research

for Women and Families

Jae Hong Lee, M.D. M.P.H. 7

Title 2 Community AIDS National Network

Jeff Bloom 13

Public Citizen Health Research Group

Sidney M. Wolfe, M.D. 24

BlueCross/BlueShield Associations

Allan Korn, M.D. 40

Questions from the Panel 47

Pharmaceutical Research & Manufacturers

of America

Jim Kotsanos, M.D. 78

Gretchen Dieck, Ph.D. 80

American Medical Association

Joseph W. Cranston, Ph.D. 90

International Pharmaceutical Consultants, Inc.

Herbert Swarz, M.D. 97

The Patient and Consumer Coalition

Diana Zuckerman, PhD. 106

Questions from the Panel 114

American Pharmaceutical Association

Thomas E. Menighan, RPh, MBA 150

American Society of Consultant Pharmacists

Thomas R. Clark, RPH, MHS 167

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American Society of Health-System Pharmacists

Gary Stein, Ph.D. 177

National Association of Chain Drug Stores

Gary Wirth, RPh, MBA 184

CERTS/Duke University

Robert Califf, M.D. 195

Questions from the Panel 210

PUBLIC COMMENT 226

Wrap-Up 235

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DR. GALSON: Good morning. Welcome to the FDA Part 15 Hearing on Risk
Management of Prescription Drugs. We\'ve got four objectives today:

The first is to obtain public input on improving risk management for
prescription drugs. The second is to identify stakeholders for further
collaboration and implementation of risk management tools. The third is
to obtain greater understanding of the strengths and the weaknesses of
existing risk management tools. This understanding will help us guide
improvements or creation of new tools, and, fourth, to obtain input on
strategies to assess the effectiveness of tools used for risk management
of prescription drugs.

Let me just check. Everybody can hear me in the back? Yes. Good. I\'d
like to start by introducing the panel members and talk about the ground
rules of Part 15 Hearings before we begin.

First, Dr. John Jenkins at my left is the Director of the Office of New
Drugs in the Center for Drug Evaluation and Research.

Next to him is Dr. Sandra Kweder, who is about to

begin as the Deputy Director of the Office of New Drugs.

Next to her is Dr. Florence Houn, Director of Office of Drug Evaluation
III. And at my right is Dr. Paul Seligman.

Walking in right now is Dr. Jonca Bull, who is the Director

of the Office of Drug Evaluation V. And I expect coming any minute will
be Dr. Janet Woodcock, who is the Director of CDER.

We\'re going to give each speaker 20 minutes to present their views, and
then there will be a 20 minute question and answer period after each
panel. The questions will come from the members of the panel, but the
other FDA staff members who are here should feel free to jot down
questions and bring them up to us during that question period.

Please try to keep your talk focused on the hearing questions, and limit
it to 20 minutes. We\'ve got a full day\'s worth of people who wish to
talk today, so we\'ll try to be pretty strict about the times.

The ground rules for a Part 15 hearing include the following:

First is that the hearing is informal. The rules of evidence don\'t
apply. No participant may interrupt the presentation of another
participant. Only the presiding officer and panel members may question
any person during or at the conclusion of each presentation. Public
hearings under Part 15 are subject to FDA\'s policy and procedures for
electronic media coverage of FDA\'s public administrative proceedings.

Representatives of the electronic media may be permitted, subject to
certain limitations, to videotape film or otherwise record FDA\'s public
administrative proceedings, including presentations by participants. The
hearing will be transcribed and copies of the transcript can be ordered
at the registration desk or accessed on the internet. An instruction
sheet is available for internet access at the registration desk.

For your safety and comfort, the rest rooms are in the registration
lobby, just outside, and please note the exits from the room. I want to
also ask people if you could please turn your cell phones on vibrate to
reduce our distractions, and thanks a lot for your interest and
participating in this hearing which is very important as the FDA
develops and has the evolution of risk management programs for our
drugs.

I appreciate your cooperation in making this an orderly day, and we look
forward to listening to your ideas on this important topic. Thanks a
lot.

So we\'ll go ahead and start with our first speaker. Different from the
initial agenda that folks may have seen, our first speaker today is Jae
Hong Lee, M.D. MPH, from the National Center for Policy Research for
Women and Families.

DR. LEE: Good morning. Can everyone hear me? I\'m very thankful for the
panel to allow some comments this morning. I\'m very thankful also to
Mary Rouleau of the United Auto Workers who leant me her speaking time.

In recent years\--I\'m Dr. Jae Hong Lee speaking on behalf of the
National Center for Policy Research for Women and Families.

DR. GALSON: Could you move the microphone a little bit closer to your
mouth?

DR. LEE: Yes, sure.

DR. GALSON: Thanks.

DR. LEE: I\'m Dr. Jae Hong Lee. I\'m speaking on behalf of National
Center for Policy Research for Women & Families. In recent years, a
great portion of FDA\'s resources have focused on the acceleration of
the drug approval process. Drugs that pose safety concerns are now
approved with the promise that risks will be managed.

Unfortunately, post-marketing safety programs have been weakened as a
result of inadequate resources. The additional resources that will
likely be made available for risk assessment as a result of PDUFA III
provide an opportunity for improvement. However, there are major hurdles
that remain.

As noted by the May 1999 report of the FDA\'s Task Force on Risk
Management, the current pre-marketing risk assessment process is clearly
inadequate for evaluating two elements that are critical to patient
safety. These are (1) rare but potentially dangerous side effects; and
(2) long-term outcome.

Pre-approval clinical studies are far too small in size to detect rare
side effects and much too short in duration to assess long-term outcome.
These intrinsic deficiencies in the new drug approval process must be
addressed as the FDA works to improve post-marketing risk management
programs.

As demonstrated by a number of cases in the past decade, for example,
Lotronex and its deadly side effect of ischemic colitis, close
monitoring of the adverse events is essential for ensuring patient
safety. Prescription drugs are frequently prescribed for uses and
patient subpopulations for which they were not initially intended.
Unfortunately, the FDA currently relies on a passive and voluntary
adverse event reporting system that misses the vast majority of adverse
drug events. Some estimate as \[high as\] 90 percent.

Possible remedies include: instituting an active and mandatory adverse
event reporting system where the FDA actively solicits adverse event
reports for newly approved drugs, perhaps for the drug\'s initial three
years on the market.

Health professionals who have prescribed a new drug would be required to
respond to such FDA requests for adverse event reports. The current
passive voluntary system could be then used after this initial intensive
monitoring period.

Two, substantially increasing the number of FDA staff assigned to
monitoring and reporting on adverse drug events.

Three, fully engaging patients in adverse event reporting process by
providing easy-to-understand MedGuides for all prescription drugs and
prominently displaying information about the FDA\'s MedWatch program on
all product labels.

With respect to long-term outcome, the current emphasis on rapid drug
approval does not permit the gathering of long-term outcome data prior
to the marketing of a new prescription drug. It is therefore crucial
that drug manufacturers perform comprehensive long-term safety and
outcome studies after a new drug is marketed. This is especially
essential for drugs that are used for chronic conditions.

As a recent FDA report to Congress showed, pharmaceutical companies have
failed to complete most of the post-marketing commitments that were
required of them.

A recently-negotiated agreement between the FDA and industry would
permit the use of a small portion of prescription drug user fees for
post-marketing surveillance activities. However, use of those user fees
would be restricted to drugs approved starting in fiscal year 2003 and
would be restricted to two years for most new prescription drugs. These
limitations do not reflect an appropriate concern about managing risk.

Possible remedies for these problems include:

\(1\) requiring comprehensive long-term post-marketing safety and
efficacy studies for all newly-approved prescription drugs;

\(2\) committing a greater share of prescription drug user fees and
appropriations to funding the FDA\'s post-marketing surveillance
programs, and I would argue for at least half;

\(3\) removing any time limits placed on the FDA to using user fees in
post-marketing safety activities. Why limit the use of user fees to just
two or three years after approval?

\(4\) requiring pharmaceutical companies to file annual reports on the
status of required post-marketing safety activities; and

\(5\) granting the FDA greater authority to enforce post-marketing
surveillance requirements including the authority to impose civil
monetary penalties and to review direct-to-consumer ads prior to their
release.

Clearly, implementation of more effective risk management programs will
require greater resources and regulatory authority for the FDA. For too
long, the overwhelming emphasis has been on the rapid approval of new
drugs. The concerns presented in this statement are only a few of the
important issues that must be addressed in FDA\'s risk management of
prescription drugs.

However, the most basic need is clear: pre-marketing and post-marketing
risk management activities must be given equal priority and resources.

Thank you.

DR. GALSON: Thank you very much. Are there questions for Dr. Lee from
the panel, clarifying questions? FDA, other staff, questions?

DR. BULL: Could you provide more information on your recommendation to
involve patients more in post-marketing reporting? Any suggestions along
those lines?

DR. LEE: Sure. I certainly think one of the important things with
respect to having patients involved in this risk-management process is
to educate them about the drugs that they\'re using. I think a very
simple and effective way to do that would be to provide clearly written
easily understandable MedGuides for all prescription drugs.

Every time the patient gets a new prescription for a drug, they should
receive a MedGuide with that drug, and included in that MedGuide should
be information about how patients can refer information about adverse
drug reactions to the FDA directly, for example, through the MedWatch
program, and that would be, I think, two very simple ways that patients
can provide direct data to the FDA.

DR. BULL: Thank you.

DR. GALSON: Any other questions? If not, we\'ll go ahead and go right on
to our second speaker who is Mr. Jeff Bloom, who is speaking on behalf
of the Title 2 Community AIDS National Network. Jeff.

MR. BLOOM: Thank you, Dr. Galson. Thank you to the FDA for inviting me
here today. I would also like to state that I am speaking not only on
behalf of the Title 2 Community AIDS National Network but also as a
person living with AIDS and taking these medications for the past 15
years.

I also want to be clear that I am currently serving on the HHS
Secretary\'s Advisory Committee on Regulatory Reform. However, none of
my comments today should be construed as the positions of that
committee. However, I will be discussing several proposals that the
committee will be taking up in Minneapolis in June.

However, they should not be construed as official views of the
committee. These are my own views and not the committee\'s views.

I guess I\'d like to sort of start at the beginning and really say that,
you know, risk management starts when the first person enrolls in a
clinical trial, not after a drug is on the market, and we have a very
large problem in that.

The clinical trial system is broken. It is very ineffective at actually
giving a picture of exactly what goes on in the real world once a drug
is approved. Most of the trials, and in this case, I\'m mostly speaking
about AIDS trials since I don\'t know that much about other trials, so I
have to speak about what I know about, the AIDS trials that are
currently conducted are usually conducted on a carefully selected group
of patients that are normally much healthier than the people who will
actually be taking the drugs, that are carefully screened to make the
drug look as good as possible, and rarely are the trials done on the
people who will actually be taking the medicines.

Part of the deal with PDUFA was that we have accelerated approval and
certainly for people with serious and life-threatening illnesses, we
don\'t want to see a slowdown in access to those medicines, but part of
that agreement was to have good Phase IV trials on the back end. And
that back end unfortunately has not been very good.

The Phase IV trials that are currently conducted are usually conducted
to expand the pharmaceutical company\'s marketing or change the dosing
from once a day dosing to twice a day dosing, but rarely do we get
trials that are done to provide clinical information for patients and
doctors to know how to use the drugs in combination with other drugs and
giving out good treatment information.

I think the FDA does an extraordinarily good job on a measly budget in
comparison to the purview that you have and the responsibilities that
you have, but unfortunately\--and you do a good job of making sure that
the drug is fairly safe as well as can be known at the time of approval
and effective for the label indication.

But you do not provide the clinical information necessary for doctors
and patients to be able to use the drugs in the real world in
combination with the other drugs that they use. And I think that\'s one
of the problems right now that we have.

Before PDUFA, drugs were approved overseas first, and we had the benefit
of finding out about adverse events, especially the rarer ones, much
\[earlier\]. Now we have drugs approved here first a lot, so we\'ve lost
a lot of that information that we were able to get by seeing the
experience in Europe and other places.

And that\'s one of the things that\'s changed. The other thing that\'s
changed greatly, at least it has in AIDS, is we used to have very large
expanded access programs before a drug goes on the market. The best
example that comes to mind at the moment is DDI, where there are about
30,000 patients in the expanded access programs, and with those expanded
access programs, that was a great laboratory to find out about potential
adverse events, potential rare adverse events, complications before the
drug was approved and out on the market.

Those programs unfortunately have been curtailed to the point where
they\'re actually at some times a few thousand, maybe even a couple
hundred, and amazingly enough, of course, the expanded access tends to
occur initially about a month or two months before the drug is approved,
and you don\'t really have any long-term expanded access programs prior
to approval anymore.

I guess some people would say that\'s a good thing, because that means
the drugs are getting out faster. On the other hand, we don\'t get the
benefit of finding out what\'s happening in a greater sense before the
drugs are approved.

The other problem is is that the trials that are conducted are not
conducted in a combination with the drugs or how they\'re likely going
to be used. I have the benefit of sitting on a new drug advisory
committee for a company who will remain nameless for purposes of this
hearing, but this company tested the drug only in combination with their
drugs, and without any, you know, anything with reality to how the drug
was going to be used once it was out in the market.

And, of course, eventually this company also used it to come out with a
combination drug of testing it with their own drugs, but once the drug
was approved, clinicians had no idea how to use it in combinations with
the other drugs that people would take, and these things do not serve
the public well.

I think I\'d like to talk now about some of the proposals and getting to
your question about what patients can do that we\'re going to be taking
up hopefully in Minneapolis because there will be a panel on adverse
events for the Secretary\'s committee.

And some of these proposals are very, very mild proposals, but the thing
about risk management I think is we have to walk before we can run, and
these are perhaps little baby steps, but these are steps nonetheless
that I think could provide valuable information and provide a very good
platform for figuring how to take the next steps.

One of the steps is that everybody knows that adverse drug reactions are
severely underreported. You can take a number, pick one that you like,
but most people believe that MedWatch collects anywhere between one
percent and ten percent of the adverse drug reactions.

Most people think it\'s probably closer to the one percent figure than
the ten percent, but pick whichever one you like. One of the suggestions
that we\'re going to be discussing in Minneapolis is thanks to the
current pediatric bill that just passed Congress, there is mandated a
1-800 number for reporting side effects that will be going out with
every prescription.

In the Minneapolis meeting, hopefully we will convince the committee
that it will be a good recommendation to have that for all drugs, and if
all of the people, giving patients greater responsibility for their care
and empowerment, I think, is very important thing, and if there was a
1-800 number on every prescription including all the literature, the DTC
advertising that we could use to our benefit, even a yellow sticker on
the prescription pill bottle, and the information sheet that the
pharmacist gets, we could have an adverse\[event\]reporting system that
more greatly expands the ability for patients, their doctors, their
clinicians, to easily self-report it.

It can even be a system where it\'s a computer generated thing where you
have a menu system. Obviously it has to be triaged. Not all side effects
are equally the same. There is mild ones. There\'s medium ones. There\'s
high risk ones. There would have to be some development in that.

But there\'s a way of gathering more information than we get now, and
you might be surprised at what you\'d actually get from a result of
that. I think that this alone would be an extraordinarily good thing,
and I would add that I wouldn\'t only do this for prescription drugs,
but also for OTC and herbal supplements, which I think are something
that\'s tremendously overlooked, and as we\'ve seen, these natural
therapy herbal supplements actually have very severe drug interactions
at times that are at points certainly injurious, and at times deadly for
patients. Particularly \[for\]people with AIDS, St. John\'s Wort \[has
had\] terrible complications with protease inhibitors. So that\'s one of
the proposals that we\'ll be taking up in Minneapolis.

Another proposal, and I think this is a very modest one, and this is
something that has grown out of\--in 1997\--I\'m sure that people that
are here from that era used to know that AIDS used to get special
privileges at the FDA. It was something that we constantly heard.

So in 1997\--we\'ve never asked for those special privileges\--and
thankfully in FDAMA we got rid of some of those special privileges. We
had a clinical trials information system that was posted on the internet
for years. Now, we have clinicaltrials.gov for all serious and
life-threatening illnesses. That\'s good. We have never wanted those
special privileges.

We also had an accelerated approval which now, of course, is fast track
and it\'s in the law. And it was also something that, you know, we
wanted everyone else to have. We didn\'t feel that just people with AIDS
should have that.

One of the things people with AIDS currently have, and this isn\'t done
through the FDA, is we have a web site called aidsmeds.com, where an
AIDS patient can go and then could put their drug regimen in, including
herbal supplements and over-the-counter drugs, and it will spit out a
report, and this is done in combination. Some of the pharmaceutical
companies have been generous enough to work together with the
organization that does this. And the report comes back with the
drug-drug interactions and the drug-food interactions, and it rates them
as low, medium and high risk of interactions.

And this is terribly, terribly important, and particularly that I\'m
serving on this committee which is looking at Medicare and Medicaid, and
when you looked at senior citizens who, most of them take a minimum of
six drugs, probably many of them taken with grapefruit juice, have no
idea what the effect is on the medication, may be getting no benefit
from the medication.

And it was very interesting. The nursing home people, the home health
people, there are people on the committee who think this is a fabulous
idea, and would be a wonderful tool for people to have. And this is a
simple idea that I think could be implemented relatively quickly, and
the way the advisory committee works, that we\'re going to make
immediate reforms, intermediate reforms, and long-term reforms.

And this is something that I don\'t think is that complicated, because
you have a template for it already\--aidsmeds.com. I would encourage all
of you to take a look at it and see how it works. Obviously there can be
a disclaimer that you need to talk to the doctor, but the information
has been terribly helpful for people understanding that, you know, drugs
do have interactions that have terrible consequences.

I unfortunately just had a friend that was hospitalized in New York in a
psychiatric institute because it turns out that protease inhibitors wipe
out Wellbutrin. He was on a very high dose of Wellbutrin, and then they
measured his blood in the hospital, there was no Wellbutrin in his blood
at all. He tried to commit suicide.

And they were shocked that there was no Wellbutrin at all, and they
found out there was interaction between protease inhibitors and
Wellbutrin that wipes it out entirely. This is the kind of stuff that\'s
very, very important. As I\'m sure all of you know, the California Board
of Pharmacists recently issued a report that showed there\'s 100,000
deaths from adverse drug events annually, at a staggering cost of \$177
billion in additional health care which is not money that we have right
now where we\'re scraping for cash for health care, and these are
unnecessary injuries, unnecessary deaths, and unnecessary costs for
money that we don\'t have in the system right now. So I think something
like this is a very simple tool that can help people quite a bit.

One of the other proposals that we\'re going to have is the current
MedWatch system, as I said, only collects a small amount of information.
There is a huge pool of information out there in managed care companies,
in other data bases, in Medicare, and other HMOs and things like that,
where they have adverse event things.

I happen to be serving on a panel with Humana. Humana actually has very
detailed medical records on every single one of their patients,
including what drugs they are allergic to, which drugs have reactions
to, and what adverse events have occurred. And there is this huge pool
of information out there, and it would be my ideal and my dream to have
an information technology system that would automatically pick out
reports of adverse event reports, adverse drug events and medical
errors, and have this go into some sort of central collection system.

Currently, my suggestion would probably be to use the CERTS, the Centers
for Education and Research on Therapeutics, simply because of your
inadequate funding. Unfortunately, I think the potential for them doing
it may be better, and you can certainly work with them in combination,
but at least this information would get collected and then can be turned
over and looked at and used and hopefully improve things.

I know most people on the panel obviously are very familiar with the
CERTS. People in the audience may not be. I would encourage everyone to
get their annual report from last year and you can see the extraordinary
work that they\'ve done even by going back and looking through patient
records, and finding out things about arrhythmias and other side effects
and it\'s unfortunate again they\'re also funded at a very meager
amount, \$299 million a year, but I think the potential is there, and I
know someone from the CERTS will be speaking this afternoon, and I look
forward to that quite a bit.

And our recommendation is going to be \[that\] a working group be
established of all concerned stakeholders to develop a \[better\]
adverse event reporting system and collection with the CERTS.

I\'m sort of running out of time here so let me get to one last thing
that I think is very, very important, and this has been an issue that is
percolating on Capitol Hill now, and perhaps the committee can head off
legislation and maybe things can happen faster. But there has been a sea
change in how institutional review boards work and \[also in\] clinical
research organizations.

We used to have not-for-profit IRBs, and we also had basically
not-for-profit clinical research organizations. Now, we have for-profit
IRBs and for-profit clinical research organizations. We don\'t have any
system at the moment that does any sort of accreditation of the IRBs,
and this is sort of the wild, wild west of clinical research, and it
goes back to my first comment, that you can\'t have good risk management
unless the beginning part is fixed.

So one of the suggestions that we\'ll be taking up, and this has been
recommended by the Ethics Advisory Commission. This is not a new idea.
It certainly is not an original idea. For those of you that have the
benefit of reading the Time magazine from April 22, 2002, the front
cover was a very excellent story about human guinea pigs that really
described the problem in clinical research.

And the recommendation is that we have a single office for protection of
human subjects in clinical trials. Now that doesn\'t mean that it would
eliminate all the other agencies\' offices that they have, but that it
would clarify the rules that people have to operate under, and given the
high profile failures that we\'ve had in some clinical trials lately,
undermining the trust that we have in the clinical trial system would be
detrimental to medical research in this country.

People have to trust the clinical trial system, and we need to have
people have faith in the clinical trial system for medical research to
move forward, and having a single office to control this and looking at
accrediting IRBs, looking at every aspect of it, to make sure that the
clinical trial system is designed to protect the patient interest while
we advance, realizing there is an element of risk I think is a very
important thing.

And the last thing I\'d just like to finish with is that, and this has
been, you know, an ongoing thing. This is nothing new for those of you
that are familiar with me. I find it appalling that Congress continues
to fund the FDA at a meager amount of \$1.7 billion a year when you\'re
responsible for 25 cents of every dollar of the gross national product.

It\'s amazing that you can actually do what you do with the limited
amount of money that you have, and we have a public health care system
that\'s out of whack. We have NIH that\'s funded at \$27 billion. We
have the CDC that gets \$20 billion, and then for the funnel that
actually gets these amazing medical advances out to the public is this
little drip of money. And it\'s appalling. Some of you are probably
familiar with Senator Hatch who occasionally comes up with good
proposals at the FDLI, who recently proposed that the FDA\'s budget be
taken out of the Department of Agriculture and go straight to Congress
like Social Security and some other budgets because of the hope that you
would get some more funding.

And I think until the FDA gets more resources, all of these things that
are very ambitious unfortunately will never get done unless Congress
lives up to their responsibility to fund the FDA. And I thank you for
the ability to talk today.

DR. GALSON: Thanks a lot. And I want to just clarify my instructions at
the beginning. Each speaker has 20 minutes, and then we\'re going to
have a 20 minute question and answer period after the entire panel, not
after each speaker. I shouldn\'t have asked after the first speaker, but
since we\'re way ahead, we\'re okay.

Our next speaker is Dr. Sidney Wolfe who is going to speak on behalf of
the Public Citizen Health Research Group. Dr. Wolfe.

DR. WOLFE: Is this mike turned on now? Yes, it is. Just a couple of
comments. One, the fact that we\'re meeting at the National
Transportation Safety Board should not be viewed as the beginning of
separating out drug safety from the FDA. I was as many of you know not
one of the people in favor of creating a separate out of the FDA body
for drug safety. There are serious problems going on with drug safety,
but I think that they have to be addressed and hopefully will at some
point be addressed within the FDA as opposed to something like the
National Drug Safety Board.

The other issue just mentioned by Jeff is resources. We now have had ten
years of experience of resources coming through the Prescription Drug
User Fee Act, which means that of the total, at least modern era since
1906, 96 year history of the FDA, 86 years the FDA was thought so
important, and it is, that the funding came through the appropriations
process, and now for reasons having to do with tight budgets and a
number of other issues are really I think unacceptable, there\'s been
this tendency to start getting the money directly from the industry and
it comes inevitably with lots of strings attached, the strings that were
attached in the side deal that is about to be passed, concerning ways in
which post-market surveillance money will be spent with the industry
being able to inculcate itself more than before.

I think it\'s dreadful and I think that eventually prescription drug
user fees will have to be stopped. They are sort of the beginning of, in
some ways, the end of some of the more important issues that the FDA has
to deal with.

In order to more fully explore this topic of risk management as it\'s
titled, we\'ve broadened the discussion to include, first, the processes
of acquiring risk information by the FDA and, secondly, the processing
of the information by the agency to evaluate the nature of the risk as
well as the process of deciding on risk management itself and risk
prevention, more importantly.

And finally, the topic of better dissemination of information is clearly
stated as one of the purposes of this hearing. Both prior to approval
and after a drug comes on the market, there\'s a need to get much more
complete and prompt data from industry. To motivate the industry, there
is a need for much more criminal prosecution of reporting violations.
Back now, almost 20 years ago, we helped to initiate successful criminal
prosecution of SmithKline, now GlaxoSmithKline, and Lilly for failing to
report serious adverse reactions including deaths on two drugs that they
made, Selacryn,(SmithKline); Oraflex,(Lilly).

After that Herkes was criminally prosecuted successfully for withholding
information on Merital. All three of those drugs came off the market and
it is arguable that none of them would have come on if this information
prior to approval had been submitted.

More recently, we have raised questions about criminal activity on the
part of Warner Lambert for withholding some important details of clear
evidence of hepatotoxicity with Rezulin prior to approval, and for some
reporting problems with Redux, Wyeth Ayerst American owned products.
Yesterday, we asked for criminal prosecution of Abbott, based on an FDA
inspection of the company in the last few weeks in which there was some
manipulation of information on eight deaths that occurred with Meridia.

We suspect that there is far more than meets the eye there. A physician
who used to be the head of Drug Safety Monitoring with NOAA before it
was bought by Abbott came to us complaining of many of the same things
that FDA found in its inspection, and we have arranged last month I
believe for this physician to talk with FDA staff including the Office
of Criminal Investigation.

I suspect the more you look for these kinds of things, the more you will
find, and given the present absence of civil monetary penalties,
although these kinds of things clearly reach the threshold of criminal
violations, there just needs to be more enforcement. We\'re taking a
look now at a lot of what appear to be reporting violations from a
number of different companies.

Second issue having to do with the acquisition of information about risk
has to be the question why are FDA epidemiologists not sent out to track
down possible point source drug-induced epidemics. This is something
that the Centers for Disease Control and Prevention have been doing
through their Epidemiological Intelligence Service officers for decades
and decades for infections.

The magnitude and severity of many of the drug induced epidemics is just
as severe and life threatening as many of the infectious disease
outbreaks and yet this doesn\'t seem to be done. A couple recent
examples\--in the case of Lotronex, the company, Glaxo, made it appear
as though the early cases prior to approval of ischemic colitis were
related to infections as opposed to being drug induced.

And at that point, given that this was not a rare event, it\'s an event
that appears to be occurring as often as one in a hundred patients, it
would have made sense to go out there and do some epidemiological
intelligence work.

This is not to say that most of the time on the part of FDA an
epidemiologist should be used for this, but it is to say that there need
to be at least some pilot programs to \[figure\] this out. I think it\'s
almost never been done.

There also needs to be much better coordination with academic
epidemiologists and clinicians doing such studies. I mean it is not
infrequent that I will see a report in the [Annals of Internal
Medicine]{.underline} or other places about liver toxicity with a drug,
and it is not clear that early on way before the article was submitted
or at the time it was submitted that FDA was involved and could sort of
start its own resources going to try and explicate some of the problems
that have been raised.

Since risk and benefit must be considered together, certain risks are
intolerable if it\'s a drug for treating allergy which would be
tolerable if it were a drug for treating cancer. We need to have more
head to head trials of efficacy so that the benefit-risk balancing can
be more accurate.

Some of this, I think, could be accomplished now with some FDA guidance
documents. Some of it would probably require a change in the law. Dr.
Woodcock appealed to drug companies back four or five years ago at a
conference at NIH to try and do more head to head trials. Obviously, it
would be a benefit to doctors, to insurance companies, to HMOs, and most
importantly to patients.

We published an article a couple weeks ago in the [Journal of the
American Medical Association]{.underline} pointing out, not terribly
surprisingly, that over a 25 year period after a drug comes on the
market these days, the odds are one in five that it will either be taken
off the market or be subject of a new black box warning.

In other words, it is the first bunch of years, half of them in the
first seven years, that a drug has problems, and if the drug isn\'t
arguably any more effective than an existing drug, the default should be
not to use the new drug and to use the older drug.

But this would be much easier to accomplish if there were far more
head-to-head studies.

Fourth, as has been mentioned by both of the previous speakers, it\'s
clear that if the reporting of adverse drug reactions to the FDA rose
from the current estimated ten percent, generous estimate, to 20
percent, it would take only half as long to accumulate the number of
reports of deaths or injuries necessary for post-approval decision to
ban or to put a box warning on a drug.

Despite successful experiments, some funded by the FDA and some funded
by others, which have shown remarkable increases in adverse reaction
reporting, if you get involved and make it less passive, this concept
has never been nationalized or even regionalized on an ongoing basis. In
France, there is a series of pharmacovigilance centers which collect, I
think, much more accurate and complete data than we do here.

In Rhode Island, and this is a paper published in the [Journal of the
American Medical Association]{.underline}, an FDA funded project
resulted in a 17-fold increase in adverse reaction reports submitted
annually from Rhode Island to the FDA compared with the yearly average
before the project.

Similar increases were not experienced nationally. There were some
increases but nowhere near the 17-fold.

The next topic that I said I would discuss is the processing of risk
information by the FDA, both, again, before approval and afterwards,
this being a necessary pre-step, obviously, to making decisions about
risk prevention as in not approving a drug, or taking it off the market,
or \[instituting\]risk management.

There must be a major effort to prevent risk management from becoming a
device to rescue and salvage drugs that should be withdrawn. Recent
examples include Lotronex, Meridia, Posicor, Rezulin, Duract and so
forth.

There have not been enough serious critiques of the previously failed
risk management efforts that ultimately resulted in withdrawals. I
remember back 20 years ago, Bob Temple initiated a review of silicone to
find out what \[went\] wrong, and I think there was some useful
information from that, but we certainly haven\'t seen a rigorous
post-mortem on these mistakes which I think most of them are.

It\'s interesting that it coincides with a dramatic and dangerous
decline in the autopsy rate in this country, which was 45 percent after
the Second World War. It\'s now about nine percent. And I think that we
need to restore both the autopsies of people who are dying and also of
drugs that turned out to be a mistake either in approval or in failure
to take them off the market more quickly.

One of the reasons the morale in the Center for Drug Evaluation and
Research appears to be lower than at any time in my view in 30 years has
to do with what Dr. Janet Woodcock has amply described as the quote
\"sweat shop environment\" created in the wake of the Prescription Drug
User Fee Act.

In a survey by FDA of CDER personnel last year intended to find out the
reasons for the high rate of staff turnover, the problems found included
the following, quote from the survey:

\"About one-third of respondents did not feel comfortable expressing
their different scientific opinions. Over one-third felt that decisions
such as holds, refuse to file actions, and non-approvals are stigmatized
in the agency. Over one-third felt that their work has more impact on a
product\'s labeling and marketability than it does on public health. A
number of reviewers added comments stating that decisions should be
based more on science and less on corporate wishes.\"

These results are similar to those of a survey we conducted in late 1998
of CDER medical officers which found that 27 times medical officers
stated that their decisions against approving drugs were overturned by
their superiors. They also cited 14 instances in the past three years in
which they had been instructed, usually by the office director, not to
present their own opinion or data to an FDA advisory committee, when to
do so might have reduced the likelihood that the drug would be approved.

More recently in this hearing that occurred a few weeks ago on Lotronex,
it is clear from what we have learned from talking to people in the FDA
that one of the presentations at that meeting by an FDA person was made
more benign in terms of the views about what should be done about
Lotronex than it should have been.

Fortunately, in the written statements, there was at least some
suggestion as to a much stricter approach to what would happen if
Lotronex came back on the market, an approach so strict that it really
would be more compatible with a clinical trial than with a marketing
decision.

So this suppression of people being able to say what they want to and
what makes sense and what is scientifically based is certainly a way of
destroying morale.

As I have discussed with at least the last four or five people running
OPDRA or the Office of Drug Safety as its now called, there has been a
historic split, an imbalance of power between drug review divisions and
the post-market surveillance, now Office of Drug Safety Division.

Having an atmosphere not conducive to scientific inquiry and dispute
results in esteemed epidemiologists such as Dr. Paul Stolley leaving the
agency. Dr. Stolley has been the president of all three of the major
epidemiological associations in this country, has published hundreds of
papers and came to the agency with the hope that he could help out with
his expertise in these issues on better post-market surveillance.

But he was really very badly treated there as a result of his
involvement in Lotronex and left the agency a year before he was
planning to. He\'s on our staff now. So we are the benefactors of it,
but it saddens me to think that people of his stature cannot be retained
in the FDA. Unless this poisoned atmosphere is changed, others will
leave for sure.

Third issue under this processing of risk information is the failure to
remove drugs thought too dangerous in other countries from the U.S.
market. Recent examples are Trovan/Trovafloxin, which was taken off the
market entirely in Europe, whereas in this country it was left on the
market only to be used in nursing homes and with hospitalized patients.
It is a fluoroquinolone antibiotic, the ninth approved since 1986 with
no evidence of any advantage clinically over any of the other ones, and
clear evidence of liver toxicity.

Prior to its approval, ten percent of men in a study to try and see
whether it could be used to treat prostatitis, ten percent of them had
significant liver \[enzyme\] elevations, and it was put on the market, a
mistake, and it\'s been left on the market, another mistake.

Other recent examples are Tolcapone, again taken off the market in
Europe, left on the market here in a restricted way, but still on the
market. And Orlaam, which amongst many other drugs has significant
evidence of QT prolongation, an electrocardiographic abnormality, which
increases the likelihood of life-threatening ventricular arrhythmias.

Fourth under this topic, the failure at any consistent policy for box
warnings. Recently, both Actos and Avandia, two pioglitazone diabetes
drugs, have had bold warnings put on, but not box warnings. We have
asked the FDA to put much stronger warnings on for these drugs, and this
week we received an anonymous phone call from a physician at
GlaxoSmithKline who was alarmed at the failure of his own company to
require a black box warning concerning heart failure caused by Avandia.

He maintained that the company currently has 450 reports of heart
failure associated with the use of the drug and over 1,200 reports of
edema.

Other examples in this category, and it bespeaks the fact that there
isn\'t a consistent and even reasonably clear policy as to what the
threshold is for putting black box warnings on \[labels\], is the
recently approved drug for treating schizophrenia, Geodon (ziprasidone).
Again, we have serious evidence of QT prolongation, and it has been
approved without a black box warning.

However, there are a number of other drugs which we list here, Serentil,
Mellaril, Trisenox, Inapsine, Orlaam and Sporanox, which do have black
box warnings with similar degrees of QT prolongations. So the policy is
just not very consistent.

I think I just have about five minutes more. I will try and summarize
the rest. Risk management must be evaluated just as our clinical trials
of well-designed studies for assessing outcomes. The oft-stated mantra
of quote \"all drugs have risks@, although true, does not mean that
quote \"the risks of all drugs are acceptable.\"

The FDA and the drug companies which increasingly fund the FDA are
causing the public to tolerate, as indicated above, many unacceptable
risks. What about communication on safety to patients and to doctors? I
think first we need to look at what has not worked.

Failure of most pharmacists and physicians to provide useful drug
information. First, in the area of verbal information the FDA conducted
surveys in \'92,\'94,\'96 and \'98 to find out how much information,
including risk information, is received by consumers.

For orally provided drug information, the percentage of consumers who
were counseled about at least one category of information has increased
but slowly. In 1998, 24 percent of people were given both directions for
use and risk information at the doctor\'s office, and 14 percent were
told both directions and risk at the pharmacy.

In 1997 an Office of the Inspector General report found that the
enforcement of federal and state oral counseling laws requiring
pharmacists to provide verbal drug information has been minimal.
Pharmacists are qualified to provide this information, but they practice
in an economic environment that doesn\'t allow the reliable provision of
this kind of information.

Written information. An analysis of the types of written information
consumers received with prescription drugs found that in 1998, 70
percent of Americans received written information that was longer than a
brief sticker on the medicine container. This figure compares with lower
figures in \'96 and \'94. However, the percentages do not reflect the
quality or usefulness or lack of quality and usefulness, as is the case,
of this information prepared by unregulated commercial information
vendors.

We petitioned the FDA in 1998 to ban distribution of written drug
information provided by pharmacists produced by unregulated vendors
because of its misleading nature that renders it dangerous, and we\'ve
done surveys of two categories of these labels, one on NSAIDs and the
other on fluoroquinolones.

Medication guides. The single most important risk management strategy
the FDA can undertake has been mentioned earlier this morning is in the
short term to reduce the public risk from preventable adverse reactions
by going forward as rapidly as possible with regulations to require
pharmacists to distribute scientifically accurate useful written drug
information or medication guides approved by the Agency.

Unfortunately, the FDA has been blocked by trade groups representing
pharmacists, physicians, and the pharmaceutical industry for over 20
years to implement regulations that would place objective,
scientifically accurate written information about prescription drugs in
the hands of the public.

The history of this can be found in FDA\'s failed 1995 proposed rule for
MedGuides. The FDA now only has limited authority to require
distribution of MedGuides and it\'s only been used rarely. Public Law
104-180, signed in 1996, required FDA to conduct a national survey to
assess the quality and quantity of written drug information for
consumers voluntarily being distributed by pharmacists.

If these quality and quantity standards were not met, consideration
would have to be given to providing the public with useful and accurate
information by regulation. The assessment was to have been completed by
January 1, 2001. The failure to meet the deadlines in the new law
without FDA taking over the MedGuide program constitutes a violation of
the terms of this 1996 law.

FDA has proposed a lot of revisions in the professional product
labeling, and we agree with many of them, including indicating that
it\'s a new drug as opposed to not a new drug. We would also argue that
what should be included is \[that\] there is no evidence this drug is
any more effective than previous drugs, if this is the case, which it
usually is.

However, the same kind of logic that would better inform doctors should
also be incorporated into the mandatory MedGuides - that will hopefully
start occurring one day when the voluntary industry effort is shown
clearly, which looks like the case now, to have failed.

Another thing that needs to be done is much more active and well-staffed
enforcement by DDMAC to counter the often false and misleading
commercial advertising messages. I have a chart in this testimony
showing through the first half of 2001 basically a 50 percent decrease
in enforcement actions which are warning letters or notices of violation
letters sent out by DDMAC to the pharmaceutical industry.

It peaked in mid-\'98 at 84 violations in six months, and it\'s gone
down to 36 and 38 in the last part of 2000, the first part of 2001. The
last part of 2001 it stays down at the same low level, and we are still
waiting for a backlog of such letters that is being processed now by a
new guidance by the Office of General Counsel in the FDA.

Misleading advertising kills people because if doctors prescribe drugs
that are more dangerous and less effective than they are led to believe
or that patients are led to believe, because of the ads, this is a bad
decision which can result in deaths.

Expand the Freedom of Information Act and the Federal Advisory Committee
Act so that there is much earlier access prior to approval of data that
is generated by the FDA. We now have a 24 hour interval before an FDA
advisory Committee meeting when on the internet some of the safety and
efficacy information that the FDA has processed goes up. It should be
much earlier than that.

Public accessibility to the AERS, or Adverse Event Reporting System data
base, needs to be happening more promptly. There is currently about a
five month hiatus between when the last data went up and now. They are
missing data for the first parts of 2002.

DR. GALSON: You\'re finishing up, right?

DR. WOLFE: Right. I have one more point to make, which is to encourage
Medicare and Medicaid and other health service facilities \[to use\]
safer formularies that exclude the large number of recently approved
me-too drugs such as those that have come off the market.

It\'s interesting that the Seattle-based not-for-profit Group Health
Cooperative of Puget Sound did not allow many of these drugs, most of
them, that came on and then off the market on the grounds that there is
no evidence that they had any advantage over existing drugs, and there
was some concern about safety.

We would strongly encourage Medicare \[as it\]begins to start paying for
more drugs and Medicaid to start saying no to the large plethora of
risky, newer me-too drugs that have no evidence of any advantage over
existing drugs.

Thank you.

DR. GALSON: Thanks, Dr. Wolfe. Our next speaker is Dr. Allan Korn
representing BlueCross BlueShield Association. Thank you, Dr. Korn.

DR. KORN: Good morning. I am Dr. Allan Korn, the Chief Medical Officer
of the Blue Cross and Blue Shield Association, and I\'m speaking here
today actually on behalf of RXHealthValue, a coalition of more than 20
national organizations representing consumers, employers, unions, health
plans, and, yes, providers.

Our membership is broad and diverse, and includes numerous prominent
consumers and purchasers of pharmaceuticals such as the American
Association of Retired Persons, Families USA, Midwest Business Group on
Health, Ford, Daimler-Chrysler, the United Auto Workers, AFL-CIO, Kaiser
Permanente, the Alliance of Community Health Plans, and, of course, the
Blue Cross and Blue Shield Association. And I truly appreciate the
opportunity to speak before the FDA on the critical issue of risk
management for prescription drugs.

RXHealthValue believes that an integral part of delivering new drug
therapies to physicians and consumers is assuring consumer safety after
the drug has penetrated the market. In addition, our coalition believes
that the rapid flow of new drugs to market must be accompanied by health
outcomes information that allow consumers to make value driven
decisions.

We also support continued increases in federal appropriations for the
FDA to provide resources for agency programs that may truly impact
public health.

Driven by the performance goals set forth in the Prescription Drug User
Fee Act, the FDA now acts on new drug applications with great speed
under considerable pressure. This can result in inadequate clinical
experience with new drugs before they\'re marketed.

At the same time, massive promotional effort to physicians and consumers
result in accelerated market penetration of these same new drugs.

This one-two combination - faster approvals with less clinical
information and more rapid market uptake -means that risk management
functions are critical to maintain the same level of public safety with
respect to drug utilization as in years past, and that we\'ve all come
to depend upon the FDA to provide.

Unfortunately, many serious adverse drug reactions can emerge long after
FDA approval. According to recent research published, as you all know,
this month in [JAMA]{.underline} by Lasser, \"only half of newly
discovered adverse drug reactions are detected and documented in the
Physician\'s Desk Reference within seven years after a drug\'s
approval.\"

The FDA clearly acknowledges that pre-marketing trials in a few thousand
uncomplicated patients do not detect all of the new drug\'s potential
adverse effects. For example, 12 drugs, as we all know, have been
withdrawn from the market since \'97 due to safety concerns including
Lotronex in 2000 and Baycol in 2001, et cetera.

Nevertheless, pharmaceutical companies continue to market new drugs
heavily, though the full range of potential adverse drug reactions is
not known at the time of approval. One can only imagine the numbers of
patients who might be awaiting heart value replacements if direct
consumer advertising were employed during the brief but tragic heyday of
Fen-Phen. Direct consumer advertising may promote the public health by
encouraging patients with undiagnosed and untreated conditions to see
their doctors. However, use-inducing advertising raises issues with
respect to consumer safety in the absence of complete information about
product benefits and risks.

FDA resources for critical safety monitoring activities for new drugs
have not kept pace with market developments. Although RxHealthValue
believes that recent user fee implementation takes a step in the right
direction by authorizing fees for post-marketing surveillance, the
public interest in a high standard of safety for approved drugs requires
a commitment to long-term predictable funding for the Food and Drug
Administration.

Because the safety of new therapeutic agents cannot be known with
certainty until the drugs have been on the market for a number of years,
we believe it is important for manufacturers to provide information that
allows the FDA, consumers, prescribers, yes, and even purchasers, to
compare drugs for the same condition on the basis of benefits, risks,
and costs.

RXHealthValue recommends that FDA should promote initiatives that
require manufacturers to provide information comparing the relative
safety and value of new agents that will substitute for existing
effective agents. Moreover, consumers should be provided this
information in the format the permits a quick evaluation of the relative
risk, benefit and cost of comparable drugs.

For example, the FDA could devise a safety index that compares the
safety data on new and existing drugs for the same or similar
indications. Such information should appear in labeling and advertising.

RxHealthValue believes that labeling of new drugs and advertising should
be clear and simple and convey relative information on risk and value
whenever possible, perhaps as simply as by using the color code on a
label.

Description of critical information such as adverse events should be in
layman\'s terms so that patients can understand potential harms.

Further, we believe the FDA should consider whether labeling should
include information on the underlying clinical trials reviewed by the
agency during the approval process including the number of trial
subjects, the duration of trials, and most importantly the age and
gender distribution of trial populations, that is, whether seniors or
women participated in them.

In addition, RxHealthValue recommends that drug labeling and advertising
include a toll-free number for reporting of adverse events by
clinicians, and, yes, by patients, to the FDA. When the FDA identifies
serious adverse drug reactions, it should review all drugs in the same
class to determine if a class effect is likely.

Changes in labeling and black box wordings for adverse drug events
should be implemented rapidly, highlighted and dated.

Drug advertisements should also include information that informs
patients that their doctors may prefer to describe alternative therapies
for their condition. RxHealthValue applauds the FDA for maintaining an
excellent web site that tracks adverse drug event reports. We believe
that the web site should be promoted to prescribers and health plans and
medical societies could also help increase awareness of this excellent
resource.

Beyond the web site, we hope that the FDA believes that it needs to be
able to reach prescribers quickly when a significant adverse drug event
is identified and a drug needs to be withdrawn or severely restricted in
use. To accomplish this, RxHealthValue recommends that the Food and Drug
Administration develop the capacity to communicate directly with the
nation\'s prescribers.

For example, the FDA should be able to contact all practicing physicians
by e-mail and a national list should be developed and maintained.

Health plans and professional organizations are eager to work with the
agency on this effort and support the creation of a national drug safety
communications infrastructure.

For example, health plans and pharmaceutical benefit management firms
can assist the FDA in monitoring potential adverse drug reactions among
health plan members. The health plans and PBMs can track alerts from the
Food and Drug Administration and identify patients prospectively
receiving drugs in question.

Alert letters can then be generated to patients and to the physicians
treating those patients and health plans and PBMs can reinforce these
alerts within their own pharmacy networks.

Only a very small percentage of adverse drug events are currently
reported by clinicians under voluntary reporting policies. Under a
recent initiative launched by the Blue Cross Blue Shield Association and
its member plans, a collaborative model was presented to the FDA\'s
Center for Drug Evaluation and Research, which if successfully
implemented will permit the agency to identify most of the currently
unidentified, perhaps 19 out of 20, unreported adverse reactions.

RxHealthValue wishes us both godspeed in this undertaking. PDMs and
health plans may thus surely be able to play a role in identifying
adverse drug reactions. RxHealthValue recommends that the FDA considers
developing incentives for clinicians to report known adverse drug events
as a part of the overall drug development of an activity safety
surveillance system.

Finally RxHealthValue believes that the public interest in a high
standard of safety for approved drugs requires a commitment to
predictable long-term funding for post-marketing regulatory activities.
We recommend promotion of policies to better identify risks, benefits
and values associated with new drugs, better communicate these risks,
and better track adverse events.

Health plans and PBMs may and will play an important role here. Thank
you again for the opportunity to speak today. We look forward to working
with you on this important public health and public safety issue. And on
a personal note I will add only that we recognize that the FDA is
fulfilling its mission completely and ultimately. We know that when a
drug is released to the market today, it is fully tested.

I would submit that fully tested still means incompletely understood. To
deny this is untruthful. Not to act on it is unwise if not unethical and
I challenge all in the industry to rise to the occasion. Thank you.

DR. GALSON: Thank you very much, Dr. Korn. We were scheduled for a break
after Dr. Korn\'s, but since we\'re a little bit ahead, I think we\'d
like to go ahead with the next speaker if that\'s okay. Dr. Jim Kotsanos
and Dr. Gretchen Dieck are representing the Pharmaceutical Research\--

DR. SELIGMAN: Dr. Galson, we\'re supposed to have questions now before
that.

DR. GALSON: I\'m sorry. I\'m sorry. Yes, yes. Yeah, I guess it makes
sense to do it now after half the speakers so why don\'t we do that.
Thank you for pointing that out. Let\'s start out with questions.

DR. HOUN: Thank you for coming and sharing your views with FDA. I had a
couple questions for some of the different panelists. One is, Dr. Lee,
you made suggestions about active and mandatory adverse event reporting,
MedGuides for all medication, and civil money penalties for lack of AE
reporting, and some other suggestions.

Does your organization feel FDA has the current authority to do all
these things?

DR. LEE: With respect to civil monetary penalties for, for example,
companies that are required to perform post-marketing safety studies but
do not perform them, I don\'t believe the FDA currently has the
authority to impose any significant penalties in that case.

This is in contrast to the situation for medical devices where the Safe
Medical Devices Act of 1990 explicitly gives that authority. It\'s
puzzling why the FDA does not have similar authority with respect to
prescription drugs.

As for mandatory adverse drug reporting by health professionals, I
don\'t know why the FDA would not have the authority to do that. I
assume if that\'s not the case, if they don\'t have the authority, it
certainly should be given to the FDA. Right now I think this voluntary
reporting process is highly inefficient. I think the reports that do go
through and are logged into the FDA system are relatively selective, and
so it\'s a selected group of adverse events that are reported.

Sorry. I don\'t see any reason why the FDA should not at least be more
actively engaged in encouraging adverse event reports. Certainly, the
FDA could send out notices to physicians requesting adverse event
reports on the drug after it\'s been approved. I don\'t see any reason
why the FDA has no authority to do that.

DR. HOUN: Dr. Korn, you had suggested that FDA develop incentives for
clinicians to report adverse events. What types of incentives can you
share with us?

DR. KORN: I think that\'s wonderful grist for our collaborative mill. I
think that our health plans and PBMs would be delighted to work with you
to develop the kinds of incentives in our various contracting strategies
to encourage physicians to do this type reporting. It\'s something that
we would do together.

DR. HOUN: You also had mentioned the health plans and PBMs could track
alerts and identify patients receiving drugs in question. What is your
organization\'s review on restricted distribution medication? So far
there have only been a handful of drugs that come under regulatory
authority for restriction, and how does your organization feel about
that risk management tool?

DR. KORN: I think that we feel that if it helps the American consumer to
use pharmaceuticals more safely, that we would certainly support any FDA
effort to implement such strategies. We\'re neutral on whether they\'re
good or bad. You tell us that.

What we have for you is the infrastructure to make it happen, to link
prescribers to drugs or combinations of drugs in such ways that at the
moment of prescription, we can identify potential hazard and intercede
on your behalf. So as a national policy issue, we certainly would be in
favor of anything that would enhance safety and would be ready, I think,
to help you put the infrastructure in place to make it really work.

DR. SELIGMAN: I\'d be interested actually in the other members\' of the
panel view on restricted distribution programs as well, if there are
any?

DR. WOLFE: We\'ve had a couple of examples. One, 24 years ago,
Phenforim, and secondly, Cisapride, which were not restricted
distribution. They were available under an IND. I think that FDA\'s
ability to control what is going on and to protect patients is far more
enhanced under an IND than it is under some form of restricted
distribution.

As I was mentioning before, when the discussion started focusing down on
what to do with Lotronex, the I think most appropriate of the series of
suggestions made at least in the written statement by FDA was pretty
much restrictive to the point where it would much more reasonably happen
under an IND.

If we\'re talking about making a drug available to a few thousand people
it would seem that the option is far safer to do it under an IND than
under restricted distribution. FDA has equivocated for a long time on
whether it thinks it has legal authority. We petitioned FDA about 17
years ago to restrict the use of Accutane to dermatologists and to do a
few other things, and FDA really never chose to do that.

So I think that if the entire package that\'s being considered is
restricted distribution which may well be to a small number of people
and/or an IND availability, I would opt for the IND availability.

I would just like to comment, though, on one other thing that was just
asked, which is this whole issue of adverse drug reaction reporting, and
when I was a resident in internal medicine, back, 30 plus years ago, I
believe that the FDA or the Public Health Service gave the residents\'
fund, the lunch fund\--this is a different form of lunch as opposed to a
drug company lunch\--\$20 or something like that for every adverse
reaction report that was filled out. That\'s one thing that happened.

A second thing though is when FDA used to send out the Drug Bulletin, we
did a tracking and found that there was a wave of adverse drug reactions
\[reports\]. Dr. Korn has sort of alluded to this a little bit. There
was a wave of adverse drug reaction reports that followed every issuance
of the Drug Bulletin. In other words, the unavailability of a form right
there to fill out obviously appeared to be a limiting step, and there
was always, after the publication of this \[Bulletin\]and sending it out
to every doctor, this was available.

But I think that neither doctors nor patients know that right on the FDA
home page is the form to be filled out, the MedWatch form. It does not
take very long to do, and it can be used for both doctors and patients.
I think it needs to be explained much more.

Every time I give Grand Rounds in medicine in various places around the
country, and frequently I will say how many people here have seen an
adverse drug reaction in the last month or two, and I even ask several
of them to describe it, and I say how many of you have reported these to
the FDA? Rarely is there more than one or two persons. I mean once I
think I brought MedWatch forms and handed them out.

But the point \[is that\] there are a number of creative ways, short of
making it mandatory. I think that it would be a little bit difficult
since FDA is said to regulate prescription drugs and other items, rather
than the practice of medicine, to make it mandatory on the part of the
physician, but between the Rhode Island experiment, which worked very
well, and other more local ones, there is a whole range of options that
if taken will clearly increase the number of adverse reaction reports,
and therefore the rapidity with which FDA will be able to do something
about the problem that is being described in these reports.

MR. BLOOM: If I could comment on that? If I can comment on this as well.
I think you clearly have to separate that question into two different
areas. Obviously, for people with serious and life-threatening
illnesses, there are different considerations in terms of restricting
access as opposed to me-too drugs. People with serious and
life-threatening illnesses obviously accept the fact there is going to
be a certain amount of risk when the alternative is death when you take
drugs.

But unfortunately right now in AIDS care, 50 percent of the people in
AIDS care \[have\] the side effects of the AIDS medicines as opposed to
the disease. And nothing is being really done very much to find out
exactly what\'s causing these side effects. Your restricting access to
it wouldn\'t improve the health of these people because the alternative
would be death, so I think it has to be done very cautiously.

I will say this about talking about the adverse event thing. One of the
benefits of being on this panel with HHS is that I\'ve had the benefit
of traveling around the country, and interestingly enough in Pittsburgh,
they have something called the Pittsburgh Regional Health Care
Initiative. The web site is www.PRHI.org, and through a cooperative
effort with insurers, carriers, hospitals, they have actually been able
to, they set a target using Toyota management systems, and they\'ve been
able to reduce in-hospital infections and medication errors almost to
zero.

So it shows that these things can be done and they are achievable, and I
think that\'s one of the things that certainly everyone could do is look
at the best practices that are going on in different areas in different
regions and adopt those practices and expand upon them, but it\'s not an
intractable problem, and quite frankly people were stunned at how well
this program works, and the fact that it\'s not done more\--it\'s also
done in coordination with the CERTS, and I do believe FDA had a role in
creating a program as well.

And, you know, restricted access is something that you don\'t want to
set up a two-tier system where some people are lucky enough to get some
drugs and some people aren\'t, and that\'s, you know, that\'s always a
touchy thing, and for people with serious and life-threatening
illnesses, I just don\'t think it\'s a very good option obviously. We
are willing to take the risk, but we\'d like to know what the risks are
and have some control over what happens after they\'re out so we can
find out what\'s actually happening, because we\'re willing to be the
guinea pigs, but we\'d like to be able to have the study done to find
out what you are learning from us.

DR. BULL: This question is directed at Dr. Korn. Could you expand on the
concept of the safety index for drugs?

DR. KORN: I think that as we go through the pre-approval process, I
think one of the things that would be very interesting and probably
meaningful is to include others, in that, in terms of analysis of the
data that could be made public and particularly the formulation of the
final document and get a sense in terms of drugs what the known risks
are and the anticipated risks might be.

And then come up with some scale of relative safety that might be used,
and by the way, that\'s a dynamic, not a static, process, one that we
have to acknowledge. For example, what we learned about Viagra after its
release, we might have changed the color of the label after several
months before we finished the studies on patients with heart disease,
for example.

But I think the concept is worth pursuing in terms of what we anticipate
the risks would be, and then over the next five to seven years, as we
learn more about what the risks really are. And I think as time goes on,
the label color would be a far more meaningful indication to a patient
and/or prescribing physician that it\'s something to pay attention to
here. On this one, read the PDR.

You know maybe MedWatch is something you ought to have your secretary
print and bring to you every week, rather than just delete before it
gets lost in e-mail, you know, whatever.

So I think it\'s a concept we\'d like to explore with you, something
that is simple and easy to deal with, and would be dynamic over time,
and ultimately would probably properly categorize the drug and catch the
attention of those whose attention we need to get.

DR. BULL: Question for Dr. Wolfe. You had alluded to some concerns
regarding the ability of reviewers to make their opinions known. What
improvements would you recommend in that regard?

DR. WOLFE: Well, again, this is based on the FDA\'s own survey last year
and ours. Obviously, differences of opinion are going to occur and no
one should try and suppress differences of opinion. But it seems that
asymmetrically, I mean we ask the question how many times did you think
a drug should have been approved and wasn\'t, and there were six of
those as opposed to 27 of the other. So it\'s very asymmetrical, but I
think that the larger issue is that open discussion and debate is not
exactly encouraged. People are sort of silenced, told not to make these
views known in an FDA advisory committee and so forth.

I think the scientific method is such that it can\'t thrive really
unless there is open debate and discussion and on the merits of the
science and the medicine \[about which\] the decision is being made, not
as was pointed out in FDA\'s own survey on the basis of corporate
pressure. I mean when any significant number of people perceive that,
and again that was the FDA\'s survey, not ours, that means that the
atmosphere is really not very good, and particularly when the drugs that
were identified or alluded to in these surveys were drugs which have
subsequently come off the market. You know that at least more often than
not, these people were right.

So I think it\'s recreating the kind of scientific -I mean I was at NIH
as was Bob Temple for awhile - and I think that an open scientific
discussion there and elsewhere needs to happen. Otherwise, people are
not encouraged to come to an agency and will leave more quickly as seems
to have been going on for the last few years.

So I think there needs to be some open adjudication process if there is
a difference of opinion rather than just sort of saying the person up on
top is going to win and rule the day and the person, the medical
officer, the physician who spent most of the time reviewing this is not
going to have their way taken. It\'s anti-scientific.

I\'d just like to comment on the question about the risk index.
Obviously, risk index is in proportion to the benefit. There was an
excellent paper presented I think by some researchers from Hopkins a
couple of weeks ago at the Society of General Internal Medicine meeting,
and it was a study of the use of different drugs for stopping atrial
fibrillation and then maintaining a normal sinus rhythm.

And they had used a huge data base to find out how effective these drugs
were at either converting someone with atrial fibrillation to a normal
rhythm and separately maintaining normal rhythm. They also had data from
this data base on the incidence of drug induced arrhythmias, and for
some drugs, they were very good at both converting and/or maintaining
and the incidence of arrhythmias was very low, and so this to me is an
example of how within a class of drugs you really need to make this
decision that evaluates both benefit and risk and come up with something
that really is useful both to the prescribers and the patients rather
than just focusing on safety. I don\'t think you meant to say that you
wanted to focus just on safety.

DR. KWEDER: I wanted to follow up on the three speakers who spoke about
types of reporting and again go back to that if we might. Dr. Lee, you
did talk about mandatory reporting of adverse events. We have a small
system in this country where reporting is mandatory, which is the VAERS
system for childhood vaccines. One of the issues that comes up with that
is who enforces that? Who enforces a mandatory system?

Certainly, the FDA doesn\'t have a mechanism for enforcing and ensuring
that physicians are reporting everything they see.

Mr. Bloom, you spoke about the expanded access programs which I agree
have in the past at least for HIV drugs provided us with a great deal of
safety information that ultimately was relevant in us understanding the
profile of the drug at the time of marketing, something that otherwise
would have taken - DDI comes to my mind as well - would have taken
several years for us to have available.

But again that\'s an IND mechanism; that\'s not post-marketing. And then
Dr. Wolfe, you mentioned the Rhode Island project, which was an FDA
funded program. I think that there were several others. I think there
were three of them. I forget what the other\--

DR. WOLFE: Maryland was another one.

DR. KWEDER: Yeah, Maryland was one, which was, you know, sort of one
time funding that we had to run that. That was not mandatory reporting.
It was basically promoting reporting in a local community.

DR. WOLFE: The Rhode Island one was the same kind of thing. It\'s just
sort of cheerleading, organizing and encouraging; right.

DR. KWEDER: Exactly, yeah, exactly, which was what the agency tried to
do when MedWatch was first launched.

DR. WOLFE: Right.

DR. KWEDER: But funding for that program has subsequently dwindled, you
know, once it was out there, although it still exists, but not in the
form that it was at that time.

I guess I\'d like to hear from you just your thoughts about the pros and
cons of trying to develop a mandatory reporting system that would
certainly require legislation as VAERS did, because our current system
specifically does not make it mandatory, as well as pros and cons of
promoting more expanded-access type programs under INDs.

And in terms of thinking about programs like Rhode Island and Maryland,
how could FDA better partner with state health authorities, pharmacy
boards, medical boards, to facilitate enforcement and even encouragement
of these kinds of programs?

DR. WOLFE: Well, as you know, for medical devices, at least as of 1990,
the law was modified to require facility reporting, hospitals, as
opposed to just the manufacturer of the medical device. I can see that
for average drug reactions, since some of the most serious ones result
in hospitalization, that an intermediate approach to having mandatory
physician requirement for reporting, which I have mixed feelings
about\--I\'m not sure that\'s a great idea\--but I think that if somehow
hospitals, as they are for devices, were required to report adverse drug
reactions, that this would again greatly increase the rate and
completeness of reporting.

I think the pharmacovigilance program in France is, in fact,
hospital-based so there are some examples for that. But I think that
there are too many things. As Jeff said, we have lots of good examples
of a lot of solutions to problems, and they\'ve never been taken
seriously or nationalized. I mean the FDA tried and it worked, and then
didn\'t have any budget to do it. I think if you look globally at the
cost of health care and the cost of the 100,000 deaths and the million
and a half hospitalizations a year, caused by adverse drug reactions and
believe that these could be at least reduced somewhat by faster more
complete average drug reaction reporting, the cost of that cheerleading
kind of system and encouragement system I think would seem very small
compared with the money that is saved.

Of course, it comes out of lots of separate pots except for an insurer
like Blue Cross. In a sense, it comes out of the same pot. So, I think
there are a lot of people that haven\'t really thought through this, a
lot of institutions. If they did, they would, I think, support a budget
for the FDA or other entities that would encourage through mandatory
hospital reporting, or encourage doctors wherever they are in the
hospital or not, to report these things.

It\'s too good of an opportunity not to take advantage of, and, again,
it\'s been tried in other countries, and it seems to work. We just
don\'t do a very good job of it.

As far as the restricted distribution question, I mean I was talking
really about drugs where an alternative may be taking them off the
market entirely. I was not talking, as Jeff was talking about, a drug
for a very dangerous condition such as cancer or people who are HIV
infected. I was really talking about a risk prevention/risk management
decision after it becomes known or even before marketing that a drug
really has some serious problems, but yet you want to make it available
to a relatively small number of people.

I think that\'s a very different logic than a drug that should be
marketed if it\'s effective for treating cancer or a new drug for adding
to what is known for the treatment of AIDS.

MR. BLOOM: As far as the pros go, I think the pros far outweigh the
cons, and as far as a hammer, if you want a hammer, you know, the best
hammer obviously is Medicare. With 39 million Americans, it\'s the
largest health plan in America. It\'s not that hard for the federal
government to say report these things or you don\'t receive your
Medicare and Medicaid money. It\'s a perfect example of a way of getting
these things reported.

And as far as the health plans go, as far as the patients go, the
benefits to avoid the adverse events and the deaths and the injuries and
the suffering to the patients and their families, not to mention the
extraordinary costs in this era of shrinking dollars for health care
that are so necessary to provide good health care for people, instead of
paying for adverse events that are avoidable, I mean \$177 billion a
year. Just focus on that number for a second.

If you could cut that in half, that\'s \$88.5 billion. Even 25 percent
is \$44.25 billion that could go back into treating people. I\'m sure
RxHealthValue would rather spend their money on keeping people healthy
and well than having people paying for injuries and avoidable deaths
from adverse drug events. I don\'t think there are very many cons.

As far as your IND question goes, I think it\'s a shame that we don\'t
have those larger expanded access programs, particularly well people
don\'t have options anymore. We have a very large AIDS population now
that are resistant to all known therapies. It\'s growing and growing
more and more, and for those people, they have no options.

And when they\'re very small expanded access programs, it\'s very, very
distressing to people, and if you\'re lucky enough to be connected to
the right researcher or have the right avenue, you get in the expanded
access program, but unfortunately a lot of people don\'t.

And I think those large programs do that, and I wouldn\'t look at risk
assessment and risk management as just as post-marketing. I think it\'s
a continuum. I think dividing this out into IND and then post-marketing
isn\'t really the way to look at drug safety. I think drug safety starts
when the first patient enrolls in a clinical trial, and it continues for
the whole life of that drug.

We need to look at it as a continuum of how we study it and not dividing
it up into these different parts. But it\'s actually the life cycle of
the drug on a market and the product.

DR. KWEDER: Can you just, to follow up on that, do you think that there
should be\--you said that for expanded access programs that a particular
need exists for people who have no other options. It\'s been proposed by
some that we should have expanded access programs more broadly to better
learn about things prior to marketing when we have better control over
what happens to the drug ultimately. So would you be in favor of
expanding the concept of expanded access at pre-marketing to other kinds
of conditions or needs?

MR. BLOOM: I certainly think that if you could make a good public health
case to get the information that you need because we don\'t have the
benefit of having the drugs available in Europe first and you have lost
all that information, and that would help us identify a better safety
profile and get the information to better understand the drug before
it\'s on the market, I certainly don\'t have a problem with that.

I think the problem is with me-too drugs, you\'d really have to evaluate
the benefit versus the risk before you approach that. But, you know,
it\'s a question of what the perfect example is, I think going to
arrhythmias and high blood pressure, it\'s a well-known thing GM has
been able to control their costs basically by making sure that people
that can take atenolol instead of very expensive high blood pressure
medicines that are newer, they\'ve been able to keep their medical costs
at \$700 million for the last three years by having good prescription
benefit managers.

And there\'s a lot of older drugs on the market that we have a much
longer history and a much better safety profile, but of course there is
not that much interest in selling a drug for \$4 when you can sell one
for \$150 instead. And so that those longer histories, getting back to a
safety profile, I think that\'s very important, but, yeah, absolutely,
if you think there is a good public health reason for it, and we can
gain some good information for it, I see no problem with that at all.

I think anything that we can do to make drugs safer and more effective
and learn more about them to make sure that people are taking them
\[safely\], and people have to realize that all drugs have unknown side
effects. All drugs have risks. We have to get away from this concept
that drugs are safe and effective, because there are unknown risks when
they\'re approved, there are unknown things that we don\'t know that
happens, and there are unforeseen risks with all drugs, and to make a
blanket statement that they are safe and effective for the label
indication, as far as we know.

One of the things that we would certainly endorse and recommend is that
if a drug has not been studied in a particular combination with other
drugs, that it should be on the drug label and the package insert that
this drug is unknown how to be used with these drugs, no clinical trials
have been done, and the risk or benefits of using this drug in
combination with these drugs are unknown at this time.

And we really don\'t make that very clear right now in the packages, and
if there haven\'t been any clinical trials done in combinations with the
drug that\'s on the market, it should clearly state in the package
insert the risks and benefits are unknown at this time, use at your own
risk.

DR. GALSON: Dr. Korn, did you want to add something?

DR. KORN: A plea. I would venture that the low reporting rate by
physicians is partially due to the unavailability of a form or
inattention, but I think it also has a great deal to do with the
administrative frustration that physicians feel with the system in
general right now. One more thing to do. Uncompensated, unappreciated.

And so my plea, and by the way, health plans feel it in spades, so we
are all aware of the fact that this is an issue and that for lack of a
better target we\'re blamed.

My plea, and I think some of you may be aware of it, is that because of
the importance of this issue, we somehow work collaboratively with those
who impose administrative burdens on all of us to define an agenda that
truly will move the needle on the safety issue and improve public
health.

NCQA has already expressed an interest in partnering with us to see if
they can consolidate some of the requirements of those which are going
to be meaningful. How that plays out in the world, we don\'t know, but
it certainly is important in the HMO world, and I salute Dr. Greg
Pawlson the Chief Medical Officer, for at least saying he would like to
discuss this to see if there is a role to conserve resources, minimize
administrative hassle, and get the entire nation focused on two or three
or four or five meaningful problems, so that at the end of a set period
of time, we have done something.

Because right now in that world everybody does their own thing according
to what a particular customer wants, and at the end of the year, nothing
has changed.

In the non-HMO world which is even larger, we have the URAC and the JCAH
worlds to consider and URAC is very important here. I mean if we\'re
talking about pre-authorization kinds of programs or whatever, that\'s
their bag, and if there\'s a way, again, to work with them, to
streamline some of what\'s out there and not really having a great
effect, but it\'s easy to measure, therefore we measure it, and use
existing or fewer resources to do it, we\'ll be better off.

The problem I hear is that we\'re going to be doing something else, and
(a) nobody has got the resources for it, at least on the health plan
side, and (b) nobody has the patience for it on the provider side.

We want to make it simpler. We want to make it better. We want to make
it work. And I think we need to work much more collaboratively with
other players to actually breathe life into it, and we\'re committing to
be a part of that process.

DR. GALSON: Dr. Lee.

DR. LEE: I do appreciate Dr. Korn\'s remarks and while I do agree that
it would be a good step to, for example, with respect to mandatory
adverse event reporting, to put much of the responsibility on hospitals
and health care plans, I do recognize that there will be some resistance
to that.

I think one way that some of the resistance can be minimized to some
degree is to make sure that the FDA provides feedback to those
individuals and institutions that provide adverse event reports. Many
times the physician will fill out an adverse event report and hear
nothing about it ever again.

This will be obviously require far more personnel than the FDA currently
has available for monitoring adverse events. I\'d be interested in
hearing how many personnel the FDA currently employs to monitor adverse
events, but I think the number of personnel needs to be increased to the
point where providing feedback is feasible for, you know, any set of
adverse events that are reported for a particular drug.

If a new drug is generating a significant number of adverse events,
everybody who has submitted a report on that drug should receive some
feedback in a timely fashion from the FDA about how many reports are
coming in, how many are similar to the events that they reported. And I
think this will provide some useful information to health care providers
and may minimize at least some of the resistance that mandatory
reporting is bound to generate.

MR. BLOOM: Dr. Korn wasn\'t here when I was giving my presentation, but
I would like to reiterate that on the regulatory reform committee, we
will be taking up a proposal that addresses this issue, because we are
very sensitive to the fact that that doctors, nurses, health care
professionals spend an awful lot of time doing paperwork that they could
otherwise spend treating patients.

And that\'s where, you know, information technology is a great tool, and
if we can come up with information technology systems that automatically
kick out reports about adverse event reactions, adverse drug reactions
and medical errors, and no one has to fill out any forms. They\'re
filled out already. It automatically kicks out the things. There are
systems available now, and it\'s a question of making the investment,
and when you\'re spending \$177 billion on the cost right now of adverse
drug deaths, it doesn\'t take a genius to figure out that we can invest
some money in information technology to have these reports kicked out
automatically where we don\'t have to have a system where people are
going to be burdened with extra administrative burdens of filling out
reports. And I really think that information technology offers great
opportunity in this area.

DR. GALSON: Great. We\'ve gone over our 20 minutes for questions for
this panel. There is time if there is one other pressing one from the
panel. John.

DR. JENKINS: Yeah. I\'d like to ask the panel members to speak to
something that I know is a complex struggle. It\'s the intersection
between FDA regulation of prescription drugs and implementation of risk
management strategies versus practice of medicine. And it\'s one we
struggle with a lot.

Risk management strategies can include education which probably everyone
would view as being good, but then you can escalate the risk management
strategies all the way up to withdrawal of the drug from the market
which is the ultimate risk management strategy. All of those have
increasing impacts on the ability of physicians to practice medicine and
to treat patients in the way they think is appropriate for those
individual patients that they\'re seeing in their office.

I\'d be interested in hearing panel members\' views about the role and
the intersection between implementation of risk management strategies
such as restricted distribution, restrictions on who can prescribe a
drug, and weighing that against the ability of physicians to
appropriately practice medicine.

DR. KORN: A couple of brief responses to that. No physician harms a
patient knowingly. I mean I believe that with all of my heart.
Unfortunately, many physicians treat patients with incomplete knowledge.
Who would have done Baycol with Gemfibrozil had they only read the
materials they needed to know?

And so the statement that physicians need to practice as they see fit is
true insofar as they\'re practicing with a full and complete database,
and they often are not. And I would submit that that\'s not necessarily
an indictment of anything that physicians are doing differently, but it
wasn\'t very long ago that when a new drug came out, those of us, and I
was in general internal medicine and medical oncology in the early days,
when a new drug came out outside of my field, we generally let the
specialists use it for a year or two in the hospital. That\'s what
happened.

They read the obscure journals that report on these drugs and they go to
the meetings that report on impact on patient populations they treat,
and over a period of a year or two, it trickled down to the rest of us
through conversations with doctors and on curb-side consults. That\'s
how it worked. Those of us who would read drug reports in the major
medical journals didn\'t know what the drugs were because they only used
chemical names and we didn\'t recognize them, and because we didn\'t
read about them coming along the way, we had no idea what they were
talking about.

And since they weren\'t yet in the PDR, we couldn\'t even look them up.
Now something has changed. Okay. We don\'t have that opportunity anymore
because the day after you approve the drug, it\'s on TV, and that
physician is under pressure to use it probably before he knows what it
is and has had the opportunity to become comfortable with and at least
have it endorsed by trusted specialists in the area that he had
previously relied upon.

So the paradigm has changed enormously, and yet the mind-set of the
practicing physician has not. Can we wait for that to happen? I suppose,
but how many more recalls will there be or do we need to put something
else in place to deal with this one-two punch\--faster approval,
immediate market penetration with patient demand upon people with
incomplete data, demands upon people with incomplete data on which
they\'re now making decisions, assuming they\'re safe because they\'re
FDA approved\--and that simply is not true. So that\'s what has changed.

DR. WOLFE: When we and others have made efforts over the last 30 years
to try and get FDA to do certain things, the mantra that comes back is
we regulate drugs, not doctors, which is really what Dr. Jenkins\'
question is alluding to, the problem of an agency that does regulate
drugs and doesn\'t directly regulate doctors.

But I agree with Dr. Korn, there is ever-enhanced need for rapid
dissemination of information to physicians. It is not likely that it\'s
going to be disseminated through the 18 plus billion that are being
spent this year on promoting prescription drugs mainly to doctors and to
some extent to patients. And the doctors also see these same ads which
are as often as not misleading.

So someone is already interfering with the practice of medicine and
it\'s called the pharmaceutical industry by massive expenditures of
overstatements of benefits usually, understatement of risks frequently,
and the question is what can be done to neutralize that? We have for a
long time proposed to various FDA commissioners that the FDA needs to
use the information it has to get much more involved in medical
education. That is not to say to start an FDA medical school but to make
available slide shows.

For instance, the FDA has an excellent MedWatch slide show. I would bet
that most people in this country have never seen it at all. It can be
duplicated. Someone who doesn\'t work for the FDA can show it, and it
has case examples, the feedback that was discussed a few minutes ago of
why it\'s important to report these examples of drugs that wound up with
stronger labeling and in some cases being taken off the market as a
result of what came into the MedWatch program.

So I think that FDA has not scratched the surface in terms of the role
it can play in educating medical students, residents, and physicians
after they get done with practice as to what kinds of things to look
for. What is your algorithm when you have a new diagnosed hypertensive
patient who comes into your office or newly diagnosed diabetic patient
about accepting the newest drug? Is there evidence that it\'s any better
or as good as other drugs?

I think that the whole issue of educating physicians on how to make
prescribing decision and how to fend off, which is the best advice most
of the time for most of these me-too drugs, it\'s just not done.

The amount of time in medical education for this is very minimal. We
have done some informal work ourselves teaching various medical schools,
but I think that the FDA has got enormous amount of data that could
easily be converted into slide shows. They could pilot test them around
the country. A little bit of this was done at Georgetown a few years
ago, but I don\'t think it was ever followed up on. So a number of
historically clever FDA ideas have not been nationalized, have not been
followed up, have not been expanded on.

I think the education of physicians is the best way of dealing with this
issue of FDA not being able to dictate the practice of medicine, but
being able to educate it and make it much safer.

MR. BLOOM: I would certainly concur with Dr. Wolfe\'s comments, and just
to add to that, I think, you know, one of the disconnects is we have a
very aggressive drug approval process, but we have a very passive
adverse event reporting system right now, and what the FDA needs to do
is balance out the information and provide the best information about
the risk and benefits as quickly as possible about drugs when they come
to the market.

And to add to Dr. Wolfe\'s point, if I go to my doctor\'s office and
it\'s about lunch time, there are frequently more drug detailers in the
office than patients waiting to see the doctor, and when they\'re 70,000
drug detailers going into offices right now with information, usually
within several days of approval of a drug launch, there\'s an imbalance
between the information that comes from the industry and from what the
FDA has to put out.

And while, you know, risk management is a concept that for AIDS in
particular I\'m very uncomfortable with because it is such
individualized therapy and it really does have a lot to do with the
particular patient and the particular doctor, and I really don\'t think
that there is probably a role for getting involved in dictating the
practice of medicine to doctors, because different things work for
different people. It\'s such an individualized case, that it would be
extraordinarily difficult, but the responsibility to provide as accurate
as possible information about the potential risk and benefits I think is
enormous and extraordinary, and unfortunately you\'re not funded well
enough to do this well.

DR. GALSON: Okay.

DR. SELIGMAN: I just have a quick fairly narrowly focused question
related to the accessibility of the AERS data base and this is a comment
that you raised, Dr. Wolfe, and I was curious as to what thoughts you
might have as ways that we could improve public accessibility to the
AERS data base as well as utilization of those data?

DR. WOLFE: Well, we are also not only the benefactor of having your
former employee, Dr. Stolley, working, but Dr. Dee Knapp, who helped
develop some of these adverse reaction reporting systems, is now also on
our staff, and I have asked her about that. I mean the point I raise is
that we only have data through the end of 2001 now so it should be made
more promptly available, but also it\'s in a very difficult to use
format, the stuff that\'s publicly available.

I mean if you\'re sitting in the FDA with more fields available and
Oracle software package you can do something with it. But if it\'s going
to be made publicly available, I mean we have figured out some ways of
doing this, but there are lots of other people who I think would be
using this system to inform themselves, inform the physicians and
patients who they are responsible for if it were in a more user friendly
form.

So I think that we would be glad to have discussions with you just from
our experience of trying and I think succeeding up to a point to use it
as to how it could be made more user friendly, because there is no
question that large insurance companies, Medicare, Medicaid I\'m not
sure use the AERS database as much as they should given all the people
who they\'re paying for drugs for. So we\'d be glad to have those
discussions with you.

DR. GALSON: Okay. That was a very successful first panel. Thanks
everyone. We are right on schedule now and I\'d like to have a 20 minute
break. We will start back here promptly at 10:20. Thanks.

\[Whereupon, a short break was taken.\]

DR. GALSON: First, I want to welcome Dr. Janet Woodcock who has joined
us here on the panel, Director of CDER.

Second, if folks have handouts that they want to make available, the
best place for that is on the table out in the lobby, and there is room
for them there. So if there are things that you want to hand out and
make available, please put them back there.

For the FDA staff who are here, we will try to make sure to go around
and see whether you have written questions for the panel to ask, but if
no one has collected them, just walk right up here and give them to us
if you have questions.

And I want to take this opportunity to thank the staff from CDER who
have worked really hard to put this meeting together. It\'s a huge
challenge. It\'s going flawlessly. The preparations really, really went
well, and the panels have been set up beautifully. So I want to thank
Chris Bechtel, Lee Lemley and Khyati Roberts for all their hard work in
putting this meeting together. Thanks.

Okay. We\'re going to go ahead and start the second panel. The first two
speakers sharing the time are Jim Kotsanos and Gretchen Dieck from
PhRMA. Go ahead, Jim.

DR. KOTSANOS: Thank you. My name is James Kotsanos. I\'m a physician at
Eli Lilly and Company and Eli Lilly and Company paid for my travel to
this meeting.

I am speaking on behalf of the Pharmaceutical Research and Manufacturers
of America.

DR. GALSON: Is your mike on?

DR. KOTSANOS: Does it work now? My name is James Kotsanos. I\'m a
physician at Eli Lilly and Company and Eli Lilly and Company paid for my
travel to this meeting. I\'m speaking on behalf of PhRMA, the
Pharmaceutical Research and Manufacturers of America as chair of the
Safety Committee.

We appreciate the opportunity to speak here today. PhRMA represents the
country\'s leading research-based pharmaceutical and biotechnology
companies. PhRMA members are devoted to inventing medicines that allow
patients to lead longer, happier, healthier and more productive lives.
The Safety Committee serves as an expert scientific resource within
PhRMA on clinical safety matters incorporating benefit to risk
assessment.

This includes collaborations with many external groups. For example, our
collaboration with the FDA and the Centers for Education and Research on
Therapeutics, the CERTS, have resulted in a series of workshops on risk
management, communication and assessment.

For decades, pharmaceutical companies have had a sustaining commitment
to promote safe use of medicines as a top priority. Companies are
committed to expanding the understanding of the safety of a medicine
throughout its life cycle. A large proportion of all data collected in
the clinical trials are collected for safety purposes.

By way of example, at the company that I work for, we receive over
20,000 lab values per day from ongoing clinical trials and a vast
majority of these results are used to evaluate patient safety.

Once a medicine is marketed, companies continue to monitor the safety
through aggressive surveillance. The pharmaceutical industry is the
provider of most of the post-marketing adverse events received by the
FDA.

For example, in year 2000, 94 percent of over 250,000 spontaneous
adverse event reports received by the FDA came from pharmaceutical
companies.

In addition to collecting and analyzing adverse event reports,
pharmaceutical companies commonly conduct large post-marketing
retrospective and prospective studies to further understand the
benefit-risk profile of their medicines.

A significant number of additions to safety sections of drug labels are
initiated by the industry. No medical intervention is entirely risk free
and therefore the goal of post-marketing surveillance is to provide
ongoing assurance that there is an acceptable balance of benefit to
risk.

The determination of what is acceptable will depend on the severity of
the disease being treated and the risk of treating versus the risk of
not treating. The only way that pharmaceutical companies can be
successful is if the medicines that they discover and develop are
beneficial to patients and provide an acceptable risk profile.

Risk management programs have the potential to enhance safer use of
medicines. These programs require that we use the best science available
when developing the information to be used in decision-making and also
that we maintain flexibility in how we practice risk management across
different categories of drugs and even across different patient groups
for a single drug, understanding that there cannot be a
one-size-fits-all approach to risk management.

Achieving this potential requires that we work together in partnership
with the FDA and health care practitioners to fully understand both the
benefits and the risks of our medicines. We must communicate these
effectively to prescribers and patients.

Dr. Gretchen Dieck will further discuss these concepts.

DR. DIECK: I have some slides. Is this on?

\[Slide presentation.\]

DR. DIECK: Great. I\'m Gretchen Dieck and Senior Epidemiologist for
Pfizer although I\'m here speaking on behalf of PhRMA. And I\'d like to
discuss today the concept of balancing risk with benefit of products,
and this is an important concept. It\'s very difficult to think of one
without the other.

I also look at it as a dynamic sort of evaluative process that goes
forward in time because medical science itself is advancing and
therefore we\'re constantly learning new things about the drugs and what
they do and new information about mechanism of actions.

A very simplistic example is how we\'ve treated pain and reducing fever
over the years. In the Middle Ages, you applied leeches to your arms and
legs, and this was considered standard medical practice, and I\'m sure
it was thought to be safe and effective at the time it was used, but
medical science advanced, and we had aspirin that unlike leeches
actually was effective at reducing pain and reducing fevers, and unlike
leeches it had a risk associated with it of gastrointestinal toxicity,
ulcers and so forth.

The benefit was there and the risk was there, and aspirin continued to
be used safely among many people. As medical science then advanced, we
have our Cox 2 inhibitors that have the same effect on fever and
reducing pain, but are felt to have a lower gastrointestinal risk or
toxicity.

Now, if we follow Dr. Wolfe\'s model, and aspirin was removed from the
market, perhaps we wouldn\'t have learned new things that aspirin can do
such as being protective against heart disease. So again you have to
constantly evaluate the risk and benefit as medical science progresses.
And now the Cox 2\'s are also being evaluated for new things and
benefits that they can do, perhaps reducing the risk of colon cancer or
delaying onset of dementia.

So this is a concept with which I want to talk about the evaluation of
risk and benefit. I won\'t go over again what Jim has said. The benefits
of drugs are what they\'re supposed to do. We provide innovative
medicines that do good things, but as it\'s already been stated before,
the risks are also there with drugs. There is no medicine that has no
risk, but I think it\'s the collective goal of everyone in this room to
try to provide maximum benefit to patients with minimal risk.

I don\'t think there is anyone here that would disagree with that goal.
How do we strike this delicate balance between them? One of the things
that we\'ve been talking about is the area of risk management. Risk
management can be thought of as components, more umbrella system that
has many components to it. We\'ve heard it described as risk detection.
We\'ve heard it described as risk minimization or risk communication and
perhaps we can broaden the concept to include both pre-approval and
post-approval time periods which was something that was also suggested
earlier this morning, and the concept of risk management really is over
the whole life cycle of a drug.

There are many things that we can learn pre-approval that help us to
minimize risks in a post-approval time period.

Our ultimate goal of risk management is the patient. There is another
way we can think of risk management and how it can provide benefit or
structure for us to move forward in evaluating benefit and risk. We have
many risks throughout our lifetime, and one of the risks you may have is
with managing your household budget. If you don\'t plan ahead, it\'s
very easy for that to get out of control and very costly to bring it in
control.

If you plan ahead, and this is one of the most important concepts of
risk management, you can help minimize risks.

And what are some of the things that we can do in terms of planning
ahead, and what are some of the things we can do in the pre-approval
time period? We can carry out proactive studies up-front to help us
evaluate how patients differ or how they\'re the same and how drugs work
in an certain situations. We can look closely at signals we may get from
clinical trials, and actually evaluate them in other ways using other
techniques and methods.

We can use proactive design of post-marketing surveillance studies. For
instance, if we suspect that there is an issue that needs further study,
we can plan a study ahead of time that it would be available at the time
of approval that would help us build our knowledge about the risk and
benefit of the products.

And this is one way that we can minimize safety issues before approval
and manage them better in a post-approval time period.

As it\'s been stated earlier today that the baseline knowledge that we
have when a drug is approved is based on extensive testing that\'s done
in the clinical trial program, and this includes pre-clinical as well as
clinical, and it can include studies in thousands of patients up to
perhaps 10,000 patients.

The public expectation of what our knowledge is at approval may be that
we\'ve actually studied it in millions of people, and that we can
identify risks that are as low as one per 100,000 or one per million,
and this is not something that is available. Again it\'s something that
the public expects. But how do we build that knowledge? And how can we
help in the understanding of how we all work together to build that
knowledge?

Here again we see that as a result of the clinical trial program, we can
identify commonly occurring adverse events and we actually get an
incidence rate. It\'s one of the most important forms of information
about how frequently adverse event reactions occur with our products.

Then we can carry out studies that look at the background epidemiology
of the disease. What do we mean by that? If we\'re developing an
anti-hypertensive drug, we can look at anti-hypertensive patients. We
can look at their similarities. We can look at their differences. We can
find out whether or not those differences or similarities are important
in how that drug works in them.

We can look for other risk factors that are important to understanding
the disease, the disease process or how the drugs work. For instance,
looking at whether people smoke or whether people are overweight, and
for instance with the increasing knowledge about how oral contraceptive
use has been related to smoking is the fact that we know that women that
smoke have a greater risk of thromboembolism, and this is something
that\'s been developed. It\'s part of the building of knowledge as we go
forward.

Some of this we can actually look at in a pre-approval time period and
try and minimize risks before the drugs are approved.

After the drug is approved, we can use the spontaneous reporting system
that\'s been discussed a lot this morning. And it is an important tool
for identifying signals and particularly in identifying signals of very
rare events. But it\'s only one tool and only one method that we need to
build our knowledge about the benefit and safety of drugs.

But it does also help us sort of raise the level of risk that we can
detect to much smaller numbers. Then we can do focused observational
studies. Here the concept this morning was discussed where you can
actually compare drugs that have similar benefits and see if ones are
safer than others or whether drugs should be used in certain populations
differently than others, and again it helps us to build our knowledge
about how drugs can safely be used.

And we can again try and find and detect even lower and lower risks. And
then we can do other types of studies, hemodynamic studies that can help
us learn how the drug impacts the cardiovascular system. We can do
studies that help us learn how the mechanisms of the drugs work inside
the body itself, and can help support what we feel we\'ve learned about
the benefit and risk of the products.

It\'s all of these tools combined that are necessary to help us learn
what\'s happening with the benefit-risk balance, and they have to be
evaluated constantly throughout the life of the product in terms of
bringing new knowledge and evaluating the information in light of the
scientific medical advances.

We need to tie the risk management tools to a formal process. It\'s
really the responsibility of the pharmaceutical agency in large part to
bring important types of information to the regulatory decision-making
process. If the types of studies that we\'ve been discussing,
observational studies, epidemiologic studies on background rates,
targeted types of studies that go back to the clinic or to the lab,
these are types of information that the pharmaceutical company can bring
to you and augment the spontaneous reporting system information and help
us make regulatory decisions.

Partnerships with the regulators is critical. We need to reach a
consensus on areas of risk that need to be explored and then plan how
we\'re going to assess and how we\'re going to interpret the information
as it comes forward.

Any guidelines that are developed should be developed and based on
tested systems. There are many things that we can hypothesize that may
work in terms of helping to manage and minimize risks, but it\'s
important that these tools actually be tested to see if they work and
which ones are more successful than others. It\'s important to keep
flexibility, enough flexibility in the system to account for different
drugs doing different things, and some are easier to study and others
are harder.

One way that we\'ve been working with the regulatory agencies,
particularly with you at FDA, is to try and incorporate the concept of
risk management, and by risk management I mean the whole spectrum of
risk management, both post-approval and pre-approval, is to have it part
of a prescription drug user fee reevaluation, and here I\'m not going to
go through all the actual components of that, but again it\'s using very
much the techniques that I\'ve discussed earlier and bringing forward
information that we can collect more clearly and efficiently in the
pre-approval time period to help minimize risks before the drugs are
even on the market.

An important part of this process is that there\'s FDA concurrence with
the plans and that you understand what we\'re looking at and that you
rereview on a regular basis whether the risk management plan is
effective or not.

Now, one of the comments that was made earlier was about the two to
three year end of this formal risk management process, but I don\'t see
it that way. I feel that for many, many drugs, two to three years is
certainly sufficient to understand the concept of risk and benefit but
for other drugs it\'s not. And I don\'t see that the dialogue with the
agency would end after a two to three year period. We\'re constantly
evaluating the balance of benefit and risk.

Industry has also contributed to trying to develop new tools or working
new ways to help identify risk in creative ways and some of the examples
that we have are the use of automated databases. Many of these are
provided by managed care. Our colleagues at Blue Cross/Blue Shield have
large amounts of data that help us to analyze data in a very rapid way,
and again it\'s something we can bring to the decision-making process.

The development of registries. For instance, pregnancy registries, in
some instances these are set up by specific companies alone, or they may
work together to support an academic registry in certain therapeutic
areas such as epilepsy. And in these ways we can contribute to finding
out more information so that the physicians can safely monitor or
counsel patients who have to take a chronic disease medication during
their pregnancy.

We need to ensure that the use of systemic approaches are used for
managing risk, and here again it\'s to raise everyone to the same level
in terms of what our responsibility is bringing more and complete
information to the decision-making process.

So, in conclusion, I feel that risk management is an important part of
the balance, evaluating the balance of benefit and risk. It really is
across the whole spectrum of the drug\'s life cycle, and there are many
things that we can do in the pre-approval time period to help minimize
risk in the post-approval time period.

And we\'re constantly trying to raise the bar. I don\'t agree with the
statement that new drugs are riskier because they are new. One example
we can look at how cancer therapy has been developed over the years in
the \'60s and \'70s. This is an area where very high risk is accepted,
and those therapies may have been effective, but they had debilitating
side effects.

In the \'80s and \'90s, new drugs were developed that minimized some of
these debilitating side effects, and now in 2000-2001, we\'ve a
breakthrough product with Glevick which takes a formally fatal disease
and makes it a chronic disease with very low risk, and I hope we don\'t
stop there. I hope we continue to raise the bar with what we do and try
and find, bring even more benefit with even lower risk. Thank you.

DR. GALSON: Thanks very much. Our next speaker is arriving late, so
we\'re going to go ahead, if it\'s okay, Dr. Cranston, move on to you.
Dr. Joseph Cranston is here representing the American Medical
Association. Go ahead.

DR. CRANSTON: Good morning. Is this on? My name is Joseph Cranston. I\'m
a pharmacologist by training and serve as the Director of Science,
Research and Technology at the American Medical Association.

The AMA is the largest national professional association representing
physicians and physicians in training, and I am speaking on behalf of
the AMA at this public meeting.

The AMA has had a long-standing commitment both to improve the quality
of medical care delivered by physicians to patients and to promote
efforts that will improve patient safety. For example, the AMA
established the National Patient Safety Foundation in 1997 and it has
participated in a number of initiatives in clinical quality improvement.
The AMA also has been a partner and strong supporter of MedWatch, the
FDA\'s adverse event reporting program.

There have been a number of drug withdrawals from the United States
market in recent years. And evidence suggests that some of these drug
withdrawals were the result of inappropriate use rather than to inherent
nonpreventable safety problems with the drug products themselves.

This has led to the conclusion that the current primary mechanism to
communicate important new risk information to physicians, that is the
\"Dear Doctor\" letter\--

DR. GALSON: Excuse me. Can you get a little closer to the mike?

DR. CRANSTON: Sorry. This has led to the conclusion that the current
primary mechanism to communicate important new risk information to
physicians\--that is the \"Dear Doctor\" letter\--has been ineffective.
Some physicians are not being informed and therefore they are not
modifying prescribing behaviors to minimize the risks.

This is of grave concern to the AMA. It is a primary goal of any
physician to do no harm to his or her patients. Thus, the AMA is eager
to work with the FDA, the pharmaceutical industry, and other
stakeholders to identify more effective means of communicating newest
information about drugs to physicians.

During this presentation, I will suggest some possible options for more
effective and timely risk communication to physicians. However, there
does appear to be a lack of good research in this area on what really
does, in fact, work. Thus, the AMA is supportive of the efforts of the
Centers for Education and Research and Therapeutics Program, or CERTS,
to develop a research agenda in risk communication.

One option, physician education. The AMA believes that the FDA, the
pharmaceutical industry and physician organizations should undertake a
major physician education initiative on risk communication about drugs.
Many physicians, probably most physicians, probably do not actively look
for labeling changes. Thus, they likely would be unaware of new warnings
on drugs and, more important, that serious adverse events could be
prevented by modifications in prescribing behavior.

Continuing medical education could be offered as an incentive to
physicians to learn about risk communication. Such an education
initiative could also identify standard places, such as specific columns
in medical journals or specific pages on medical society web sites that
physicians can be directed for important new risk information.

Another option, the \"Dear Doctor\" letters. As noted earlier, mass
mailing of \"Dear Doctor\" letters appears to be ineffective in
communicating risk. Given all the mass mailings that physicians receive,
it is not unreasonable to expect they might be unaware of these
important messages. It would seem reasonable to explore alternative
mechanisms to transmit new risk information to physicians.

In conjunction with an education initiative, important new risk messages
could be published in major medical journals, possibly as paid
advertisements by the companies. \"Dear Doctor\" letters or some other
type of risk information message could also be put on medical society
web sites. As more physicians are using fax and computers to
communicate, important risk information could be transmitted via blast
fax, blast e-mail or by direct daily download to personal digital
assistants or PDAs.

Unlike letters, this information could be reinforced time and again by
additional electronic transmission. If the FDA, the industry and
physician organizations work together, effective transmission of risk
information should be possible.

Even if one is aware of the new risk information, there still remains
the need to act on it. Often \"Dear Doctor\" letters, which are sent by
the pharmaceutical company, are not written in a manner that emphasizes
the need for action, that is the need to modify prescribing behavior.
Perhaps if the message was more profound, physicians would be more
likely to act.

For example, a \"Dear Doctor\" letter might contain a bold-faced opening
paragraph that emphasizes the possible severe outcome to patients from
the new adverse event, that the adverse event is probably preventable if
the drug is used appropriately, and what necessary steps the physician
must take to prescribe the drug appropriately.

Another option, pharmaceutical sales representatives. It is estimated
that there are 80,000 pharmaceutical sales representatives in the United
States. It is well documented that sales representatives are very
effective in promoting the benefit of their company\'s products to
physicians.

Pharmaceutical companies should be obliged to train and send their sales
forces out to physicians to also educate them about important new risk
information about company products. In fact, they should provide
incentives to do so. While no one enjoys conveying bad news, it should
be the highest priority of any company to prevent harm to patients who
use their products.

Another option, professional labeling. The AMA believes that current
professional labeling for prescription drugs, that is the package
insert, is a barrier to effective risk communication because it has
become a legal document rather than a resource of useful information for
busy practicing physicians.

In December 2000, the FDA issued a proposed rule to modify the format
and content of professional labeling with the goal of making the
information more useful and user friendly to physicians. The AMA has
supported this effort, especially the proposed \"Highlights of
Prescribing Information.\" The AMA urges the FDA to issue a final rule
implementing these changes to professional labeling.

Furthermore, the FDA must develop and make readily available, for
example, via the internet, a computerized database of the most
up-to-date prescription drug labelings for all products. Such a database
could have permanently placed safety alerts for new risk information on
selected drugs.

As part of the aforementioned educational initiative, physicians need to
be trained to use this database for their professional labeling needs in
lieu of the hard copy PDR that is both cumbersome and probably dated for
many products.

Another option, information technology. Information technology offers
enormous opportunities for improving communication about risks. I have
already alluded to the use of e-mail, the internet, and downloading to
personal digital assistants as methods to more effectively communicate
risk information.

However, in the ideal world, physicians really need decision support
information at the time of prescribing for individual patients. Now
despite concerns, and these include concerns of the AMA as well as
others, about the implementation costs, data security and liability, it
seems inevitable that the use of electronic medical records and
computerized physician order entry will continue to grow. Prospective
drug use review at the point of prescribing with feedback from the
comprehensive clinical database, ideally patient-specific, would provide
up-to-date and clinically relevant risk information at the most
appropriate time.

I\'d now like to turn to risk management to end my presentation. In
addition to looking for ways to improve risk communication about drugs,
the FDA also asks for comment on its role in risk management. The AMA
believes the FDA must look at the risk of so-called me-too drugs more
critically, both pre and post-approval. While the AMA is not proposing
randomized control trials against an index product, the AMA does believe
it would be desirable to require more risk information on a me-too
product before it is approved for marketing.

Similarly, the FDA should be more aggressive in removing a me-too
product from the market when new risk information becomes available.
Such an approach may have\--I emphasize \"may\"\--have limited the
problems associated with drugs such as mibefradil \[ph\], bromfenac
\[ph\], and cerivastatin \[ph\].

Among its questions, the FDA also asks about what risks management
interventions it can initiate for physicians. The AMA expresses its
concerns about potential FDA risk management approaches such as:
limiting prescribing of a drug to a subset of physicians; mandating
physician registration to prescribe a drug; or requiring evidence of the
results of a laboratory test before a drug can be dispensed.

Frankly, the AMA is concerned that the FDA may be attempting to regulate
medical practice and we do not believe the agency has that authority.

The AMA believes it is essential that there be open communication among
the FDA, the industry and physician organizations on the subject to
achieve an appropriate balance between what is needed to protect
patients from harm and the need to avoid heavy-handed regulations that
interfere with medical practice.

For example, when a product is truly innovative, the risks of the
therapy are very high, education alone isn\'t likely be successful, and
a reasonable risk management technique is known to be effective in
protecting patients from harm, then use of that risk management tool may
be acceptable. However, the AMA would anticipate this to be necessary
for a limited number of drugs. Thank you very much.

DR. GALSON: Thank you. We\'re still missing Dr. Zuckerman here, so I
think we\'ll go ahead on to Dr. Swarz? Is she coming? Why don\'t we go
ahead with Dr. Swarz and we\'ll give her time to get settled.

DR. SWARZ: \[Slide presentation.\] Good morning. I\'m Herbert Swarz.
I\'m a consultant in International Pharmaceutical Consultants. It\'s a
very small company. It just has me in it. And I\'m an internist so I\'m
not really representing anyone but my own self and my own company.

When I read the proposal for the meeting in Section II. Scope of
Hearing, B. Tools for Risk Management, you raised the question what new
tools can be created to better address specific drug risks?

And this is a proposal for a new tool. I don\'t know how to make the
slides go up there. Thank you. So like I say, it\'s a proposal for the
use of a standardized rating scale for the classification of the
severity of adverse events, changes in electrocardiograms, and clinical
laboratory results.

The presentation will review severity determinations, review current
rating scales, review the results of the PDR search, review selected
package inserts for use of rating scales, compare different rating
scales that are in use, and then give you the proposal for a universal
rating scale for the determination of severity.

In the section, when they talk about labeling in the Federal Register,
it says it may contain information on the categorization of adverse
reactions by severity, but it really doesn\'t define anywhere how you
determine severity.

So the questions that come to my mind is how is severity determined; is
this determination consistent within classes of drugs, among drugs to
treat an indication or a disease, among different classes of drugs, and
among sponsors? So can we look at all the beta blockers or all the
calcium channel blockers and say is \"moderate\" the same? Can we look
at all the drugs to treat hypertension and say is \"moderate\" the same?

And again, are the definitions of severity harmonized with medical
disciplines within countries and between countries? An example of a
frequently used rating scale\--mild, moderate, severe\--moderate,
symptoms which interfere with daily activities. We see this in a lot of
clinical protocols, and is this non-standard rating scale useful? Again,
these are just questions that I\'m raising.

Can this rating scale be used for all types of drugs? Does it add to the
understanding of safety results? In a multinational development program,
will the results be consistent? do these definitions mean the same to a
doctor in Rockville and the doctor in France?

Do the definitions mean the same to a cardiologist, to an oncologist, to
an internist, to a dermatologist? And how do you apply these definitions
to a patient who is already in the hospital who has had recent surgery
where if you\'re looking at a new anesthetic agent, obviously
interfering with daily activities is not relevant.

And how do you apply these definitions to laboratory abnormalities and
to electrocardiogram abnormalities?

There are four rating scales that I found. One is the NCI Common
Toxicity Criteria, used a lot in oncology studies. The AIDS rating scale
usually referred to as ACTG, the AIDS Clinical Trial Group. There is a
WHO rating scale, an there is an ECOG, and ECOG is the Eastern
Cooperative Oncology Group, but really their rating scale is the same as
the NCI CTC. They have something in there called the Performance Status,
which we\'re really not going to talk about.

So what methods did I use? I searched the PDR. I have the PDR in CD.
It\'s the January 2002 version. And I search it for the words CTC, NCI,
ACTG, ECOG, mild, moderate and severe. And if I found package inserts
that had these terms, I then reviewed them to look at what is the
consistency and are these terms used consistently?

The package insert usually that contained NCI/CTC were drugs for the
treatment of a carcinoma, and I looked at all the different drugs for
the treatment of a carcinoma. And the package insert that included ACTG
were usually the drugs for the treatment of HIV infections, and again
for adverse events, ECOG was the same as the NCI rating scale. Mild,
moderate and severe were found in some package inserts, but severe in
some cases referred to the severity of the presenting disease, gastric
erosion and so forth.

So these are the results of the search. The number of prescription drugs
in this current PDR, I couldn\'t search that, so I asked PDR how many
there were, and in their specifications, it says greater than 2,800.
Mild came up 887 times. Moderate 700 times. Severe 1,284. But like I
said, severe might be the presenting disease that\'s in the package
insert.

ACTG came up 16 times, NCI 13, ECOG eight times, and CTC five times. So
basically we don\'t use these rating scales from NCI or from the AIDS
group in a lot of package inserts.

New questions: Was the ACTG severity rating scale used for all of the
HIV drugs, and was NCI-CTC scale used for all the oncology drugs, and
within the specific therapeutic groups was the usage consistent?

And again, the purpose of my review was not be critical of any drug or
any company or any package insert, it was just really to determine
severity and intensity and how is it used in the package inserts?

So now I\'m going to go through the HIV drugs and just look at adverse
events, was ACTG used consistently for adverse events and laboratory
abnormalities, and I\'m not going to go through all these drugs, but
just to give you an idea, basically it\'s not used consistently. And so
like Ziagen, they said grades one through four were lumped together.

Combivir, they say no\--I say no\--abnormal levels were listed. For
example, an ALT greater than five times the upper limits of normal, but
they don\'t talk about grades of severity. Fortavase states that the
main table of adverse events corresponds to grades three and four.

Again, everything is inconsistent. In no place is anything really
consistent, and I\'m not going to go through, like I say, all the
different drugs. It was an exercise that I was trying to figure out to
see if there is consistency.

This particular drug, Agenerase, they only looked at the grades three
and four for rash. Then they looked at grades three and four for AST,
ALT, amylase or bilirubin. They didn\'t talk about anything else.

Norvir, again, no consistency with the rest of the different drugs.
Here, Sustiva, it\'s really yes and no, because some of the tables use
the ACT and some of the tables used the NCI grading scale, and then they
had one additional adverse event table, with moderate and severe
intensity.

So basically what I\'m trying to say is that there is no consistency,
and it goes on with the other drugs, the lack of consistency.

And then if you go to the oncology drugs, there\'s a little bit more,
and some of these are very old drugs, but when I looked at searching for
drugs to treat carcinoma, these drugs came up, so I just listed them and
looked at the package inserts.

And again, there are some that do use\--Gemzar\--they use a WHO grade of
severity, then they use some adverse events with the NCI/CTC grades.

You can see that there are a lot of these drugs that the package insert
doesn\'t mention NCI grades of severity at all, and like Proleukin,
it\'s yes and no. There was one table of grade four adverse events plus
a table of adverse events without grades, and most of the package
inserts, if they talk about grades, they really don\'t define them as
well. So no consistency.

There are some here, like Oncospar, it has, yes, they use the grades for
hypersensitivity reaction, nothing else. Some of them used it for like
hematology tests. So, again, like Herceptin, they had a description of
grade three toxicities for white blood cells, platelets and hemoglobin
but nothing else. They also used for cardiotoxicity cardiac dysfunction
and class threes and fours.

So, again, these are the rest of the drugs that I found, and like
Leukine, they used it for selected tests, Trisenox used it for
hematology tests. Interferon Alfa-2b, they used ECOG and they also used
WHO. So there really isn\'t any consistency.

If you compare the rating scales, the NCI/CTC has a grade zero, none or
within normal limits. The ACTG doesn\'t have that. So basically there\'s
five points in the NCI and there\'s four in the ACTG.

If I looked at the comparison, just looking at some adverse events,
nausea\--again, with the CTC, they don\'t have grade four. Nausea with
ACTG, they have minimal fluid intake, they have a grade four. So
there\'s a difference between NCI and ACTG. Vomiting the same thing,
requiring parenteral nutrition, but with the ACTG, they talk about
hospitalization. Hypertension, hypertension crisis requires
hospitalization, probably quite similar, but the wording is different,
and the interpretation could be different.

Then I looked at rating scales with labs. AST, again, if you look at
grade four AST with CTC, it\'s greater than 20 times the upper limits of
normal. For the ACTG, it\'s ten times. The same thing for AST, the same
thing basically for GGT. Amylase, it looks like ACTG, grade four is
greater than ten times the upper limits of normal, and then the CTC,
it\'s greater than five or clinical pancreatitis.

So the point of this is that the rating scales themselves are
inconsistent, although I think they form a good basis, and then I just
looked at rating scales for electrocardiograms, and chose one particular
abnormality, QTc interval, and it doesn\'t exist at all in the ACTG
rating scale. It does exist in the CTC.

So the proposal is to create a standard or universal rating scale to
gauge the severity of adverse events, changes in electrocardiograms and
changes in clinical laboratories. There are three rating scales
available, because the ECOG is the same as the NCI. We would need to
expand and unify the rating scales into one standard or universal rating
scale, use the NCI, I would think, as the model, and the resulting
standard or universal scale should be used consistently in all clinical
trials.

It would be incorporated, the rating scale, in all clinical protocols so
that the safety results are consistently categorized during the clinical
research process for individual drugs and for all drugs that are in
development.

The same standardized or universal rating scale would also be applied to
safety data that is collected during post-marketing if you had
designated studies, and all the post-marketing safety surveillance so
that you had a continuum consistent picture of safety.

Effect on understanding risks. Hopefully, the databases from different
clinical trials conducted in different countries by different
investigators could be combined, compared. Comparison of safety results
among drugs in a class would be possible, and among classes\--beta
blockers, the calcium channel blockers, the alpha blockers.

You could compare drugs for a certain disease or an indication. Right
now, hypertension, there must be 50 different drugs to treat
hypertension, but you can\'t say moderate is the same for all drugs,
because it just doesn\'t exist. The data doesn\'t exist. The same rating
scale would be used during the development and during the marketing
period.

The conclusions\--there would be many steps needed to implement this
proposal. We would need to generate and agree on a standard or universal
rating scale. It would need to be accepted. At the present time, we
don\'t have data really for all the package inserts for all the drugs.
I\'m totally aware of that. This would be very much of a prospective
project. You\'d have to choose a point in time and from that point on
collect the data so it could be added to the package inserts.

MedDRA has provided the industry with the ability to communicate across
borders in describing or coding adverse events, but MedDRA is not a
dictionary about severity. There is a few, I think, terms in there,
\"severe headache,\" but they\'re going to come out.

A standard or universal rating scale for determining severity would
further this communication, would help, I think, the MedDRA
dictionaries, and the ability to have consistent safety information
would be possible and worth the effort. That\'s all I have to say.

DR. GALSON: Thank you very much. Our next speaker is Dr. Diana
Zuckerman. She\'s representing the Patient and Consumer Coalition, which
is a correction from the original agenda.

DR. ZUCKERMAN: Thank you. Now that I know I don\'t have to stand up,
I\'m not going to. Thanks very much for this opportunity to speak on
behalf of the Patient and Consumer Coalition. Not all the groups that
work in this coalition had the opportunity to review my remarks, so in
our written version, we do have the groups that have signed on to this
statement, and we hope to be able to add some more.

I\'m just going to speak generally about these issues. Obviously, the
general public believes that the FDA determines whether a drug is safe
and effective, and they don\'t look at the specifics of exactly what
that means. As consumers, we like to think of the FDA as a watchdog and
a gatekeeper that protects us from unsafe medical products, period.

But, of course, we realize that a prescription drug might be safe for
almost everyone and yet unsafe or even potentially deadly for some
individuals.

But even so, we look to the FDA to make sure that those risks are
outweighed by the benefits of a new drug and, of course, by benefits,
we\'re talking about the benefits to patients and consumers.

In the decade since the passage of PDUFA, the FDA has devoted
disproportionate resources toward accelerating the new drug approval
process, and to date none of those user fees have been used for
post-market safety, risk management, whatever we would like to call it.

And on the contrary, as more and more resources have gone into new drug
approval, there really has been less money to use for risk management of
those drugs that have been approved.

Now, under PDUFA III, we think and hope that there will be some
increased resources for risk management. However, the Patient and
Consumer Coalition is very disappointed that there will still be
restrictions on the use of those user fees because we think those
restrictions will undermine safety.

For example, we believe that risk management is essential for all drugs,
not just the drugs that are newly approved starting in FY 2003 or later,
and we also believe that these risk management efforts must continue for
many years, not just for the first two or three years after a drug is
approved.

I want to talk a little bit about what it\'s like to minimize risks in
the real world as opposed to clinical trials. If we start with the
assumption that there is no such thing as a risk free drug, and I think
that\'s something we all agree on, then we have to consider how to
minimize those risks.

We know that unless a drug is placed under restrictive drug schedule
such as Schedule II drugs, we know that virtually all prescription drugs
will be used off-label. That means they\'ll be used for indications
other than those approved by the FDA. They will be used by patient
subpopulations not originally deemed appropriate for the drug, and
they\'ll be used at doses and frequencies other than those that are
approved.

These off-label uses are a major reason why we believe that the absolute
level of risk is important in addition to the benefit-to-risk ratio. We
strongly believe that risk management strategies must aim to reduce both
the absolute risk as well as maximizing the benefit-to-risk ratio.

I just want to spend a couple of minutes talking about that. The reason
why we believe that the low absolute level of risk is important is
because unless a drug is being considered for approval that is going to
be placed on a restrictive drug schedule, it has the potential to be
used by thousands or even millions of patients who will actually get
little benefit from the drug.

I think Meridia is an example. There are other diet pills that are good
examples where a pill may be approved only for people who are morbidly
obese and yet they might be used for people who just want to lose a few
pounds, and so the benefit to those people using it might be much less
than was considered if you just look at the risk-to-benefit ratio.

A drug with a high benefit-to-risk ratio but also a high absolute level
of risk, whether it\'s a diet pill or a psychotropic drug with
potentially deadly side effects, or whatever kind of drug it is, those
drugs should only be approved if its use can be limited to those
individuals who are likely to benefit and if other safer alternatives
are not available.

And the reason why we believe that is because even the best risk
management strategies aren\'t always going to be effective. And that\'s
why risk management efforts can\'t be used to justify placing more drugs
with high absolute levels of risk on to the market.

For consumers, it\'s safer and better to keep drugs with high levels of
absolute risk off the market whenever possible unless they meet a
serious unmet health need. And, of course, there are drugs that do meet
those needs, and people living with HIV who rely on antiretroviral
therapies don\'t have any choice other than to choose among harmful
prescription drugs with potentially debilitating side effects and
toxicities in order to maintain optimum health and viral suppression.

Risk management is essential for the health maintenance and outcomes of
these and many other populations for whom safer, less toxic alternatives
are just not available.

Thalidomide is another example. There is a drug that was kept off the
market for a long time and not returned to the market until it had a use
that was essential for some patients. And in cases like that, we believe
that effective post-marketing risk management strategies can be designed
for a drug because we had a great deal of information about the drug\'s
adverse effects.

In these situations, it\'s essential to have a thorough understanding of
the mechanism of all major adverse effects, clearly defined
subpopulations of patients who are at greatest risk for adverse effects,
and those who are most likely to benefit, and a comprehensive knowledge
of what influences those adverse reactions such as gender, drug
interactions and age.

We also need to have documented outcomes of those suffering from severe
adverse reactions, and an effective monitoring system for adverse
reactions.

So the practical considerations are ones that we really have to take
into account, not just the ideal world, because in the ideal world, we
could develop ways to manage risks and to communicate those risks to the
public, but in the real world, we don\'t really have much evidence of
what works.

We have surprisingly little information about risk communication and
risk management strategies that are generally effective. Those
strategies that have been evaluated, such as product labeling, have been
found wanting, and I think the last speaker actually had some very good
examples of how confusing that information can be, and how it varies
from product to product.

I have to say that FDA\'s track record on risk management strategies
hasn\'t always been inspiring, and probably the most damning example is
product labels that I think everyone agrees are sometimes impossible to
read, and that include risk information that is not understandable to
most consumers. It\'s particularly disturbing that often that risk
information is then used for advertising for direct-to-consumer ads and
the patients won\'t be able to understand that risk information.

If the FDA is going to implement new risk communication and management
strategies, we want you to prove to us how serious you are by thoroughly
evaluating each new strategy to see how effective it is and to see how
feasible it is.

The essential questions are: are the strategies effective and do they
safeguard patients\' health in the real world?

I want to put in a good word for medication guides. We think that the
FDA has done an excellent job on some med guides. We\'d like to see more
of them. We think that\'s a really good example of providing information
that\'s understandable to patients and consumers that they can really
use and that has really helped them.

They\'re written in plain and understandable language, and we need more
of them, and \[we need\] also to find ways to make sure that they\'re
actually used as directed. We also realize that the FDA can\'t do it
alone, and the effectiveness of various risk management strategies is
going to rely at least in part on the willingness of pharmaceutical
manufacturers to carry them out.

In the past, many pharmaceutical manufacturers have resisted efforts to
institute stringent risk management programs. And industry isn\'t always
willing to support risk management strategies such as patient registries
or special physician certification for prescribing high risk drugs.

We believe that if companies don\'t prove themselves willing to do so,
then the FDA needs to be more restrictive in what they approve as safe.
We believe that products should be withdrawn from the market if the
company doesn\'t follow through on required risk management commitments.

And then just to finish up, I want to talk a little bit about
enforcement strategies. We\'re concerned that the FDA currently does not
carefully monitor Phase IV trials and other post-market safety measures.
We strongly believe that post-market safety efforts need to be improved
before the FDA can rely on post-marketing risk management strategies,
and currently we know that the problem is related to lack of staff and
resources.

But we also think it\'s related to FDA\'s lack of focus on long-term
safety of drugs taken for chronic conditions, and what seems to be a
lack of will to carefully examine drugs that have already been approved.

Obviously, another problem is that FDA has lacked the regulatory
authority, such as the ability to impose civil monetary penalties on
manufacturers if they fail to institute required risk management
programs.

In conclusion, we think that the first line of defense for strengthening
the safety of prescription drugs is a careful scientifically driven
approval process, and we think that the FDA should not weaken its
approval standards just because \[of\] its risk management efforts.

On the other hand, the current situation where the approval process is
the major focus and so few resources have been available for post-market
safeguards, that has been unacceptable. And so we\'re delighted that
you\'re focusing on this issue now, and we are urging you to implement a
major overhaul of your efforts to evaluate and disseminate information
about the risks and benefits of approved drugs to control and manage the
risks that are inherent in the widespread availability and use of
prescription drugs.

And we know that to do that requires substantial additional staff and
resources, but also a new focus on ensuring the effectiveness of safety
programs and risk management efforts. Thank you.

DR. GALSON: Thank you very much. That wraps up the presentations for our
second panel, and we\'ll now take questions from up here for the
panelists. Start from the right here.

DR. BULL: I have a question with regard to the need for cultural
competency in terms of how labels are configured, and I was wondering if
Dr. Zuckerman might have any thoughts as to the need\--you had cited
labels being impossible to read\--as to whether or not there is a need
to address differences, cultural differences given how diverse America
is, and how risk communication is accomplished?

DR. ZUCKERMAN: Well, I think that\'s a wonderful question, and obviously
that\'s part of what we mean when we talk about evaluating the
effectiveness. I think currently it\'s so bad that almost nobody can
understand it. It\'s equally\--you know, it\'s equally bad almost for
everyone.

Obviously, there are people who could understand package inserts if they
really tried and if they had reading glasses. But you know in the real
world people just don\'t read them. So you know you\'re so far from
having to worry about cultural competency I think at this point because
the font size isn\'t even large enough.

But obviously, the goal should be to have something that\'s
understandable by most people, and that, you know, you\'re, as I said,
you\'re really far from that, but it has to be user friendly in the
sense that it\'s not just that the vocabulary has to be understandable,
but also that it has to be presented in a way that people actually would
want to read it and be able to read it without straining themselves.

DR. BULL: Thank you. I have a question for Dr. Cranston. You had cited
concerns with FDA labeling potentially restricting to a certain
specialty of physician or mandating or issues with mandatory registries
of physicians, or laboratory tests. I\'m just wondering what options to
you see for influencing physician behavior? Can you tell us about how,
what role risk communication can have in effecting behavioral changes
when that seems to be the main element that is a major factor in adverse
events?

DR. CRANSTON: I\'m not sure that it\'s really known. I think at the
beginning of my comments on risk communication, I emphasize our support
for what the CERTS are trying to do because I think that\'s basically
the question we\'re trying to answer.

I think my personal view is that unless it\'s at the point when we\'re
making the decision, when we\'re actually prescribing the drug, that
it\'s going to be very difficult to have a powerful impact on their
remembering all of this information. I think that\'s really the way we
need to go personally.

DR. KWEDER: I\'d like to follow up on that a little bit because I heard
some of the same themes from you as well as Dr. Dieck, and Dr. Dieck,
the way you phrased it I think was that methods for managing risks
really shouldn\'t be required until the methods themselves have been
proven. There is certainly a lot of research to be done in this area.

What are we to do in the interim? We have products before us now and
will in the next year, in the next two years, or even five years, in the
time it takes to prove that methods of communicating risk and changing
behavior which is the ultimate goal do work. We don\'t have the luxury
of waiting five years for the academic community to catch up and prove
to us what methods work and what don\'t, and yet we\'re hearing that we
shouldn\'t impose any other restrictions or very minimal other
restrictions until we know that they work.

So we\'re sort of caught between a rock and a hard place. So I\'d like
you to comment on that if you could?

DR. CRANSTON: Oh, yes, I appreciate your problems. I think that from our
perspective you really lack the authority to regulate medical practice.
And I think there is a very significant concern that there is a desire
on the part of the agency to move in that direction, and some of the
proposals in terms of risk management would, in fact, cross that line
which we feel is inappropriate.

DR. KWEDER: Can you give specific examples of what would cross the line?
That would be helpful.

DR. CRANSTON: I think that in requirements for physicians to register to
prescribe the drug, to limit the prescribing the drug to a certain
subset of physicians by labeling, requiring certain actions through
labeling what the physician must undertake in order to be able to
prescribe the drug are examples.

DR. WOODCOCK: Yes, just in follow up, I understand what you\'re saying,
we don\'t totally lack research in this area. We have a vast body of
knowledge from other fields where safety has been a very high priority
and this has been discussed a lot about by the National Patient Safety
Foundation, for example, about the need for systems intervention in
patient safety, that everybody has a role in this.

I think some of the research shows that fail-safe mechanisms like we\'re
using, thank goodness, in the air line travel and other things, where
you can\'t really perform an act that\'s dangerous because there are
multiple, you know, check points to prevent that or, you know, really a
proven safety method.

I don\'t think the FDA is saying any of these should be imposed, but I
even think the National Patient Safety Foundation and all the safety
experts have recommended that these are interventions that are helpful
in preventing error in health care. Could you comment on that?

DR. CRANSTON: Yes. I don\'t disagree with you. I think that the issue is
really the issue of regulation by the FDA which I think, you know, our
organization sees it as an agency that regulates the pharmaceutical
industry versus incorporating these types of systems changes into
medical practice, which would involve, I think, a much larger body of
stakeholders developing those types of systems. I think that\'s what
I\'m really trying to say.

DR. GALSON: Paul, do you have any questions?

DR. SELIGMAN: There was a comment in the earlier panel about the need to
develop sort of sustained efforts in educating health care providers
from undergraduates through graduate education and beyond, and I\'d be
interested in your views, Dr. Cranston, about AMA\'s position in terms
of either changing medical school curriculum or ways to either develop
required courses that would change physicians and health care provides
in terms of their ability to recognize adverse events as well as to
report them.

DR. CRANSTON: I think the AMA would be fully supportive of any
educational approaches, whether it be at the medical school level, the
residency level or in the actual practice level. That would improve
physicians\' knowledge of drugs, how to use the drugs, how to report. We
try to work with FDA over many years to improve reporting to a MedWatch
program. Whether or not we\'ve been successful or not, I don\'t know,
but you know I don\'t think we would have any objections whatsoever.
We\'re fully supportive of those. Now, what particular types of
educational interventions will work, I don\'t know the answer to that
question.

DR. BULL: What role, Dr. Cranston, do you see of drug specific CME
programs? I guess let me expand on that a little bit. If, for example,
there\'s a drug whose use probably needs some special training, do you
see a role for special training to use a particular drug, and that being
part of the recommendations in a drug\'s labeling?

DR. CRANSTON: I think certainly the AMA would support that any physician
who is going to prescribe a drug knows how to use the drug. And if a
particular drug requires special training to use, then physicians should
obtain that training.

Whether that should be mandated in the labeling of the product, in other
words, a required CME course to gain certification to prescribe a drug,
I think we would probably have problems with that.

DR. GALSON: I want to ask a question of Dr. Cranston. You told us that
you don\'t really like the idea of some of these practiced restrictions
coming from the FDA, that they should be initiated from through the
medical care system involving a lot of stakeholders and not be
regulatory in nature, just to sort of paraphrase what you said.

What group or who is going to take the leadership in doing that? Is
there such a group? Is AMA willing to take the lead to do that? How is
this going to happen?

DR. CRANSTON: I\'m not sure I can answer your question. Certainly the
AMA would be more than willing to participate in such an initiative.

DR. GALSON: But somebody has got to lead it, right, if you don\'t like
the FDA doing it? Okay. Yes.

DR. WOODCOCK: I\'d like to sort of follow up on that a little bit with
Diana Zuckerman. And first I\'d like to thank all the panelists. I think
that we\'ve really raised the level of discussion of these issues over
the last year and a half we\'ve been talking about them. And we are
really getting to what the issues are rather than people shouting at
each other. So I really appreciate that.

I think this is a very serious discussion we\'re having. Dr. Zuckerman,
you said that we should, the FDA needs to be more cautious, shall we
say, on drugs with serious side effects in illnesses that are not very
severe. And to use the example of HIV and people with cancer, for
example, as where there are not a lot of non-toxic alternatives
available, and therefore we recognize the benefit-risk, that some of
these products approved for those will have serious toxicities.

However, most of our struggle is not in that area. It\'s in the zone in
between and the problem we really face is that most diseases are neither
highly serious nor un-serious. You can have people with life-threatening
hypertension, and you can have people with non-hypertension. You can
have people with extremely incapacitating migraine, and you can have
people with migraine, you know, once a week or once a month or something
isn\'t a problem.

And that\'s why drugs are prescription. That\'s why we rely on the
prescribers with the patient to make the determination that does the
seriousness of disease in that person warrant that whatever intervention
with its attendant risks. This gets back to what we were talking about
with Dr. Cranston. That\'s why I wanted to bring it up now.

We\'re relying on the clinician to make those kind of discriminations,
and were you really saying that we shouldn\'t be relying, I mean we
shouldn\'t be putting out drugs with some substantial risks where they
would be appropriate for a subset of the population because we can\'t be
sure they\'re going to be directed toward that population?

DR. ZUCKERMAN: Thank you for asking that question. I certainly agree
with you, and that is a concern that we have that so many drugs that are
approved are not for life threatening illnesses and are sometimes the
20th antibiotic or the 32nd antihistamine or whatever.

And I think that diet pills are a good example where a person can be
seriously obese, the need to lose weight can be very substantial, or
they can be trying to lose those last ten pounds that they gained when
they had a baby. And, you know, we would like to look to the AMA and to
the medical profession to make sure that their members, that the
doctors, are more cautious in how they prescribe these drugs. But we
also recognize that the FDA doesn\'t usually regulate the practice of
medicine except in extreme situations or what are perceived to be
extreme such as RU-486.

So we\'re asking you to consider that absolute level of risk as
something that\--rather than just the risk-benefit ratio. I don\'t know
how else to say it other than if you keep adding new products that are
slightly riskier than the ones that are already available for people, so
I\'m not necessarily saying only for people who, you know, have HIV or
really where there are no other drugs at all, but in cases where there
are no other treatment alternatives, and in situations where it is a
me-too drug basically that might have some serious risks, and there are
other alternatives on the market where the risks are not so serious. We
think that needs to be taken into account, because, you know, unless you
are able to better control who gets the drug, and currently you can\'t
or you don\'t.

DR. WOODCOCK: I think we do take it into account. I think that\'s part
of the risk-benefit. If they\'re safer alternatives available, that is
absolutely taken into account, but there is a fundamental issue that
you\'re raising about the absolute amount of risk which you talked about
off-label use or use in a segment of the population that has less severe
disease. And that\'s a separate issue around risk management.

DR. ZUCKERMAN: Yes.

DR. WOODCOCK: That is a risk management issue.

DR. ZUCKERMAN: Yes. I mean we are very concerned about off-label use
because so often the vast majority of people taking certain drugs are
people for whom it wasn\'t intended and for whom it wasn\'t approved,
and we think that\'s exacerbated by direct-to-consumer advertising and
all advertising which seems to be aimed at getting, you know, the
largest group of consumers possible to buy a product even if it wasn\'t
approved for them or intended for them.

It\'s not that I think there is an easy answer, but I think that these
are the questions that really have to be raised because, you know, I
think that\'s where a lot of the problems are coming up.

DR. GALSON: Okay. I\'d like to ask a couple of the questions that came
from the other FDA staff who are sitting in the front here. The first is
to Dr. Kotsanos. 94 percent of AERs to FDA from pharmaceutical
companies, you mentioned that in your talk. Are these post-marketing? Or
can you be more specific about are these all from post-marketing
reports?

DR. KOTSANOS: These were data from the 2000 annual report, I believe,
and I believe they were post-marketing reports.

DR. GALSON: Okay. Paul, a follow-up on that?

DR. SELIGMAN: Actually just a slightly different question. We talked
about observational studies, and I\'m curious as to the kinds of
criteria you would apply to making a decision about when an
observational study should or would be applied in the post-marketing
environment and what the goals of such an observational study would be,
and whether you feel that further or subsequent marketing approval
should be based on the results of such observational trials. There\'s
three questions there.

DR. DIECK: I feel that observational studies are an important tool, as I
said earlier, to help us evaluate risk and augment the knowledge that we
have in the pre-approval time period. In certain instances, there may be
signals or issues that are identified in the pre-approval time period,
but the benefit of the product still appears to outweigh the risk, and
we may be asked in those situations to try and quantitate or evaluate
those potential risks further, and I think in situations like that,
it\'s appropriate to think about study designs that can help us evaluate
that as soon as the drug is approved.

And we have been carrying out some post-approval commitment studies in
my company, and the goal is to provide more information to the
decision-making process, and I think that the types of studies and the
interpretations of studies need to be agreed upon up-front, and then I
think that everyone will understand how the information could be used
when it comes in.

What you don\'t want is a situation where the study is completed and
there\'s a lot of controversy about what the interpretation of the study
means and how it\'s done, and also to gain confidence that the study is
using very good scientific methods in order to achieve its goals and to
be able to identify risks that we\'ve been\-- levels of risk that are
pre-agreed upon.

Did I answer most of your questions?

DR. SELIGMAN: Yeah. One of the concerns, I guess, and it was raised
earlier, was the concern that Phase IV trials or Phase IV studies
aren\'t often either followed through on or completed. How would you
suggest that that be changed in order to ensure that these kinds of
observational trials or Phase IV studies are actually completed and
followed through on?

DR. DIECK: Well, one way to do it, if I go back to the proposals that we
have for PDUFA III is to actually provide a post-marketing surveillance
plan for the product and to meet with regulatory agencies on a regular
basis to see whether or not the proposals are being adhered to.

Clearly, we want to provide you with feedback with how the studies are
progressing and to discuss any issues that may have arisen as we try and
implement the study after the product approval. So I think it\'s very
possible to engage in a dialogue. It\'s an opportunity for you to ask us
questions as well and to provide input into the study.

DR. SELIGMAN: And I guess this is a tough question. Should there be
consequences for failure to not follow through on those commitments?

DR. DIECK: Well, I think it\'s important to assess why that failure
occurred. If it\'s simply ignoring what was agreed upon, it\'s hard to
say that, you know, to justify that. But studies can fail for other
reasons such as some of the assumptions that were made earlier did not
follow.

For instance, if you underestimated the rate of occurrence of a
particular issue in the underlying population, or you may have a
situation where although you pre-tested your questionnaire, people were
unable to fill it out or were unwilling to fill it out because it was
asking very, very personal types of questions.

So in those situations, the study fails, but I think you could still
enter a dialogue to figure out what are the solutions that we can?
We\'re still committed to trying to find this information, and until
there is agreement between the agency and the pharmaceutical company
that that information simply cannot be gathered using an observational
technique, then I think that, you know, we can certainly show due
diligence and try and work with you to get the answers.

DR. GALSON: A question for Dr. Dieck or Kotsanos. Many large PhRMA
companies have safety databases. How accessible are these data and
analyses to the FDA and the public? It comes from the FDA table here.

DR. KOTSANOS: My assumption is these are the adverse event databases
that we have in our companies, and clearly those data are shared with
the regulatory bodies like the FDA and they\'re available through the
FDA through FOI. However, if people want access to individual
pharmaceutical company data, then companies tend to have privacy
policies in place and each have their own individual restrictions and
policies. Thank you.

DR. SELIGMAN: I interpreted that question slightly differently. You
talked about it in your presentation, about the incidence rate of
commonly occurring events in clinical trials. And again I was wondering,
though those are not necessarily adverse events that may have been
reported, but I\'m curious as to where are these data and are these data
available not only for the\--I guess that was sort of my question was
sort of these clinical incidence rates?

DR. KOTSANOS: And what I\'m interpreting is that beyond the
post-marketing adverse event data, we have safety data as part of our
clinical trials and what\'s the availability of that data? I think
that\'s what you were asking me.

DR. SELIGMAN: Right, exactly, sorry.

DR. KOTSANOS: And typically companies have not made such data available.
However, I\'m very pleased that within the last year, there has been a
collaborative effort between PhRMA and FDA and the American Association
for the Study of Liver Disease to understand better hepatotoxicity
associated with drugs.

And as part of those efforts and initiatives, there\'s been a
partnership and agreement to use company databases to answer some of the
types of questions that need to be answered, sensitivity and specificity
of certain lab test levels. So that is something that is happening and
it\'s for the better for the public health.

DR. GALSON: Great. Dr. Jenkins.

DR. JENKINS: This question is for Dr. Cranston but also I invite other
members of the panel to weigh in. There\'s been reference made earlier
this morning about some of the drugs that have been withdrawn from the
market over the last several years. And one of the characteristics of
some of those drugs was that we could clearly identify who was at risk
of those serious adverse events, and they were totally preventable by
appropriate prescribing action and appropriate dispensing action on the
part of the pharmacist, such as drug interactions, where if you did not
take the drug in combination with another drug, you were pretty safe
that you weren\'t going to get the serious adverse reaction in question.

In another case, it was an issue of if you took the drug for only the
ten or 14 day course that was recommended, you were pretty safe that you
were not going to get the serious adverse reaction. If you took it
longer, you were at greater risk.

In those cases, FDA went through an incremental step of trying to
educate, get the information out to prescribers and patients and
pharmacists about the risk, and that included the labeling, black box
warnings, \"Dear Doctor\" letters, media, et cetera, and we still failed
in trying to eliminate \[those risks\]. We often made a good impact on
reducing that risk, but we weren\'t successful in really eliminating it.

You made some comments about we need to find better ways to educate and
get that information to the point of prescribing, and I\'m wondering
what ideas you might have and others on the panel might have about what
more can we do in those situations where the adverse events are
completely preventable with appropriate prescribing and dispensing? How
do you get that information to the prescriber at the point where
they\'re making that decision?

DR. CRANSTON: I think that most of the presentation I gave this morning
were some suggestions on how to improve risk communications to
physicians such as using the detail people, using electronic means to
get information to physicians. Personally, I believe that the best way
to do this is ultimately through an information technology, where you
have a computerized order entry system where the physician everyday is
using their hand held or some other CRT, and when new information
becomes available, that information is the first thing they see on their
screen when they write their first script of the day.

It gets incorporated into the database. It has to be carefully designed.
It can\'t be like what\'s in the pharmacies currently where so much of
it is false positive that they overlook it. I think that\'s why there
are problems with the pharmacies on drug interactions.

That\'s kind of what, you know, I think is the way we have to go. The
problem is that that is a very costly infrastructure, I think. There are
also concerns about things like privacy and potential problems of
liability, and I think everybody, you know, the practice community has
some concern about it, moving in that direction, and we do need to, I
think, all of the stakeholders to work together to try to come to that
type of system.

DR. JENKINS: Can others on the panel comment as well? Dr. Zuckerman.

DR. ZUCKERMAN: Yes, thanks. I\'d like to respond also. I think diet
pills again are really a good example of products where if you read
carefully, it\'s very clear what the risks and benefits are, and in the
case of Meridia, people are supposed to be restricted for how many weeks
they can take the pills. It\'s also true in the case of Meridia that as
soon as they stop taking the pills, they gain the weight back.

And so I mean there\'s really two issues here. One is I think this is a
good example, Dr. Woodcock, of a drug that we think never should have
been approved to begin with, because we don\'t think that even under the
ideal circumstances the benefits outweigh the risks. But also, in the
real world, diet pills are overprescribed for people who want to lose a
few pounds no matter what the instruction says, and if the doctor that
you go to won\'t prescribe it, you can get it on the internet.

And I just want to raise that issue, too, that everyday I get e-mails
offering to let me buy prescription drugs over the internet. I don\'t
know what the FDA can do about that, but when you\'re talking about risk
management, you can\'t ignore that.

DR. WOODCOCK: Can I just say we are going after illegal sales of
prescription drugs over the internet. We do go after that. It\'s very
difficult when they are offered overseas.

DR. JENKINS: If I just could follow up on that line of questioning
about\--I\'m not sure the diet pills that you\'re referring to fit into
the paradigm that I was referring to. I\'m referring to situations where
you have a serious adverse event that\'s completely preventable such as
a drug interaction like a Seldane situation where if you didn\'t take
Seldane with a competing \[cytochrome P450\] CYP 3a4 -inhibiting drug,
you weren\'t at risk of the cardiac toxicity. If you didn\'t take Duract
for longer than the ten to 14 day treatment course, you were at pretty
low risk that you were going to have the liver toxicity.

And the question I wanted to follow up with, Dr. Cranston and Ms.
Zuckerman, is in the end, after trying the various communication tools
that we had available to try to influence behavior of prescribers and
patients and pharmacists, we still saw a residual level of serious
adverse events for those drugs.

We know that those adverse events are preventable. We\'d done what we
thought we had available. We were still sitting in a residual level,
although reduced. The only other risk management tool we had available
to us is to take the drug off the market. Do you think that\'s the
appropriate step for FDA to take at that point, or do you have ideas of
things that we could do more that would preserve those drugs on the
market, which, in fact, probably benefit 99 percent of the people who
take them and don\'t cause harm in the vast majority, but the only tool
we had to try to manage that risk at that point was to take the drug off
the market? So comments you might have about is that the appropriate
strategy when we can\'t influence behavior for things that are
preventable and if not, what other things could we do?

DR. CRANSTON: First of all, it depends on the drug. I think, you know,
that with some of these drugs like Posicor and Duract and Baycol,
withdrawal was probably the appropriate way to go. I mean there was no
need to keep them on the market, based on what else was available. Same
thing for Terfenadine once the other ones, well, even before the other
ones became available maybe.

Again, I just want to state that, you know, the purpose of my
presentation this morning was to try to present ways that we might
improve risk communication to physicians to get that number down. Can it
be totally prevented? Probably not. But I think that was the gist of
really what I wanted to say today with regards to improving the current
system in terms of risk communication to try to improve the knowledge of
physicians of the problem, and changing behaviors to prevent the adverse
events from occurring.

DR. ZUCKERMAN: Yes. I\'d like to add that I think that at least the
ability and the threat to remove a product from the market if it\'s not
being used appropriately does at least add some incentive. We\'re
concerned that currently advertisements really are aimed at getting the
maximum number of people to get their doctors to prescribe a product for
them, not only to get the ones that really need it to get the product.

And drug reps really are salesmen and women and their goal is to sell
their products. If those companies were concerned that if their products
were used inappropriately, they might be withdrawn the market, I think
that would create a nice little market incentive to not push their
products inappropriately. I think it\'s a difficult situation, because
obviously there are all these different players, and the FDA can only
regulate part of the picture, and because of the way medicine is
practiced, and because off-label use is generally legal and widely done
and widely considered fine, it does create problems even in situations
as you describe where it\'s very clear a drug is only supposed to be
prescribed for no more than ten days or no more than two weeks or
whatever, and is frequently prescribed for much longer than that.

So if you can\'t control that, I mean I do think it would be helpful to
have the black boxes and other warnings that were so clear that they
couldn\'t be missed by any doctor no matter whether he or she was paying
attention or not. I know that the pharmaceutical companies don\'t
generally like those.

But it does help make it very clear and maybe that\'s the next step
before withdrawing from the market is having those kinds of warnings
that can\'t be missed.

DR. DIECK: I\'d like to respond to some of the comments that have been
made. I feel that what we\'re dealing with is how to convey complex
medical information in efficient way to help physicians safely prescribe
the drug. I think every pharmaceutical company is concerned when things
that are clearly contraindicated in the label and drug interactions that
are contraindicated, where we follow up with a physician and said are
you aware that you\'re not supposed to use this product with another,
and the physician says I know that, but had prescribed it anyway. We\'d
make some effort\--this is not something that happens often, but it is
part of the information of how do you educate physicians and how do you
communicate that information.

From the pharmaceutical company perspective, what can we do to help get
that information out more clearly and synthesize this complex
information? Comments about the labeling, I think, are very valid
because we don\'t have standards the physicians would understand. What
does it mean if you have something in the warning section? What do you
mean if you have something in the precaution section? And have criteria
that are clearly laid out that all labels would then adhere to.

I think this is one step that could be done that wouldn\'t have to be
tested perhaps, but would be able to help clarify some of the
information that we\'re trying to convey. If the physician has to search
around or from a drug to drug situation that something in the warning
section really belongs in the caution section, then we\'re not helping
to communicate how the drug can safely be used.

DR. SWARZ: I\'d just like to make a comment. Perhaps the answer is in
the packaging. I lived in Europe for a long time, and I lived in
Belgium, and it was a price thing. So they would get an approval for a
price for 14 days of therapy or an approval for a price of seven days of
therapy. So if the drug should only be taken for 14 days, perhaps you
should approve a package, a 14-day package, with the appropriate warning
included in the package, and, you know, maybe a seven day course of
therapy for the anti-allergy pill, and in there it says you shouldn\'t
take this if you\'re taking erythromycin or another type of drug.

So perhaps as an aid to safety, perhaps you could look at packaging and
how you could limit that. If a patient only got 14 days of therapy and
says you will not get a renewal, you\'ll have to go back to your own
doctor to see this, perhaps that would help rather than dispense a
thousand bottles to the pharmacist who then counts out the 14 day
supply. But in Belgium, it was for the pricing, but perhaps you could do
it for the safety.

DR. JENKINS: If I could maybe follow up on that, I would be interested
in hearing your view as well as others on the panel\'s view about your
thoughts on FDA restricting refills. One of the options that sometimes
comes up in discussion is that there would be no refills, putting aside
whether we have the ability to actually enforce that or to have that
authority, what do you think about no refills for certain drugs as part
of a risk management plan?

DR. ZUCKERMAN: Well, I\'m happy to say I think it\'s a great idea. I
don\'t know if it\'s legal or not. But certainly that would help with
quite a few of these products, not everything, but there is\--you know,
I think sometimes these warnings are either so written in a way that is
so extreme that nobody believes them, or they are so mealy-mouth that
nobody pays attention to them, that if it says, you know, that the
approved use is 14 days or whatever, it doesn\'t mean very much to a lot
of doctors who just think, oh, that\'s FDA being so compulsively
ridiculously overly cautious, and they just don\'t take it seriously.

But if you have that kind of restriction so that it is a package and
can\'t be continued without\--I don\'t know under what conditions\--I
think that would be very helpful.

DR. KOTSANOS: With respect to the question that was asked, the answer
would depend on part on the circumstances on why a restriction on refill
would be put in place, and clearly if it\'s a chronic disease requiring
chronic therapies, it could create a barrier for access of a patient who
needs the medicine.

DR. BULL: This question is addressed to Dieck and Dr. Kotsanos, and
going back to your presentation, Dr. Dieck, where you cited the public
expectation of risk knowledge at approval is greater than reality, and
the model that you presented proposes during further studies. And as we
move into an environment where there are more Phase IV commitments, what
level of disclosure do you feel is appropriate, say, for promotional
materials or that should have been included in labeling given that, you
know, we\'re acknowledging that risk is not fully characterized?

How do you see that information being communicated?

DR. DIECK: Well, I strongly feel that information about both benefit and
risk of drugs should be based on science-based evidence, and it\'s
statements that are made with regard to both the benefit side as well as
risks. It\'s difficult if you have, bring into information where the
issues have not been fully understood and I think part of it is that
we\'ll see the label evolve over time, as the science-based evidence
comes in.

As I said in my talk, I find that we build knowledge over time, and
constantly we reevaluate the balance of risk and benefit. Certainly, as
studies are published that show risks or benefits, very often those are
put in the label or they\'re part of medical literature and are
disclosed. That\'s the current process that\'s taking place, when some
of the things that we\'ve suggested as learning more about drugs earlier
and getting that information out in the medical literature as well.

But I don\'t see\--I strongly feel that it has to be based on a
scientific framework if it goes in, well, if it goes into the labeling,
what is in the labeling has to be part of the advertising.

DR. GALSON: Thanks.

DR. KWEDER: This is a follow-up question regarding some of the methods
that were presented. Dr. Cranston, you did give us some suggestions on
how to facilitate educating physicians in particular about risks of
drugs, communicate those risks. And I do agree with you that the most
important point, timing is often everything, having information in the
hands of the clinician at the time they\'re thinking about using a
particular product.

But in addition, you often alluded to\--you did allude to one of the
problems with some of the current systems is that they seem to have so
many false positives. They just sort of throw up everything and
clinicians pretty quickly discard the information.

I think there is a more general problem with that. I think that is also
what happens with \"Dear Doctor\" letters. It is also what happens with
the adverse event section of labels. Physicians usually read them to
confirm what they already think about a drug as opposed to learn about a
drug. I mean it\'s pretty common. You look it up to, say, oh, yeah, is
rash on the legs associated with this? Yep. Okay. This patient has a
rash on their legs, it must be the drug.

How can FDA develop more of an appreciation on the part of the medical
community for the full profile of risks and benefits associated with
medical products? I just offer as by way of example, I think, in looking
at the agenda, you\'re the only person here today from a professional
medical society. Now these aren\'t things that are on the agendas of
most professional society meetings, at least not the ones that I attend,
you know, in sort of general terms.

So how can we reach out and put these kinds of issues and the importance
of tending to them broadly on the radar screen of the medical community,
because that\'s one of our biggest frustrations is we feel like we\'re
not heard?

DR. CRANSTON: It\'s interesting. As I was sitting here waiting for the
next question, it hit me, I was thinking the very same thing, because,
yeah, I am the only person here. And ironically I\'m not even a
physician.

I think there has to be a reach-out, probably initially from FDA to the
profession, on this issue. I would agree with you that even in my own
organization, I tried to raise it to a higher visibility and have not
had a lot of success doing so.

And it\'s very important. It\'s an extremely important issue, and I
think one option might be to go to large medical meetings to try to get
on the agendas or possibly try to set up some type of meeting with all
of the large key specialists societies, the high prescribing specialty
societies, and ask specifically that physicians attend, and present your
case, and try to get feedback and discussion going. That\'s probably the
best I can suggest right off the top of my head right now.

But as I said at the beginning of my comments, you know, we certainly
would be happy to continue discussions with the agency and the industry.
I think one of the concerns that I had personally, and one of the
reasons that I tried to raise this issue at the AMA, is that I\'m aware
of your frustrations, and they obviously came out in the questions to me
today.

And I\'m also aware of the realities of my own organization, having been
there for 20 years, and physicians, you know, are very angry right now
in particular with everybody who is trying to impose regulations or
restrictions or paperwork on them, and, you know, if it comes out as an
FDA thing, we\'re going to regulate medical practice by our requiring
this and labeling, it\'s just going to get very strong negative
reaction. And I think we need to have this type of communication and it
has to be with all these large specialty societies where there are high
prescribers, you know, the family physicians, pediatricians, internal
medicine and so on and so forth.

DR. GALSON: Dr. Houn.

DR. HOUN: I have a question for the PhRMA representatives. How do you
think we can incentivize safety messages, AE reporting by doctors, and
what do you think the role of the sales force is in the items that
people had suggested in terms of increasing doctor knowledge of safety
issues as well as doctor reporting of safety issues, and what have
companies been trying to do over the last two years?

DR. KOTSANOS: First, we encourage adverse event reporting from health
care practitioners, and we would like to see more reporting by health
care practitioners. Your question about providing incentive to
physicians to report is an interesting one. There is a whole host of
interventions or possible approaches that come to mind immediately, but
what would probably be the best answer is that we would be open to
consider any type of proposal that would help improve or increase the
adverse event reporting. And even measuring the effectiveness of those
types of proposals.

DR. HOUN: Is this an ongoing thing or it\'s not yet really begun?

DR. KOTSANOS: You are talking about\...?

DR. HOUN: Encouraging doctors to report AEs and programs like we talked
about - educating physicians and hospitals about MedWatch reporting,
residents and fellows at luncheons about how to report AEs, do you think
that\'s happening or it\'s not really happening right now from PhRMA\'s
point of view?

DR. KOTSANOS: It\'s clearly happening. I\'m not prepared to give you the
list of all the detailed programs that are currently in place, but at a
minimum sales force or other pharmaceutical companies that learn of
adverse event reports need to report them to the companies, which in
turn get reported to the FDA.

Different programs are applied, whether they be continuing medical
education programs that have some element of adverse event reporting in
them or even some of the publications that go out, but there are
activities ongoing.

DR. HOUN: We heard a lot about the concern for me-too drugs. I guess
these are drugs that are for the same indication, maybe in the same
class, close chemical or related chemical structures, that have been
characterized as not providing any breakthrough benefits, so similar
benefit as the other drugs, but either unknown, or newer risks, or risks
not fully assessed.

There has been concern on whether FDA should be looking at these
differently, and some of the panelists, some of the speakers are
suggesting that there is a real concern about me-too drugs. What is the
trade association\'s view on this issue?

DR. DIECK: I think that we can look at the development of me-too drugs
in sort of a societal sense, that they appear to do the same things
across a population or in a disease population that\'s being treated,
but here I think it\'s important to keep in mind the patient, that each
patient and their situation, their concomitant diseases, the other
medications that they\'re taking, or how their body itself reacts to a
medication, it may be that there are subtle reasons that a physician
will feel that he would like to have an armamentarium of drugs to be
able to put the patient on that\'s best suited for that individual.

I think that that has to be kept in mind and not just sort of blanketly
assuming that all drugs in a class are the same. They\'re not. They have
important differences, and we continue to learn about these differences
as we go forward.

DR. HOUN: In terms of developing a new me-too drug, is there risk
management planning in that type of development in the sense of others
in the class? You might have some, like for Baycol, there\'s a known
risk in that class with myelysis, and are there built-in strategies
should your drug have a worse risk profile what to do in terms of
finding a different benefit or a greater benefit in maybe a
subpopulation?

DR. DIECK: I think certainly what is out there and available in that
therapy class is something that\'s very much looked at. And again, I
would not look, focus, on one particular adverse event, but the spectrum
of adverse events that certain drugs in a therapeutic class may have.

So for one patient who has liver problems, perhaps in this therapeutic
class, it\'s not good to give one particular drug, but here\'s one that
may have another problem, but is safely used in people with liver
diseases. I think it\'s important to also recognize that there are some
diseases where the therapy is not as effective as is used over time, and
here again it\'s very important for physicians to have a variety of
different drugs to help them.

And certainly issues related to antibiotic resistance would also support
the idea that having a number of therapies available is a very good
thing and not a bad thing, but again the physician has to decide what\'s
best for that specific patient that he\'s treating.

DR. HOUN: I have just one last question. And that concerns restricted
distribution. Again, if both Jim and Gretchen could answer. We\'ve heard
concerns about restrictions in terms of practice of medicine, and I\'m
wondering how the industry views restricted distribution programs,
benefits as well as problems with them?

DR. KOTSANOS: Well, as I had said before, at a high level we\'re open to
consider and evaluate any type of risk management intervention or
approach. For restricted distribution, the questions that come up is
that there may or may not be a reduction in the risk. However, there
will definitely be a reduction in the benefit of restricting the drug
getting to the patients who need it.

DR. DIECK: One way to think of it, again, in terms of our common goal of
wanting to maximize benefit and minimizing risk, if you look at the
entire equation, I think restricted distributions in situations like
Thalidomide do work, but in looking at different products, you\'re
sacrificing benefit in order to reach that goal of reduced risk.

And the question is are there other ways that we can reduce the risk
without denying access of products to patients that need them, and
that\'s the question. Can we maximize benefit and minimize risk through
other means for certain types of drugs?

DR. SELIGMAN: Dr. Kotsanos, you used the term \"aggressive
surveillance\" in the post marketing period, and I was wondering what
you meant by \"aggressive surveillance\" and what kinds of tools or
techniques you would anticipate using to be more aggressive about
acquiring information about either adverse events or drug utilization
during that period of time?

DR. KOTSANOS: Well, currently the system of post-marketing surveillance
is pretty good. I mean companies have clearly the collection of adverse
event reports that they receive spontaneously. There are also studies
that companies may conduct, whether they be observational or otherwise,
clinical trial, to further study the safety, and we believe with the
risk management approaches, it will continue to help us enhance the
safer use of products, which may include the methods I mentioned,
whether they be studies that may be needed depending on the
circumstances or other types of approaches.

DR. DIECK: May I add to that? I feel that there are a number of
\[activities\],by aggressive, that implies that we can actually go
beyond what the regulations ask us to do in order to try and get as
complete information on reports that come into us, and I think it\'s
important to do that, not just in the U.S., but on a global basis.

And in some instances, where we feel that there is an area of risk that
needs to be further explored, we can actually write up a series of
questions that are asked to someone that reports a certain type of
adverse event so that we can get as much information not only for us but
for you, because we send these right down to you, and the more complete
information that you have allows you to evaluate what\'s happening with
this patient and is what\'s been reported actually associated with the
use of the drug or is it due to other risk factors or concomitant
diseases that the patient has?

And this is something that we can work together on, and certainly I
think it\'s one way of looking at sort of going beyond what we\'re asked
for, because we need the information and you need the information too.

DR. ZUCKERMAN: I just would like to add that the Patient and Consumer
Coalition would really like to see a much more proactive reporting
system. We don\'t think it\'s a good reporting system when approximately
90 percent of adverse reactions are not reported. We think it\'s
confusing to physicians whether they\'re supposed to report all adverse
reactions or only those that think are related to the drug.

I think that\'s a dangerous misconception, because the whole idea is to
look at patterns to find out what some unexpected adverse reactions
might be, and so we think much more needs to be done, and certainly
having a voluntary system that is not used very much and not completely
understood by all physicians across the country we think is a real
problem, and that a lot more could be done even within the current
restrictions to make it used more effectively and that you should
consider making changes to make it less voluntary and better understood.

DR. GALSON: Let me ask one last question from the FDA table for Dr.
Cranston. You mentioned use of computer order entry, such as PDAs. Can
you envision use of similar technology to allow immediate rapid
reporting of adverse events?

DR. CRANSTON: Yes, I certainly would think so. I also think that if this
country eventually gets to the point where it does, you know,
computerize the clinical side of medicine, that the database potential
for you folks is going to be tremendous in terms of doing these types of
proactive adverse event monitoring once the drug is on the market.

DR. GALSON: Okay. Great. I\'d like to thank everyone for a very
interesting and productive morning. We are right on schedule, but we
have really just one hour for lunch. So if folks could be back promptly,
we\'ll start at 1:20, and let me tell you quickly what\'s happening this
afternoon.

We\'ve got six speakers from five different groups and we\'ll have
questions like we had this morning, a short break, and then we\'ve got
some public, five minute public comments. I\'m not sure if folks have
signed up for that, but we\'ll have an opportunity late in the
afternoon. Thanks a lot. Back in an hour.

\[Whereupon, at 12:20 p.m., the hearing recessed, to reconvene at 1:37
p.m., this same day.\]

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\[1:37 p.m.\]

DR. GALSON: Good afternoon. Welcome to the second part of the FDA Part
15 Hearing on Risk Management of Prescription Drugs. Happy that you\'re
all back. We\'ve got a panel and then some public comments if we have
time this afternoon, and I think we\'ll just go ahead and start right
off. For those of you that are new, we\'re going to have 20 minutes for
each speaker in the panel, and then we\'ll have a 20 minute period at
the end where the people sitting up here and the other folks from FDA
can ask you questions.

So we\'ll start with the first speaker who is Thomas Menighan from the
American Pharmaceutical Association. I hope I\'ve pronounced your name
right.

MR. MENIGHAN: Close enough. Good afternoon. Thank you for the
opportunity to present the views of the American Pharmaceutical
Association, the national professional society of pharmacists. I am Tom
Menighan, a long-time community and home-infusion pharmacy practitioner
who for the last two years has been involved in the delivery of health
information and tools to consumers and pharmacists via the internet.

I\'m the immediate past president of APhA and appearing today on the
association\'s behalf. Our more than 50,000 members are pharmacists
providing care in all practice settings such as community, hospital,
long-term care and hospice settings, pharmaceutical scientists and
student pharmacists.

In each of those settings, pharmacists help consumers manage and improve
their medication use. And have an essential role in helping maximize the
benefit and minimize the risks of those medications.

My comments today are based on the perspective of the pharmacist as a
medication use expert. My goal today is to impress on this body that we
have an opportunity to build on our experience and existing technology
to create a new system that professionals can use, that the industry can
afford and that will protect our patients while affording them access to
the best drugs to meet their needs.

It\'s important for our discussion today that the recognition of all our
efforts, regulators, health professionals and the pharmaceutical
industry, be focused on helping patients as the ultimate manager of the
risks they face when taking medication.

While prescribers consult, diagnose and select medications, consumers
are bombarded with numerous influences as they determine whether or not
to follow their doctor\'s advice. It\'s the individual patient who
decides what life style changes to make, what side effects to report,
if, how and when to use their prescribed medications, often with other
prescription and nonprescription meds, dietary supplements, herbal
remedies and other compounds.

Pharmacists can assist in this process. All risk communication and risk
management efforts must support and encourage good decision-making and
action by consumers. Unfortunately, the current system is not structured
for the activist patient nor for the pharmacist to support that rule.
Our training is of little use if the health care system does not support
that role, and it will be difficult to improve our practices if some of
these problems are not addressed.

Risk communication is obviously essential to the appropriate use of
medications and important to supporting pharmacists in their efforts to
maximize medication use. If we do not receive the information, do not
understand what is presented because of the format or content, or cannot
retrieve it at the appropriate time, then risk management efforts are
hampered.

An essential mechanism for the pharmaceutical industry and FDA to
communicate is through the drug label. In contrast with other
professionals, pharmacists have physical access to drug labels of nearly
all the products in their inventory, an inventory including thousands of
individual products.

We consider the drug product label a valuable resource. We refer to
prescription drug labeling information frequently as part of our normal
pharmacy practice. In an informal survey conducted by APhA during the
first four months of last year, most pharmacists stated that they
accessed drug product labeling information frequently.

They check for contraindications, verify dosage, examine potential
warnings and adverse reactions, or determine other dosage forms
available.

Respondents were most likely to refer to labeling for recently approved
products, about 48 percent of them, or when dispensing a drug for the
first time. Every time a product is dispensed, unless automation is
used, pharmacy personnel handle that container with the product label.
As we\'ll discuss in a bit, that external label can be important for
identifying certain categories of products as is now done with
controlled substances.

The label physically attached to the product, though, does not always
contain the most up-to-date information. The FDA receives more than
1,000 proposed labeling changes for approved new drug applications and
biologic license applications each year.

There is a time lag between the review and approval of these label
changes, and when those changes appear on the label as attached to the
product in the pharmacy. That time lag, a result of production,
distribution and dispensing cycles, may be extensive, and in the current
labeling format, identification of those changes on labels is difficult.

In the current situation then we face a conundrum. We have physical
access to drug information from the manufacturer and FDA but nothing
confirming the currency of that information.

This challenge as well as challenges with content and presentation of
the information diminished the label\'s utility. We support the
agency\'s investment of additional resources to improve product labeling
and offer our support in that process.

Another problem exists when the risk communication tools of product
labeling are combined with the risk management tools of restrictive
marketing. In a situation where pharmacists in certain practices are
precluded from carrying certain products, they are also precluded from
easily accessing the product information for those medications. At the
same time, however, they may well serve patients who use those products
or have questions about them.

Limiting access to product labeling is just one of the many problems
with current construct of restricted marketing. I\'ll touch on some of
those problems in a minute.

The move to electronic labeling as proposed in the May 3 Federal
Register may offer some improvement to the current paper-based approach,
and in general we support those initiatives.

\"Dear Health Professional\" letters are another mechanism for
communicating with pharmacists. While these documents can provide
information in a timely manner, there are problems with document
dissemination and information overload.

In every pharmacy practice setting, time is at a premium, and the need
for quick access to accurate information is vital. One challenge with
these health professional letters is that the communication may arrive
in a pharmacy mail and be reviewed only once by the entire staff.

Critical to success is the ability of multiple practitioners to
assimilate the information contained in these letters in easily
retrievable formats, and to maintain the information for future
access\--when the pharmacist recalls receiving the information, but
would like to review the specifics of the communication. Chasing random
pieces of paper is not easy in an office setting and is obviously
challenging in pharmacy environments where more and more records are
stored electronically.

In part because of this challenge, most pharmacists rely on drug
information contained in their pharmacy management systems, along with
printed and bound references.

Information overload is more than a buzz word for pharmacists. In the
first 20 days of this month, seven \"Dear Health Professional\" letters
were distributed. I got one last night in my mail. If one extrapolates
those 20 days to the 365 days in 2002, we can expect at least 127 of
such communications this year, a figure that does not include the
additional separate communications from individual manufacturers.

The 20 non-standard letters from this month range from warnings about
counterfeit products to product recalls, changes in labeling, and
confusion with names. Unfortunately, the letters were not categorized to
readily identify the importance of urgency of the information and thus
are very difficult to assimilate, let alone recall days or weeks later.

We urge the agency to work with APhA and other organizations to develop
systems that can categorize this information, consistently highlight the
most important content, and deliver it in ways to support reliable,
standardized retrievable systems.

Posting this information on FDA\'s web site and other frequently used
web sites is helpful, but many pharmacists do not yet have convenient
access to the internet in their practices. Certainly we\'re increasingly
capable of accessing the internet and exploring this channel of
communication will be essential even in near-term future systems\'
decisions.

However, in the interim, we urge the FDA and the industry to work with
APhA and vendors of pharmacy operating systems to explore mechanisms to
integrate the content of \"Dear Health Professional\" letters into
databases that know when to serve up immediate information or action at
the appropriate time in the normal workflow in a pharmacy.

The primary mechanism for manufacturers to communicate with patients is
the patient package insert and the medication guide, as required in
limited situations for drugs with serious and significant side effects.
These mechanisms are not, however, the pharmacist\'s primary mechanism
for communicating with patients.

That mechanism continues to be one-on-one interaction between us and our
patients. Written information can support that interface but should not
be considered a replacement. The communication between pharmacist and
patient is vital to support patient understanding, particularly if
products are being used for unlabeled indications, and especially when
patients are on complex regimens or therapy where the patient and
caregiver understanding can have such a major impact on appropriate use.

A common method for communicating drug information to pharmacists in all
practice settings is through computer programs to aid in screening
multiple drug regimens for conflict\--the DUR programs within pharmacy
systems. And many manufacturers are including these messaging
capabilities in proposals to manage product risk and communicate
information.

Care must be exercised to reduce noise in these systems before this
mechanism as a component of risk management programs is used.
Unfortunately, these systems suffer from the same problems as numerous
\"Dear Health\" letters\--too much information without sufficient
prioritization or stratification.

In one observational study, more than 80 percent of alerts generated by
these systems were overridden by pharmacists. It\'s a staggering
percentage and a signal of problems that must be addressed.

Beyond the noise factor, these alerts also pose problems with
significant variability among pharmacy operating systems, among third
party plans and with PBM generated alerts. In an analysis of one set of
alerts from 17 Medicaid programs, the inconsistency was clear. Out of 23
possible alerts, only five were included in a majority of the states in
their systems.

No two states used identical criteria sets even if the same software
vendor supported both systems. The alerts provided by different vendor
systems vary widely. So a pharmacist addressing the same clinical
situation may get a different alert from one program than from another.
Clearly, this is not good for pharmacy practice, risk management or for
clearly communicating risk information.

The profession is working to improve these systems both to decrease the
noise and increase the consistency. As the agency evaluates risk
communication mechanisms, current limitations of these alert systems
must be recognized. Capabilities should clearly be utilized and
explored, but not without recognition for workflow issues in busy
practices.

One risk communication mechanism to consider is creating a new
classification scheme for prescription drugs under which higher risk
products would be identified as belonging to a category of drugs which
demand special attention from clinicians and patients.

This risk stratification schedule could be analogous to the schedules
defined in the Controlled Substances Act. Health professionals would
know that a drug in a high risk category bears special or unusual risks
that require close monitoring.

When one pulls a Schedule II narcotic off the shelf for dispensing,
it\'s easy to see the CII label. A similar large and bold notation on
labels of products requiring additional risk management could be useful.

We urge the FDA and product sponsors to evaluate closely the role of the
pharmacist in risk management. We can play a vital role in helping
consumers make the best use of their medication. But unfortunately,
we\'re often bypassed in risk management systems or relegated to
positions that minimize the contribution we could make.

I\'ll first discuss some of the challenges we face with FDA\'s current
systems and then articulate some recommendations for improving these
interventions.

In the past 20 years, 14 drugs that had received FDA approval and were
on the market were later withdrawn for safety reasons. This action,
usually voluntary and in cooperation with the FDA, is an indication that
post-marketing systems to monitor adverse reactions are functioning.

The loss of these products can also at least in part be attributed to
our failure to appropriately manage good drugs through their known or
unknown risks. Despite the FDA\'s efforts to change the actual use of
medication, the role and the effectiveness of the FDA in this area is
limited. Practitioners and consumers must also participate.

This reality creates an opportunity for us to work together focused on
our goals to help patients make medications work. Unfortunately, a
primary barrier in our participation in risk management occurs when
restricted marketing is used and pharmacists are excluded from working
with the product. Restricted marketing as currently used causes
significant concern in our community. Arbitrarily restricting products
to certain providers creates problems for both health care professionals
and patients, posing substantial risks, including problems with drug
interaction checking, product availability and communication with the
prescriber and pharmacist of choice.

In the typical restricted marketing situation, pharmacists cannot fulfil
their role in helping patients make best use of the medicines because we
can\'t access the product. The one-on-one communication I discussed
earlier, a vital component to consumers fulfilling their role as risk
managers, is disrupted when we\'re excluded from working with certain
drugs. Restricted marketing disrupts existing pharmacist-patient
relationships and disaggregates care from existing providers.

The structure requires multiple clinicians to get involved in patient
care, each having access to only a portion of the relevant record.
Disrupting an already fragmented health care system does not support
patient care nor risk management.

We have vehemently opposed restricted marketing since before this agency
was founded. Our support for the FDA, Federal Food, Drug and Cosmetic
Act in 1938 was based on a concern for public health and support for the
distribution of medication through pharmacists.

In the 1970s, APhA challenged the FDA\'s restriction on methadone in
court and won. As expressed in an editorial from 1973, the profession is
concerned that FDA may decide that only blue-eyed, red-haired,
left-handed pharmacists are entitled to possess and dispense some
medications. And while I happen to be one of the very few pharmacists
who would meet such criteria, the problems with such an approach are
clear.

Although the agency apparently sees some advantage in restricted
marketing, perhaps in data collection, the risks of this approach
outweigh any perceived benefits. A new approach, one that builds on our
role rather than eliminates it, could be structured to yield necessary
data collection.

A third challenge emanates from the current product-by-product approach
to risk management program development. When challenges are identified
with one product, a new program is developed to address the identified
problems with little if any similarity to existing programs. This
product-by-product approach may yield short-term success for specific
products, but that success is short-lived in the real world as the
agency uses such programs with increasing frequency, and with drugs we
haven\'t even conceived of yet.

Pharmacists become faced with a thalidomide program, a clozapine
program, an isotretinoin program and the list continues.

For example, a patient registry operated through one program may have an
entirely different set of requirements and procedures from the patient
registry for a different medication. Such inconsistency frustrates
participating health professionals and may defeat the goal of risk
management. For pharmacists, these requirements begin to resemble the
myriad of third-party payer policies and formulary requirements. At a
time when we should be capitalizing on patient care capabilities of
pharmacists, we are instead laying new administrative burdens on them,
relegating us to paper pushers rather than caregivers.

Finally, the standards for determining when products should be placed
into various risk management programs are not clear. Why are some
products subject to substantial risk management interventions while
others with seemingly similar risk profiles are not? It creates
confusion in the pharmacy and may yield situations where patients are
moved from one product to another because of a decrease in the
administrative burden rather than clinical superiority.

We have evaluated many of the challenges with existing risk management
tools and propose the following principles to improve risk management
interventions:

The first step to improving risk management tools should be the
identification of criteria to determine when formal risk management
tools will be used. While all drugs have risks, there is no delineation
with the prescription medication class to identify those products that
have a higher risk, require more attention or special patient screening.

A collaborative \[agreement\] with FDA, manufacturers, health
professionals and consumers could outline a mechanism to facilitate this
process.

The second principle is the need to address risk management in a systems
based approach, recognizing that the current product-by-product
mechanisms must operate in a broader health care system. We recommend
developing a standardized process to work with medicines demanding
special attention as identified by the process just suggested.

As a mechanism to help pharmacists and others distinguish these products
from prescription medications, products using this system could be
placed in their own subset or medication class, readily identifying them
as requiring a formal risk system.

This approach is analogous to controlled substance scheduling where
pharmacists and others can readily identify the requirements of such
drugs. The broad system would consist of a number of tools such as
category labeling, targeted education, registries, laboratory test
validation, and periodic medication monitoring.

Each program could be built from these tools, standard tools, creating a
program to manage a specific medication. For example, the risk
management program for a drug requiring specific lab tests to detect
adverse reactions would involve documentation of such tests. A
documentation by both the prescriber and the pharmacist helps confirm
the completion of the work and underscores the importance of the testing
with the consumer.

A program requiring patient education would have pharmacists= documented
interaction with the patient and the patient\'s understanding.

Quite simply restricted marketing must be reevaluated. An appropriate
alternative is an opt-in program, one where physicians and pharmacists
agree to comply with risk management tools, rather than a
manufacturer\'s or regulator\'s limitation of a product distribution.

This scenario allows prescribers and pharmacists to maintain
relationships with their patients. It allows every pharmacist to choose
whether or not to work with these products. Such programs ensure
medication access to those pharmacists and other providers willing to
meet legitimate use and monitoring requirements, but do not arbitrarily
limit health care provider participation.

Let me explain how such a system could work with hypothetical Drug A, a
fictitious product requiring liver function testing after three months
of therapy. The first step in the process would be to require the
product sponsor and the Agency to determine according to criteria that
the product requires such a system. Drug A would then become part of an
identified sub-class of prescription drugs readily identifying to the
pharmacists and other professionals its inclusion in the system.

The program to manage the product would then be developed with two risk
interventions used: patient education and confirmation of patient
testing. These interventions would be the same as any other systems
products requiring the same intervention. Documentation of compliance
with the tool would be accomplished through a central standard system,
and payments for the intervention could be accomplished through the same
system.

With an opt-in program, any pharmacist or professional would be eligible
to work with the product providing they agreed to comply with program
requirements.

Using these principles to develop and integrate existing risk tools will
help support the activity of patients, pharmacists and other
professionals.

The evaluation of risk management tools is essential to the expansion of
the tools to other programs. It appears that the sticker component of a
program to reduce fetal exposure to isotretinoin is being thought of by
some as the holy grail in risk management. Unfortunately, anecdotal
reports by pharmacists suggests significant dissatisfaction. We do not
know whether they are effective and that effectiveness and impact on
pharmacy and medical practice should be evaluated before the tool is
widely adopted.

We applaud the product sponsor for their attempts to protect consumers
including the substantial problem of dealing with a product already in
wide use, but we have significant concerns that sticker programs will be
broadly used before the effect of the program has been shown.

Rigorous evaluation of existing interventions and any proposed tools is
essential. Letters and stickers as risk management tools are sticks in
the spokes of most pharmacy operations. Technology exists today and the
will exists today to create and preserve access to good drugs with
special requirements.

With the help and commitment of FDA and industry, APhA is willing to
lead and pharmacists are prepared to play an important and increasing
role in risk management, but that role requires improved communication,
standardization, and payment for those services.

Thank you for the opportunity to present the views of the nation\'s
pharmacists on these important issues. I look forward to working with
the Agency and other stakeholders.

DR. GALSON: Thank you very much. Our next speaker is Tom Clark from the
American Society of Consultant Pharmacists.

MR. CLARK: Thank you. My name is Tom Clark, Director of Professional
Affairs for the American Society of Consultant Pharmacists. ASCP is an
association of 7,000 members who provide medications and pharmaceutical
care services to older adults, both home and community based, as well as
those who reside in nursing homes and assisted living.

Our comments today will include a focus on risk management issues as
they relate to older adults and long-term care.

Thank you for this opportunity today to present testimony on the
important issue of risk management for prescription drugs. The FDA is to
be commended for devoting attention to this issue and seeking ways to
improve the current structure and systems for managing risk associated
with prescription medications.

I\'d like to add my support and ASCP\'s support to those voiced earlier
today by other speakers on the need for increased funding for FDA,
particularly to focus on post-marketing drug safety issues. The Office
of Drug Safety and the MedWatch program in particular could benefit from
greater resources with which to implement programs to improve drug
safety.

We support more resources for MedWatch in particular to enable several
things. One would be increased marketing and awareness of the program on
the part of health care professionals and others so that the program
would be more widely used. Some of the things in the Rhode Island
program can certainly be better implemented with more funding as well as
rapid data analysis and aggregation to identify trends and problem areas
with medications and then more feedback to health care professionals,
both at the individual level of those who generate reports through
MedWatch to get feedback from their particular report, as well as at the
aggregate level through a web site or periodic e-mails to provide
information and feedback to health professionals on what\'s being
reported to MedWatch and what are some of the problems that are being
identified, perhaps in the early stages to enable prescribers and other
health professionals to use that information in their practices.

Older adults are especially vulnerable to the risks of medication use.
They take more medications than other persons and are more likely to
have diminished ability to metabolize drugs due to declining kidney and
liver function. Adverse drug reactions are observed two to three times
more frequently in geriatric patients than in adult patients younger
than 30 years.

It is also estimated that adverse drug effects are responsible for up to
ten percent of hospital admissions in older patients. Older adults
consume 30 to 40 percent of all prescription drugs, yet few older adults
are typically included in clinical trials prior to marketing.

Once a medication is approved for marketing, manufactures have little
incentive to conduct or sponsor trials specifically in older adults.
Research on drug use is particularly lacking for use of medications in
the frail elderly, those over the age of 85, who often reside in these
long-term care settings.

Information on prescription drug risks in this population is difficult
to obtain. ASCP supports increased research on drug use in older adults
and the development of strategies to encourage funding of such research
by pharmaceutical manufacturers, federal agencies or others.

With regard to risk communication, a number of the challenges have been
highlighted here today already. We have one suggestion that we would
like to offer in response to the issues of the information overload and
trying to cut through the clutter. And that would be an idea based on a
strategy that FDA currently uses when issuing notices about recall of
medications. A Class I recall, for example, is a situation in which
there is a reasonable probability that the use of or exposure to a
violative product will cause serious adverse health consequences or
death.

This system of prioritizing medication recalls enables health care
professionals to quickly identify situations where urgent action is
needed to avoid loss of life. The class of the recall provides guidance
to the practitioner on the urgency and importance of the issue. Perhaps
the FDA should consider developing a similar prioritized system for
issuing medication safety alerts.

A Class I medication safety alert would involve a situation where
patient lives may be lost or serious adverse health consequences may
occur if certain precautions or actions are not taken with use of the
designated medication. The information about the need for liver
monitoring with the use of troglitazone, for example, might have fit
into a Class I medication safety alert category. The drug recall
framework might also be used to establish guidelines for Class II and
Class III medication safety alerts.

These medication safety alerts should be provided in a consistent format
and should emphasize information in four key areas. First, a description
of the safety issue or problem. Second, strategies to prevent the
particular problem such as avoid use of the drug if heart failure or
conduct an electrocardiogram baseline prior to initiating therapy.

The third area to focus on would be how to promptly detect or identify
problems that may arise with use of the drug, and this may include
monthly liver panels, or it might be educating the patient on signs or
symptoms, early signs or symptoms of toxicity, so that they seek medical
attention right away when problems occur.

And fourth, and finally, what to do when the problem occurs. Is
discontinuing the medication sufficient or are other steps necessary or
other types of interventions needed in that particular setting? What
should the health professional who\'s taking care of that person do in
response when a situation does occur?

I\'d like to comment also on some of the existing tools for risk
management. It\'s been noted that a variety of risk management
strategies have been implemented by FDA with various high risk
medications. Of course, it\'s been noted before, the ultimate risk
management strategy is to remove a medication from the market. When
useful medications are withdrawn from the market, patients who could
benefit from them are deprived of the benefits.

The withdrawal of Cisapride heightened ASCP\'s interest in the
medication risk management issue. Cisapride is a medication used to
increase motility of the upper gastrointestinal tract and of value in
managing a common complication of diabetes called diabetic
gastroporesis. Without Cisapride, therapeutic options are now more
limited.

Metoclopramide can be used, but in older adults metoclopramide
frequently causes movement disorders including extrapyramidal symptoms
and tardive dyskinesia. These symptoms are similar in appearance to
Parkinson\'s disease and are sometimes irreversible even when the
medication is discontinued.

One recent study found that prescribers frequently confused the drug
induced side effects of metoclopramide with the onset of true
Parkinson\'s disease. In fact, older adults who take metoclopramide are
three times more likely to be placed on a medication for Parkinson\'s
disease. As a result, these patients are exposed to the risks of
unneeded drug therapy.

Another treatment approach is erythromycin. It does increase upper GI
motility and is used for this purpose, but erythromycin is an
antibiotic. In this era of increasing concern about antibiotic
resistance, the fact that clinicians are using this approach is a clear
indication of the need for additional therapeutic options.

It\'s been noted already that the multiplicity of drug risk management
programs is confusing, expensive, represents significant challenges, and
we certainly agree with that. The restricting of the source of supply
for the drug product is one issue that we want to address specifically.

When patients are required to obtain the restricted medication from only
an exclusive pharmacy provider or a very highly restricted network, this
segregates that particular medication from the patient\'s usual source
of supply for other needed medications.

As a result, any drug interactions involving the restricted medication
would be difficult to detect. The designated provider for the high risk
medication may attempt to collect information about other drugs in use
by the patient, but if the patient later needs a new medication, the
usual pharmacy provider may not detect the interaction with the
restricted medication and, of course, may not even be aware the patient
is taking it.

Removing the local pharmacist from the loop with a restricted medication
also keeps the pharmacist from being able to assist the patient with
identification of possible adverse effects from the restricted
medication or additive side effects with other medications the patient
may be taking.

Residents of nursing homes and assisted living facilities are usually
served by specialized long-term care pharmacies that provide needed
services such as specialized packaging, drug delivery, 24-hour emergency
service, and others.

When special distribution programs exclude these pharmacies from
participation, these needed services, especially the special packaging,
are usually not available from the exclusive pharmacy distributors. This
creates significant logistical problems for the long-term care
facilities and increases the risk of medication errors.

Concern was expressed earlier today about physician resistance to
prescriber restrictions and possible lack of FDA authority to implement
such restrictions.

Restricting a medication to use only by physician specialists also
presents challenges for the patient. In some cases, patients may have to
wait for weeks or months to get an appointment with a specialist to
begin drug therapy. The specialist may also be geographically distant
from the patient requiring substantial time and effort to make the trip
to the specialist.

The strategy of having the prescriber place a special sticker on the
prescription to show that certain risk management steps have been taken
also has a number of problems. In the long-term care setting,
traditional prescription forms are seldom used. Prescribers may write
prescription orders in the medical record at the nursing facility or
very commonly telephone orders from their office.

Nursing homes have about 1.6 million residents and an additional one to
two million persons reside in assisted living or board and care homes.
Any risk management approach must consider the unique needs and
requirements of these long-term care settings. And ASCP would be pleased
to offer assistance to FDA in developing or revising risk management
strategies to consider the special needs of patients in these long-term
care settings.

The existing menu of options used in risk management of medications has
failed to employ a key resource, the community pharmacist. In some
cases, the community pharmacy is bypassed altogether through exclusive
distribution arrangements with a single mail order pharmacy or highly
restricted distribution network.

Involving the pharmacist as a key player in medication risk management
is highly desirable for several reasons. Pharmacists have, in fact,
always had an important role in managing risk of medications. Evaluation
of the appropriateness of the prescription by the pharmacist is the last
safety check before the medication reaches the patient.

If the pharmacist believes the medication dose may be too high or the
medication may interact with another drug the patient is already taking,
the prescriber will be alerted to ensure that the patient is not
inadvertently harmed.

Why not strengthen this structure and provide the pharmacist with tools
and resources to assist with managing risk of these designated high risk
medications? Existing risk management programs focus heavily on
prescribers. The United States has about 676,000 practicing physicians
plus many more mid-level prescribers such as nurse practitioners and
physician assistants. We\'ve already noted the resistance and challenges
with some of the prescriber prescriptions that we\'ve seen already.

ASCP suggests that a voluntary network of participating pharmacies could
form the basis for a comprehensive risk management strategy. This
network would include any pharmacy willing to meet the program
guidelines. The pharmacist who dispenses the medication to the patient
would be responsible for ensuring that specific risk management
strategies are implemented. Education would be provided to the
pharmacist and documented to ensure adequate knowledge and skills for
performing the tasks.

Pharmacy-based risk management strategies could include confirmation
that drug interactions and contraindications to the medication do not
exist prior to initiation of therapy. This would be conducted using
standardized check lists and forms developed by a group of stakeholders
including FDA, the pharmaceutical manufacturer, prescribers, pharmacists
and others.

Other strategies could include patient education, counseling or
training, verification that needed laboratory tests have been conducted
on schedule, and monitoring of the patient and reporting of adverse drug
reactions to the prescriber, FDA, and manufacturer.

Long-term care pharmacies must be included in any pharmacy-based risk
management approach to ensure that the three to four million residents
of long-term care facilities have access to these medications when
needed. Pharmacy- based risk management is not the total answer to the
issue, but can be an important tool in a comprehensive risk management
program.

Pharmacy-based risk management strategies may be adequate for some
medications. In other cases, additional strategies may be needed. The
American Society of Consultant Pharmacists is pleased to have this
opportunity to provide input on medication risk management. We welcome
the opportunity to continue to discuss these issues with the FDA and
collaborate in the development or refinement of medication risk
management strategies.

Thank you.

DR. GALSON: Thanks very much. Our next speaker is different from the
original agenda. It\'s going to be Dr. Gary Stein representing the
American Society of Health System Pharmacists. Dr. Stein.

DR. STEIN: Dr. Galson, Dr. Woodcock, members of the panel, my name is
Gary Stein, and I\'m the Director of Federal Regulatory Affairs for the
American Society of Health-System Pharmacists.

ASHP is a 31,000 member national professional and scientific association
that represents pharmacists who practice in hospitals including
outpatient services, HMOs, long-term care facilities, home-care
agencies, and other components of organized health care systems.

We are grateful to the FDA for calling this public hearing to receive
input on the agency\'s approach to risk management of prescription
drugs.

ASHP\'s members have a long-standing commitment to helping patients
manage the risks inherent in prescription and non-prescription
medication use. And we recognize that the FDA has the same commitment,
particularly in regard to newer, high risk drugs. Unfortunately, many of
the risk management plans that have been implemented in recent years
fall short of what is needed to manage risk.

They fall short because they lack the proper collaborative patient care
efforts of all health care providers who are involved in medication use
process. ASHP intends to provide more extensive comments on the FDA\'s
approach to risk management by the June deadline for written comments.

Today, I\'d like to discuss a couple of important points. First and
foremost, there needs to be a fundamental reform in prescription drug
labeling.

DR. GALSON: Excuse me, Dr. Stein. Can you get a little closer to the
mike.

DR. STEIN: I\'m sorry. Is that better?

DR. STEIN: That\'s good.

DR. STEIN: Okay. First and foremost, there needs to be a fundamental
reform in prescription drug labeling. Current package inserts and \"Dear
Health Professional\" letters are not adequate. Current labeling does
not present information on the drug safety, efficacy or risks versus
benefits that is oriented toward a practice environment.

ASHP suggests that the FDA in consultation with health care
practitioners develop as an adjunct labeling for high risk drugs a core
protocol, basically a check list, that progresses from diagnostic
workups to prescribing decisions based on the interpretation of those
workups.

Adherence to such a protocol would help influence practitioners\'
decisions to prescribe or not to prescribe medications, based on patient
selection criteria and interaction liabilities of one medication with
other drugs or disease states. This type of protocol would include
proper patient counseling and provision of written patient information.

ASHP believes that the development of this new paradigm is imperative
for an appropriate patient care process in all settings and for all
health care providers to ensure appropriate patient selection,
appropriate prescribing, and appropriate patient monitoring.

Currently, physicians and pharmacists often are not systematically
dealing with patients because they are not coming from the same basis of
information. A standardized protocol as we envision it is a viable tool
for drug risk management.

It could be the basis for collaborative drug therapy management
relationship between prescribers and pharmacists that is clearly in the
best interest of patients.

The second point that we would like to make relates to restricted drug
distribution systems, one of the tools that the FDA has been relying on
more and more frequently to manage the risk of new drugs. Increased
reliance on restricted, closed, or limited drug distribution systems for
new high risk drugs is a growing concern among ASHP\'s members.

These systems often exclude individual hospitals as well as community
pharmacies from distributing medications directly to patients. While a
number of drugs have been relegated to restricted drug distribution
systems, neither the FDA nor drug manufactures have come forward with
information on how well these systems work.

Pharmacists are responsible for ensuring that medications are readily
available for patients who need them and that these medications are
being used properly. Disruptions and non-standardized distribution
processes create procedural confusion for pharmacy and other hospital
staff and increase the potential for mistakes. Any restricted
distribution system or special handling procedure that disrupts that
central oversight role of pharmacists represents an interruption in
standard medication use policies and procedures in the health-system
setting.

In November of 2000, and again in January of this year, ASHP drew the
FDA\'s attention to this issue. We have suggested that when a
manufacturer implements a restricted distribution of a drug product, the
FDA should obligate the company to ensure that a patient\'s usual
pharmacist relationship is not disrupted. ASHP also recommended that if
a restricted distribution system is being considered by the FDA as a
condition for marketing approval, practicing pharmacists and
professional pharmacist societies should be consulted before any
restricted distribution requirements are imposed on the product.

Open hearing at which pharmacists can express their views concerning the
design of such a system and the impact those systems may have on the
safety and effectiveness of patient care may be one mechanism to
accomplish this.

Pharmacists must lead, balance, and manage all the considerations,
including safety considerations, about drug distribution. Any
distribution process that bypasses pharmacist control or requires
exceptional procedures in such settings would be contrary to the best
interest of patients. ASHP\'s members recognize that, despite this
general principle and goal of standardization, some exceptions will
inevitably have to be made in a patient\'s best interests. An important
point, however, is that these should truly be extraordinary exceptions.
The prospect of multiple unique restricted drug distribution systems is
a frightening picture for pharmacists.

Deviations that are unique and that greatly differ from standard
practices create obstacles in delivering and administering medications
safely.

The patient-pharmacist relationship should not be misinterpreted as
merely a product distribution function. The pharmacist\'s minimum
responsibility is to assess the overall appropriateness of all
medications with regard to purpose, dosage, and drug/food interactions,
patient education and counseling, and adherence or compliance to
medication use.

Patient-pharmacist relationships in which this level of care is achieved
depend on mutual trust, the pharmacist\'s thorough awareness of the
person\'s overall medication use, and the pharmacist\'s actions to
ensure the timely supply of drug products.

Restricted distribution systems that limit the pharmacist\'s ability to
develop these relationships are disruptive. Restricted drug distribution
systems that involve physician to patient delivery prevent pharmacists
from providing medication appropriateness, dosage, and interaction
checks, patient education and counseling, monitoring and follow-up
evaluation.

Thoughtful consideration needs to be given to the fact that some of
these medications may be initial or continued \[prescriptions\] for
hospitalized patients. Hospital pharmacies may not be able to acquire
these medications in a timely manner through some of the drug
distribution systems. And a colored sticker system fails miserably in
inpatient settings.

ASHP believes that rather than unique drug product distribution schemes,
the FDA, in consultation with stakeholders including pharmacists, should
develop models for managing patients for whom any high risk drug product
might be indicated and prescribed that incorporate core protocols.

These models should focus on requirements for ensuring appropriate use
and monitoring, such as patient workup and selection, provider and
patient education, and patient monitoring. Such a system could answer
many of our concerns about important issues such as uniformity of
procedures for patient selection, what kinds of distribution systems are
most supportive of continuity of care, and what kinds of approaches
serve best for provider and patient education.

Thank you for holding this important hearing and for allowing us to
present our views. As a stakeholder in helping people make better, safer
use of their medications, ASHP is always ready to work with the FDA to
meet our common goals. Thank you.

DR. GALSON: Thank you very much, Dr. Stein. Our next speakers are Dr.
John Coster and Gary Wirth from the National Association of Chain Drug
Stores.

MR. WIRTH: Mr. Chairman and members of the committee, my name is Gary
Wirth, the Director of Pharmacy Professional Services for Giant Food and
Pharmacy. I am appearing today as a representative of the National
Association of Chain Drug Stores of which Giant is a member. Giant
operates 155 pharmacies in five states. NACDS membership includes more
than 200 chain pharmacies that operate 33,000 community retail
pharmacies.

Chain pharmacy is the single largest segment of pharmacy practice
employing approximately 100,000 pharmacists. Chain community pharmacies
fill about 70 percent of the three billion prescriptions provided to
patients each year.

We very much appreciate the opportunity to appear today to contribute
our perspectives on the development of an effective prescription drug
risk management strategy. Chain community pharmacies are the primary
point of distribution for outpatient prescription drugs in the United
States.

In addition, pharmacists provide an easily accessible point of contact
for patients. As medication experts, pharmacists help ensure the safe
and effective use of high risk medications by their patients. Therefore,
it is important that any risk management system developed integrates the
systems and procedures already in place at community pharmacies for the
safe use of prescription drugs.

It is also important to ensure that any program represents a
collaborative effort of the entire health care team including
manufacturers, physicians, pharmacists, patients and the Food and Drug
Administration.

Prescription medications allow individuals to lead healthier lives.
Needless to say drug products are not 100 percent safe and we know there
are certain acceptable risks associated with prescription drug use. If
the FDA approves a drug, we assume the benefits of taking the drug
outweigh the risks and that the drug is safe for widespread consumption.

Still, after extensive evaluation through the approval process, no one
fully understands all of the risks associated with the product. In
reality, some of the most serious adverse drug events may not be known
at the time of approval, but only after the drug has been used in a
broader population and real world conditions.

As a broad principle, NACDS supports the concept that once a high risk
drug is approved for marketing by the FDA, the drug should be available
through any community pharmacy outlet choosing to stock the product and
willing to help ensure its appropriate use through education programs,
counseling and other appropriate interventions.

The reason is simple: it is important for the pharmacist who already has
an established relationship with the patient, and he knows the
patient\'s medical condition, to integrate the risk-managed drug into
the patient\'s existing medication regimen.

That is when the patient is already taking multiple medications, it is
important for the patient\'s regular pharmacy provider to help assure
that the new risk- managed drug does not present any potential
interaction problems for the patient.

Acknowledging that there are risks from inappropriate use of any
prescription drug, community pharmacies help patients understand how to
make the most effective use of their medications. For many years,
pharmacies have used computerized systems to check for potential
drug-drug, drug-food, and now drug-nutrition interactions, drug
overdose, and duplicative therapy. In addition, community pharmacists
give quality written information to consumers with their prescribed
medications to help reinforce the face-to-face counseling they receive.

Pharmacists also follow up with patients through phone calls and other
professional contacts after the prescription is filled to improve
adherence with the prescribed therapy. Follow-up monitoring is important
because oftentimes adverse effects of medications are only detected when
prescriptions are refilled.

Moreover, some community pharmacists are certified experts in the
pharmaceutical management of certain disease states such as diabetes.
These pharmacists provide more intense personal education and counseling
to assist patients in managing the disease. In fact, Giant operates
several pharmacies which are certified by ADA to provide diabetes
self-management and training to Medicare beneficiaries.

It is clear that for some drug products, more intense monitoring,
education, and management is needed to ensure the risk is managed
appropriately. For example, over the past few years, several drugs have
been approved by the FDA with certain restrictions on how the drug could
be sold or distributed to limit potential risk to the patient.

In other cases, drugs were removed from the market because of
inappropriate use. Some of these drugs might have remained on the market
if certain professional or patient safety programs were available.
Lotronex may be a good example. In other cases, already marketed drugs
were required to develop new professional and patient safety programs
such as occurred with Accutane.

We commend the FDA for initiating this dialogue about risk management
approaches. We also understand that if the Agency believes a new or
existing drug needs a risk management program, then the Agency will ask
the manufacturer or sponsor to develop a program and then negotiate with
the sponsor to develop a program meeting the agency\'s requirements.

Because pharmacies, physicians and patients will be the key participants
in the risk management program, it is imperative that our input be
considered during the development of risk management programs. NACDS
believes that program development should seek to avoid impractical
situations once the program is implemented.

For example, the Accutane sticker program which has been running for
about a month seems to be workable. Fortunately, the program is feasible
as a stand-alone program, but more importantly, it works in conjunction
with other day-to-day pharmacy activities. There are other risk
management programs that have not worked so well, and there is a
potential for more programs that will not work well in the real world.

If pharmacy is involved in the developmental stages of the program, many
of these problems can be avoided.

While we recognize that each drug product is unique, a different risk
management approach has been developed for each current risk managed
drug. This fragmented risk management approach creates confusion for
professionals and patients, potentially defeating the goal of reducing
risk. We need a standardized seamless computer-based system that can be
easily accessed by practitioners to deliver risk management services to
patients.

We believe that a fragmented assortment of individual risk management
programs is counterproductive to minimizing risk. Currently, it is even
possible for two separate risk management programs to evolve for both
the brand and generic versions of the very same drug. It is very
difficult to maneuver all the different risk management programs
available.

The current risk management system is analogous to the situation that
developed with the use of multiple third-party drug formularies. There
are literally thousands of formularies and each formulary is different.
Physicians, pharmacies and even patients themselves are often unaware of
which drugs are covered. This whole process is time consuming, resulting
in delays and confusion for patients, pharmacists and physicians.

We should seek to avoid these formulary type fragmentation hassles in
current and future risk management programs. Having said this, I would
like to turn to some of the issues the Agency and others should consider
for an effective standardized risk management strategy for certain
prescription drugs including: the assumption of liability and payment
for risk management services, education and training of practitioners,
access and distribution of risk managed drugs, registries and patient
eligibility, generic versions of risk managed medications, and
communication to stakeholders.

A fundamental question for pharmacies is the nature of the risk and
liability that pharmacies will be asked to assume, and how pharmacies
will be compensated for this additional liability. While pharmacies are
willing to participate in risk management programs, many are concerned
about additional liability that they might incur by participating.

In one scenario, the pharmacy may actually be asked to bear some of the
additional liability that may result from providing a drug which has a
higher than normal risk. In other cases, the manufacturer may assume the
additional liability and shield the pharmacy for any of the liability.

These factors must clearly be explained for pharmacies as they consider
participation. Payment to pharmacies also must be commensurate with the
liability that the pharmacy will be asked to assume.

Regardless of the level of liability assumed, providing additional risk
management services results in additional costs to providers. FDA
traditionally has not become involved in economic issues relating to the
financing of prescription drugs. However, if the Agency requires health
professionals to perform certain additional activities relating to the
management of a drug product, then it is logical to assume that
pharmacists will be compensated for these services.

The manufacturer should bear the financial burden of providing these
services. We would ask the Agency to explore some of these issues since
providing these services comes with a cost.

NACDS believes that educating and training health professionals in the
proper use of medications with high risk programs is an important
component of a manufacturer\'s risk management strategy. We encourage
manufacturers to develop these educational programs in conjunction with
pharmacists including important feedback and evaluation component to the
FDA and the manufacturer from the retail pharmacy community.

As we already stated, for patient care and patient safety reasons, we
are opposed to limiting distribution of outpatient drugs to a restricted
network of pharmacies or total circumvention of community pharmacy
practice. Patients should be able to obtain high risk drugs from the
same health professionals that they currently use to obtain other
medications and health care services.

Patients rely on their community pharmacist for the latest health
information. As a medication expert, the pharmacist acts as a safety net
in the patient\'s medication therapy. However, we recognize that not all
pharmacies may choose to participate in a particular risk management
program.

FDA should provide any community pharmacy the opportunity to participate
in a risk management program provided that they meet the eligibility
requirements of the program. We also support the notion of allowing
pharmacies to access these products in the traditional channels of
wholesale distribution.

Professional or patient registries identify the patients who can take,
the physicians who may have prescribed, or pharmacists who may dispense
certain high risk drugs. We understand the interest in these registries,
but want to express our concern with the potential for multiple
registries using multiple data bases.

There is real value in developing a central registry or database that
can be used by any manufacturer with a risk management program to
identify those patients, physicians, and pharmacists eligible to
participate in the program.

Each drug\'s risk management program can have its own unique identifiers
so that pharmacies can only access information for patients seeking
prescriptions for their own particular high risk drug.

Current pharmacy technology and electronic transactions standards can
readily support such a system. This system would also indicate the
quantity of medication that could be dispensed, whether or not refills
are allowed, any monitoring or follow up the pharmacist is required to
do, as well as whether the patient has met all the qualifications and
requirements for receiving the drug.

We are concerned with the potential for use of multiple colored
prescription stickers that indicate whether the patient has met these
requirements. We believe that a real time system is more accurate and
reliable than relying on this paper trail. Indeed, with electronic
prescribing becoming a reality, paper based sticker programs may quickly
become outdated.

NACDS is also concerned about generic versions of brand new programs
that have risk management programs. That is when a generic becomes
available, does the generic have the same risk management program as the
brand drug? We believe that to minimize confusion for the patient and
the pharmacist, the program should be the same.

We also do not believe that risk management programs should be developed
with the potential of making it more difficult for a generic to come to
market, nor do we think the FDA should approve generic versions with
different risk management programs than the brand.

NACDS believes that effective, timely, and consistent communication with
professionals and patients is an important part of any risk management
program. There are two components to these communications.

First, materials must be developed to help educate physicians and
pharmacists and help the professionals to communicate with patients.

Second, the FDA and the manufacturer should seek consistent feedback
from health professionals about the actual use of the drug in patients
and share this information in a non-identifiable manner with health
professionals who are participating in the drug\'s risk management
program.

This process requires the use of a single portal for collecting
information and consistent evaluation of documented events.
Additionally, pharmacies have access to real time information systems
that allow easy communication with patients, physicians, third-party
payers, the FDA, and manufacturers.

NACDS shares the goal of improving safe medication use and ensuring that
patients have access to life sustaining and improving medications
including those medications which have a higher risk of adverse effects
when not used properly.

In summary, NACDS supports a risk management system that (1) allows
adequate access to valuable prescription medications that might
otherwise be considered higher than normal risk and become unavailable;
(2) provides the broadest possible participation of patients\' community
pharmacists; (3) uses standardized programs, processes and technology;
(4) recognizes the critical role of the pharmacist in the health care
team; and (5) provides appropriate reimbursement for expenses incurred
through participation in the risk management program.

In addition to input of a product manufacturer and the FDA, an effective
system will include the participation and input of pharmacists,
prescribers and patients. We thank you for the opportunity to comment on
this important public health issue.

DR. GALSON: Thank you very much. Our last speaker in this panel is Dr.
Robert Califf, representing the CERTS. Thanks. Rob.

DR. CALIFF: Yes. Thank you. I\'m delighted to be here. This is my FDA
day. I spent this morning between biologics and drugs talking about a
clinical trial trying to figure out how many thousands of patients it
would take to understand the tradeoff between preventing heart failure
and causing stroke with a treatment.

But now as I shift gears, I\'m delighted to be representing the CERTS,
the Centers for Education and Research and Therapeutics, which most of
you know represents a public/private partnership between seven academic
centers, the FDA, the AHRQ, and consumers, brought together to try to
understand better the multiple issues that face us regarding
therapeutics.

I was also sitting here trying to remember the last time I tried to read
a speech, and I actually can\'t remember the last time I did it, so I\'m
not going to read. I\'ll sort of skip around. I know it\'s the end of
the day for you and you\'re probably very tired.

But there are six main points I want to make today. The first is with
all of the sort of ease of negativism about problems in risk
communication, it is critical to pause and remember that our population
is living longer than ever before, not only that it\'s more functional
than it\'s ever been, in large part due to the benefits of the delivery
of therapeutics.

Secondly, the current system of risk management clearly does need
improvement and no one would deny that.

Third, much of the improvement needed is really outside of the purview
of the FDA. To fix this problem or to improve upon the system will
require partnerships well beyond the FDA, particularly between the FDA
and other government agencies and between the FDA and those who deliver
health care in many of the different ways that I\'ve just heard about,
in the short time that I\'ve been here including nurses, pharmacists,
and patient advocacy groups. The fourth major point that I want to make
is that to the extent possible, we really believe that policy changes
should be based on research. It\'s easy to make statements about how
things should be done, but as we\'re learning, as we actually do
research in this field, common sense approaches often turn out to be
just plain out wrong in terms of the consequences that result.

Fifth, like everyone else, I can\'t be here without touting my own
organization, and I want to tell you a little bit about some of the
research findings that we\'re encountering in the CERTS program.

And then finally, as you would expect from any academic, I want to make
the point that funding for therapeutics research is pitiful at this
point, incredibly small compared to funding for other types of research.

So briefly, on the first point, I just want to say again that the
average woman will live to be almost 90 years of age, born in the year
2020. These are predictions based on the global burden of disease study.
The average man will live to be over age 80. This is a long time, and
these are advances largely emanating from advances in therapeutics and
public health measures.

In addition to that, though, there is even a faster rate of improvement
in freedom from disability in the elderly. This is a great blessing for
our population, but it also opposes a very important problem, that is
the tremendous growth in the elderly with multiple co-morbidities who
live for a very long time with those co-morbidities, very much dependent
not on one drug or two drugs, but up to 12 different drugs given for
different indications, often by different specialists in a circumstance
in which we now know for sure that the average primary care practitioner
could not possibly remember all of the details about dosage
administration, side effects, and we\'ll talk more about computer
systems and how they may or may not help later.

In addition to that, we now have a new population in our society. That
is children with diseases that used to be lethal. Almost all of our
congenital heart disease patients and 80 percent of our pediatric cancer
patients are now alive. They just didn\'t exist before, and they\'re
very dependent on complex medical regimens in a society in which, by
design until recently, we did not study the pharmacokinetics or
pharmaco-dynamics even of commonly given medications.

Legislation in this arena has had positive intended and unintended
consequences, I think most of us would argue, and may serve as a model,
but the model will need to be extended because the complexity in this
population goes well beyond pharmacokinetics and very much into clinical
outcomes just like in adult populations.

So we need to celebrate the positive and note that the positives are
leading us now into situations that we never anticipated. If you don\'t
think this is enough yet, the plenary speaker at the American College of
Cardiology last month predicted there will be another doubling of the
life expectancy in the next century. So think about the number of drugs
that will be taken during that 180 years of life expectancy.

Now, what about the current system of risk management? I think it was
built with all good intention on the concept that drugs are regulated
meeting two conditions, safety and efficacy when used as described in
the labeling.

The problem is that the labeling covers only a small portion of the way
in which drugs are used in everyday practice, and what\'s reasonable for
one patient may be unreasonable for another patient. Once the FDA
approves a drug for marketing, we\'re now into this arena of medical
practice, where we\'re now learning an incredible amount about how
things happen in the real world.

The approaches used by the FDA necessarily are limited because of the
legal implications of extending beyond those practices, but we now know
that the FDA alone simply could not possibly communicate adequately what
it knows about the risk and benefits of drugs because of those
limitations.

Because many of the drugs that have been withdrawn from the market, at
least in our opinion, are valuable drugs when used for the right
indication, this really raises the sort of ugly scenario of an
increasing number of drugs being removed, not because they\'re bad
drugs, but because we can\'t get the information out to practitioners in
a way that enables practitioners and patients to prescribe the drugs in
the right scenario.

So when we talk then about the insufficiency of the current program, the
major point I\'d really like to make, if you remember one thing about
this presentation, it\'s that isolated and common sense approaches
towards policy in this arena carry a significant risk of failure because
of the complexity of the interactions inherent in the delivery of
therapeutics and the substantial risk of unintended consequences of
well-intentioned policies.

We believe strongly that policy must be guided by information derived
from well-designed health services research and probably the most
interesting example today is the use of computers in prescribing, where
I believe we\'re just now beginning to learn that, as nice as it sounds
in theory, the unintended consequences of computer systems could be
substantial if not thought through very carefully and researched
adequately.

So the third point. Much of the improvement needed is outside the direct
purview of the FDA. An effective system will require partnerships. As
we\'ve been studying practitioners and how they behave and why they do
what they do in the CERTS program, we\'re rediscovering what many others
have shown before, but hopefully in a more concerted way, that will get
the point across.

Our system is dependent on a very complex interaction. Prescribers,
pharmacists, nurses, the medical products industry, consumers of medical
products and last, but not least, the press, and I\'ll say a little bit
more about the press in its potential role in a minute.

I\'d like to emphasize here that we now know for certain that for the
average practitioner, the average prescriber, the primary source of
information for that practitioner is the pharmaceutical sales
representative. There are now 80,000 representatives in the United
States and we\'ve not yet figured out exactly what the role of these
people should be and we can\'t simply continue to pretend that they
don\'t exist as we design these programs.

Inadequate knowledge is a problem. And I believe here we must point the
blame somewhat at the academic medical community, my own group. Medical
schools, pharmacy schools, nursing schools are doing very little to
teach practitioners about the system and how it works in terms of where
to get information, how the information is actually derived. As recently
as three months ago, I wrote a paper saying that the FDA wrote labels,
and several people corrected me to say the FDA doesn\'t write labels,
it\'s the companies that write the labels. The FDA approves the labels.

That complex interaction and understanding explains a lot to
practitioners about what\'s in a label and what\'s not, what they\'re
told or not told by pharmaceutical sales representatives, their major
source of information, and again, I think we have to focus on that
system, how it works and what the implications are.

But very importantly in this, we need to reform medical education. There
was just a report I would urge everyone to look at from the Commonwealth
Fund that came out this week about the need for fairly radical reform of
the medical information system.

We also have a major problem in that the drug label itself is flawed
from the beginning. It\'s trying to serve two roles. First, to be a
legal document that may affect the company\'s exposure to liability and
future claims and, secondly, as a vehicle for risk communication
intended to influence practitioners\' behavior.

You simply cannot solve the equation maximally for both purposes, and
it\'s clear to most of us in practice which purpose is most frequently
being solved at the current time. The two concepts conflict with one
achieved at the cost of the other. In order to cover all contingencies
for legal purposes, labels contain huge amounts of information obscuring
the vital information that practitioners and patients really need to
know, and that is most important to them.

In discussions that we\'ve been involved in about this, the legal system
is clearly an impediment because if the unnecessary and rare information
is in small print, then there is concern that that could be construed as
hiding information in case of a retrospective claim made about a side
effect or a toxicity.

At a minimum, though, we would argue strongly that labels need to be
tested before they are put out to ensure that the information considered
most important, not by the company\'s lawyers, but by practitioners who
have to use the drugs, and perhaps by patient advocacy groups, are
retained by those who read the labels. This is not rocket science or
highly theoretical research, but there is no funding that I know of to
do this in an adequate amount for what\'s needed today.

All of this has led prescribers to become cynical about drug labeling
and the communication that occurs. As we\'re now surveying
practitioners, we find little confidence that they can depend on reading
the PDR or their main source of information, the pharmaceutical sales
representative, to truly understand how the negative aspects of drugs
can be balanced with the positive aspects to make the right decisions.

Many drugs in pediatrics, for example, have a warning against their use
solely because they have not been tested in children. In the case of
mibefradil (Posicor), patients most likely to be treated, those at high
risk, were not entered into the clinical trials so the information
didn\'t exist.

So the information that\'s provided in drug labeling while accurately
reflecting what was done in the drug development process frequently
leaves out the most important information to a practitioner trying to
care for patients in practice.

Quantification of risk would be an important step in this regard. In
addition to knowledge, we have issues of attitudes that develop, and
attitudes here that are an impediment are not a problem with the FDA,
not a problem with the industry, but medical practice today is suffering
from significant difficulties in terms of morale.

Another Commonwealth Fund survey published last year showed that the
majority of practitioners feel that the quality of care they can deliver
has diminished significantly in the last five years. Much of this is
related to their view that they have inadequate time to spend actually
caring for patients and the majority of their time is spent answering
questions about claims payment and doing other paperwork.

So the modern practice environment is creating a serious barrier to
communication about the risk of drugs, in particularly the office-based
practice. And here I want to pause for a moment and just recognize that
most of the research today about medical errors in prescribing is
focused on hospitals. Hospitals are not the major source of the problem.
Prescribing in the outpatient arena is much more prevalent. We simply
have not had a way to get at the transaction that occurs between the
patient and the prescriber because we don\'t have systems that enable
that to be done.

But now that we\'re beginning to do research in that arena, we\'re
finding a tremendous set of difficulties. One of my favorites is what\'s
been termed the time compressed prescribing decision, and that is in the
12 minutes that a practitioner has to see a patient\--interestingly, by
the way, the time per patient has actually increased, according to the
latest data. Unfortunately that\'s greatly offset by the more rapidly
increasing complexity of the patients that are being seen and the
decisions that need to be made. But, in essence, looking at time motion
studies and practice, we see the end of the visit being the time when
the prescription is written, often without adequate time allowed to
understand, even if you could go to the computer, the time to log into
it would not be there to find out about potential interactions.

In addition, physicians are often unaware of the other treatments that
patients are on, and I\'m sure these problems have been brought up
before. But the office is not the only place where there is a problem.
The hospitals are increasingly suffering difficulties maintaining the
teams of people that have provided the safety net that was referred to
before.

Substantial cost pressures on hospitals have caused tremendous
questioning of the use of advanced practice pharmacist, even in complex
arenas such as oncology units and in units seeing large numbers of
patients with impaired renal function.

So, we need to recognize that these difficulties exist and the elements
needed to change the system in this regard with regard to risk
management are obviously far beyond the purview of the FDA. We do
believe, however, that better linkage between the FDA and other
agencies, in particular CMS, the AHRQ, and much greater involvement of
the NIH and health services research could make a substantial impact on
understanding how best to combat the difficult circumstances that we
face as we enter the baby boomer old age era where we\'re going to be
overwhelmed with elderly people with all of these problems at much
greater numbers than we currently have.

Finally, when it comes to these issues, we have to say a word about
information technology, and we would all recognize the tremendous
potential of a large computerized physician order entry, PDAs. In fact,
in my own practice last week, I finally had my own PDA with a whole
hospital computer system in it.

However, I think that most people\'s views of these systems have been
tremendously oversimplified. And we now know that the majority of alerts
that are sounded from drug interactions, for example, are false alarms.
Now the same combination that may be lethal in one clinical circumstance
can be not only okay, but highly desirable, in another clinical
circumstance.

And so the prescribing information independent of the clinical data can
not only be time consuming, but can distract practitioners from the
little time that they have to make other critical decisions.

And so it may be that the audio prescribing situation today would
actually be an impairment when it comes to good health care
decision-making because it would diminish the capability of making other
decisions that are equally or more important.

And so we need research in this arena to understand which alerts are
really important and how to devise systems that can combine the clinical
information with the prescribing information.

Now, to quickly go through the last points, to the extent possible,
policy changes should be based on research. To us this is self-evident,
although looking at the funding agencies, one would not find this easy
to believe. A simple example is very simple research, which has shown
that the order in which you put the information on the drug label on the
page makes a huge difference in terms of transmitting that information,
done by Dr. Ruth Day at my institution in collaboration with UNC and the
FDA.

And we know that this information is making a change in the way labels
are put together. I could go through dozens to hundreds of other
examples that are currently not being funded.

We also have to go back to the beginning of the research pathway and
identify the characteristics of clinical trials that provide us with the
information we need. The best label writer in the world cannot devise a
risk management scheme if we\'re, for example, comparing hypothetical
benefits from surrogates on the one hand with real risks as occurred
with the statin failure recently.

And we believe it\'s in the interest, again, of FDA and CMS to begin to
work together to identify the types of clinical trials that need to be
done to inform the public about the risk and benefits of therapies.

Finally, what about the CERTS? And I\'m just going to briefly mention
several research projects. One is an international registry dealing with
cases of torsades de pointes. QT-prolonging drugs are both vital to the
public health and carry a substantial risk. We can\'t do without them,
but we have problems using them, and by putting together registries that
attract practitioners, not just in the U.S. but around the world, to put
cases together and to begin to identify the circumstances in which
problems occur, we believe we can devise better policies.

Secondly, I think of particular importance to this meeting, we\'re in
the midst of evaluating the rollout of dofetilide. As most of you know,
this is an anti-arrhythmic drug for atrial disrhythmias. It was
developed in a very conscientious manner, very clearly specifying both
the risks and the benefits. Not only that, but also the relationship
between serum levels and QT interval, the relationship between QT
interval and lethal dysrhythmias and a large mortality trial showing
that in good hands the drug could be given safely.

A decision was made to limit the prescription of dofetilide to in the
hospital and by physicians who had been trained in the use of
dofetilide. I want to stress that these results are preliminary, but I
believe these results will hold up.

First, putting the measurement of QT interval in the label of the drug
doesn\'t teach practitioners how to measure a QT interval. Even at the
American Heart Association, we\'re finding that less than 50 percent of
physicians can accurately measure a QT interval.

And so simply putting it in the label doesn\'t do the job seeing that it
gets done in practice. Secondly, the uptake of dofetilide has been slow
relative to the uptake of other drugs. And this may be particularly
important because in our research we\'re finding that when dofetilide is
prescribed, it is much more likely to be prescribed at the right dose in
the right way with the right measurements than very similar drugs, which
we think carry very similar risks, but do not carry this risk management
labeling. And so one unintended consequence of a well-intentioned
program could be to push practitioners because of time constraints to
prescribe a more dangerous drug with less care in a more dangerous way.

We\'ll have more to say about this later as the research is completed.
And then finally because of the complexities and uncertainties that I
know have been brought up here already, we have organized a series of
think tank meetings to develop a research agenda. Hopefully, we can
convince someone to pay for the research once the agenda is developed.

The first meeting on risk communication forms the basis for much of what
I said today. The second meeting is occurring next week in Chapel Hill
and will address the issue of risk assessment, what is the state of the
art, of quantifying risk.

The third meeting will address the issue of benefit assessment, knowing
the risk without understanding the benefits obviously creates an issue
and a problem.

We then plan to have a fourth meeting which has been interesting to try
to put together on the role of the press in communication of risk. It
seems interesting to me that the press is not very interested in being
studied. That may not surprise some of you, but I think we\'re about
complete now in getting the group together to study that.

But one might hypothesize, for example, that the public stories about
the statins that emanated from the withdrawal of Cerivastatin may have
done more harm than to continue prescription of Cerivastatin did,
because so many people stopped taking lifesaving statin drugs because of
misinterpretation of what the message was.

So, in conclusion then, we need research. Policies with good intention
can have unintended consequences, and without measuring the effects of
our policies and studying through well designed health services research
the way to do it, we could make many mistakes. It\'s exciting to be part
of this because, again, I want to go back to point number one, this is
not a system that\'s broken. It\'s a system that is working and
delivering a lot of benefit to many people. We just need to make it
better. Thank you.

DR. GALSON: Thank you very much, Dr. Califf. We now have about 20
minutes for questions for the panelists, and I want to remind the other
FDA folks sitting down here that they should pass questions up to the
table here. I think this time I\'ll start to my left if Dr. Houn and Dr.
Kweder have any questions to start out, or we can come back to you if
you\'re not ready yet.

DR. KWEDER: The first three speakers spoke a great deal about the role
of the pharmacist as a health care provider and providing consultation.
I would just like you to speak as to how common that actually is,
because I would say that in my personal experience in a number of
settings that isn\'t common. So of the pharmacists who are actually
practicing pharmacy in the United States, what\'s your estimation of how
engaged they actually are in actual conversation with a patient?

I\'m not talking about looking at a computer screen to see if there is a
drug interaction.

MR. MENIGHAN: If I can, I\'ll address that from two different
directions. The first is really the societal setting. That is, you know,
city versus rural. There are certainly variations there. Very busy
pharmacies versus less busy pharmacies, and I don\'t - your experience
is anecdotal - I don\'t know what it is, but I can tell you in my
practice I spend most of my time toe to toe with patients while my
technicians took care of looking at the screens and highlighting
information that I needed to see and so on.

So I think in many, many cases, pharmacists spend most of their day
talking to patients. Additionally, I think it\'s important to say that
in today\'s environment, it\'s absolutely critical that pharmacists
manage their time effectively. And the people they talk with most are
those with complex regimens, those older folks who come in with a bag
full of medicines that they don\'t understand, and I don\'t know your
circumstance, but I suggest that most pharmacists have to manage their
time just as carefully as physicians do, and they tend to spend more
time with those people with complex regimens.

And that happens regardless of the setting. Chain, independent, big
chain, little chain, it doesn\'t matter. There are some very good
pharmacists out there working very hard to see patients.

DR. STEIN: In the health system setting it\'s a little bit different.
There\'s a great deal of literature out there regarding how clinical
pharmacists in collaboration with physicians going on rounds in
hospitals decreased the incidence of medical errors. So many of our
members are not dispensing pharmacists. They are clinical pharmacists.

DR. HOUN: Talking about restricted distribution systems, I heard a lot
of opinions that if the system excludes the pharmacy, the pharmacists\'
interaction with patients, that\'s not desirable. So, in those systems,
I guess you\'re objecting to either a central pharmacy distribution
system or patient-physician direct distribution systems. Is that
correct? Are those the two main focuses that you object to?

MR. MENIGHAN: I can speak in one circumstance. As a home care provider,
I experienced circumstances where I would be providing care, you know,
extending from the hospital similar therapies into the home and was
often faced with circumstances where one pharmacy organization had
access to a particular drug that was prescribed, and I couldn\'t get it.

So here I am doing everything else in this patient\'s home, but this one
thing, and another organization had to send another nurse into the
patient\'s home to take care of that drug. That\'s ridiculous.
Shouldn\'t happen that way. I was perfectly capable of doing that. I had
the same training as the pharmacist who were delivering that, and I
wasn\'t able to get to it to deliver it to my patients.

That\'s one circumstance. I think you mentioned\--and that applies with
central distribution from a depot, for example, in state programs. Those
are very complicated and while they may save money in one element,
they\'re very difficult for pharmacists to participate around, if you
will, in other circumstances.

In physician direct programs, where a physician would dispense a
particular medicine, we\'ve spent literally years talking about that,
and the complexities of that, the difficulties associated with that, the
conflicts associated with that, and I think there are simply proven
better ways of distributing drugs than that.

MR. WIRTH: I would like to add that you mentioned two different
scenarios. I think we would object to any situation that removes the
normal caregiver from the relationship with the patient, whether it\'s
physician dispensing it or a centralized pharmacy, or any myriad of
possibilities. The regular caregiver, the regular community pharmacist
should be a part of that system to integrate the care.

DR. HOUN: But you\'re also saying it\'s a voluntary program in that if
there is a risk management program attached to a drug, that involves a
lot of documentation, collection of data, you would like the pharmacy to
opt out or opt in? So that\'s up to the pharmacist\'s decision whether
to maintain the patient-pharmacy relationship on that medication or opt
out of that?

MR. WIRTH: Yes. That\'s no different from the marketplace today where we
choose how best to help our patients and what is best for us in the
practice of our pharmacy. Sometimes it\'s not viable to provide every
service to every patient, but we endeavor to do the best we can as often
as we can.

DR. GALSON: John.

DR. JENKINS: I have a couple of questions for primarily the pharmacists
on the panel. First is we\'ve heard today several speakers have talked
about the value of medication guides. And FDA has approved or required
ten products to have medication guides since that rule went into effect
about three years ago.

I\'m wondering from the pharmacist perspective, how are you finding it
to implement those ten, and, you know, if there were 20 or 30 of those
in five or six years from now, how is that impacting in your ability to
practice pharmacy and actually get that information to the patients?

MR. WIRTH: In our practice, we aren\'t having much difficulty
distributing the patient guides. At the time we pull the medication for
the patient, at the same time we\'re pulling the medication guide. So
today it is not a barrier for us.

DR. JENKINS: Do you have the medication guide? Do most pharmacies have
the medication guides in paper or are they printing them from an
electronic media source in the pharmacy?

MR. WIRTH: We are distributing the manufacturer\'s patient education
paperwork from the manufacturer\'s packaging. We\'re also printing with
that prescription labels, the patient drug monograph, and are counseling
patients as part of an antiquated system.

MR. MENIGHAN: If I could comment, the management of those pieces of
paper is for many pharmacies sort of out of the norm and one more layer
of adminis-trivia that they have to manage. With that said, they do have
some value. The problem is they\'re awfully one way, and sort of we
shove information at consumers with little regard for whether they
actually understand what we shove at them. And there\'s really no
two-way communication, yet the technology exists to capture that two-way
communication to be able to get from a consumer, yeah, I get it, yeah, I
can do what it says on this piece of paper.

So, you know, the med guides are one size fits all. They\'re an easy way
for pharmacies to meet the legal requirements by shoving information at
consumers. I don\'t know whether they work or not. I don\'t know whether
patients are better patients because of med guides. I don\'t really know
that.

DR. CALIFF: If I could chime in here, this is a classic example of where
a small amount of research dollars could make a huge difference. Is it
worth it or not and how should\--we would all agree we would like
patients to have better information. But is this the way to do it? It\'s
not entirely clear. We\'ve been evaluating information given out by
pharmacies, whether the official med guide or other information if there
is not an official med guide on that. And the information the patient
needs is very dependent on the exact condition that they have.

A patient with heart failure needs different instructions than a patient
who is asymptomatic post-MI. So this is an area where I just don\'t
think we know.

DR. HOUN: But let me understand. In terms of med guides, the Agency has
only authorized med guides in a handful of products that we thought were
really important for patient information, but from a pharmacist\'s
perspective that\'s viewed as a pamphlet that you give to the patient.
It\'s not actually reviewed or discussed or let me go over with you
these sections. Is that correct?

MR. WIRTH: I would say that\'s correct. The med guides are fairly
complex and the patient counseling should be more tailored to the
specific patient\'s needs and not review of a piece of a paper.

DR. CALIFF: But we should also remember there is no reimbursement for
the pharmacists to spend that time, and\--

DR. JENKINS: That was going to be my second question. Several of the
panel members today talked about the important role of the pharmacist in
helping patients to use drugs safely, and I don\'t think any of us would
deny that, and I don\'t think any of us would deny that you could
potentially have a greater role.

It sounds like you\'re feeling like you don\'t have the time to do it
now, given the way the practice of pharmacy is constructed in this
country, and I can understand that from my visits to the local CVS. So
there were several suggestions about reimbursement compensation for your
time, and I guess I have a two-pronged question. One, what are your
ideas? It\'s clearly outside of FDA\'s purview, but I\'m interested in
what are the ideas about how that compensation would be derived

And, secondly, do you have an adequate base of pharmacists who could
actually take up that new role? Right now it looks like pharmacy, when I
go to the pharmacy, they have one or two people and they\'re very
stressed, and I\'m just wondering is there an adequate pool of
pharmacists who could take up that role?

MR. MENIGHAN: There is not nearly enough education going on in
pharmacies today because no one is paying for that education. The
dispensing fees that are allowed by third parties have dramatically
reduced in recent years to the point where a viable pharmacy must
dispense more medication in order to stay alive.

We don\'t profess that that\'s the best way to do business. It\'s not.
It\'s a problem. We have pharmacy schools putting out tremendously
trained clinicians to provide excellent care, who hit a system that\'s
very frustrating for them.

There are better ways of doing it, and I have always felt, and this is a
personal belief, that the manufacturer who provides that drug has a huge
incentive to see appropriate use of that medicine. Forget switching from
one drug to another. Seeing that their medicine gets used effectively. I
think the right way to fund these kinds of programs is to ask the
manufacturer to help pay for it.

And we\'re here to talk about risk management, so I\'ll focus on that.
If a manufacturer has a new product that need to come to market that
requires a liver function test, then let them pay the user fee
associated with that piece of the system that\'s required to be accessed
to see that that happens, and let them be the ones who pay the
appropriate clinician to do whatever it is they need to do to see that
that patient gets that liver function test, whether that be the
physician, the pharmacist, or some combination of those services. So I
think the money is there. It\'s just allocated for the wrong things in
my view.

And are there enough pharmacists to take up that new role?

MR. MENIGHAN: Absolutely.

MR. WIRTH: If I could add, there is some money there, but I don\'t think
it\'s enough frankly. Pharmacists today want to provide this kind of
service. NACDS did a study a year or so ago which indicated that an
inordinate amount of pharmacist time is spent chasing down
administrative tasks associated with insurance plans. That hasn\'t gone
away. We\'re trying to use technology to free up the pharmacists to do
some of these kind of things.

Technology is in my view the answer to what is going to free up
pharmacists\' time to be able to perform these kind of functions.
Lastly, I would suggest that in designing the program, you involve
community pharmacists so that they can tell us all what is the right
format that works for them to provide this kind of patient care. They
want to do it. Some are doing it, just not enough.

DR. STEIN: There are a number of different mechanisms out there that
could be utilized from the manufacturer funding some of the services
that might be provided by pharmacists in restricted drug distribution
systems. I know there is legislation out there to get pharmacists
recognized as providers under the Social Security Act for Medicare
reimbursement. So there are a number of ways out there to reimburse
pharmacists, not for their time. That\'s a hold over from looking at
pharmacists as dispensers but for their services. They provide a
service.

DR. GALSON: Dr. Bull.

DR. BULL: Two questions. One recurring theme that I heard across
speakers was that of the older American and their use of drugs. I was
just wondering if you have any specific recommendations for how labeling
might be made more effective in the older population given that we are
in the immediate term confronted with shifting demographics?

MR. CLARK: Well, the obvious answer is increase the size of the type on
the labeling. I think all of us are getting older and certainly as the
baby boomers age, the size of the type of labels becomes an issue.

That probably is another good area for additional research particularly
with the aging of the population. Older adults, one of the challenges is
that older adults typically have multiple chronic conditions, often take
multiple medications, and so strategies that focus on the single disease
one at a time can be ineffective or less effective than they would be in
a younger population where you may be dealing with someone who only has
hypertension or some other condition. So the challenges in informing
older adults become a little more difficult.

DR. CALIFF: I might add a couple of very specific critical issues. As
you know, we have many diseases that are dominantly seen in the elderly
and yet our clinical trials that lead to FDA approval typically either
exclude those patients from the start or just simply don\'t enroll
patients even though they\'re not specifically excluded. And this has to
be fixed for all the reasons that you know.

Secondly, elderly people by normal physiology have impaired creatinine
clearance. As we\'re now beginning to look at the outpatient clinic, it
seems that most doctors just don\'t remember that you have to adjust the
doses of renally excreted drugs for creatinine clearance, and this is a
huge national problem that I think really does need to be specifically
addressed and soon.

DR. BULL: My second question to the panel relates to labels to have to
comply with regulations articulated, I believe, it\'s in 201.57 for form
and content. One concern I have that had been raised I believe by Dr.
Califf is on the comprehensibility of labels to health care providers.
I\'m just wondering is there a need to do - in the OTC domain one of the
tools FDA uses in assessing drugs for OTC switches are studies called
labeling comprehension in actual use studies.

Is there possibly a need for those kinds of studies in the realm of
prescriptive drug labeling?

MR. MENIGHAN: I think it would be hard to argue against the wisdom of
that.

DR. CALIFF: Well, I might say it\'s shocking that it\'s not done. Since
the purpose of the label is to communicate, you would think that a very
specific assessment of the ability of the label to get the message
across would be a part of every \[study\] - and a quantitative one done
in a representative population of prescribers.

But, you know, Jonca, I might just add at the risk of sounding somewhat
negative about this, I really think the label is a hopeless cause in
this regard. And, in fact, in our renewal application for the CERTS, one
of the things that we\'ve put in is to develop professional society
interpretation of the label, because you\'re simply restricted as the
FDA from saying many things that need to be said.

It\'s what\'s not in the label often that is most important. And the
manufacturer is in a position to not be able to for obvious reasons to
emphasize those things either. So the clinical interpretation of what\'s
really being said is something that a professional group could say
without the risk of the liability that incurs in the official label.

MR. MENIGHAN: And our organization does that. We have special reports,
new product bulletins that go out on virtually every product, but
that\'s dependent upon the manufacturer deciding to fund the
distribution of that. That had nothing to do with the content of it.
That\'s totally developed separately, separate editorial process. But if
a manufacturer doesn\'t want to fund that, we don\'t do it.

DR. CALIFF: Well, just without belaboring this too much, the hope is
that in societies like the American College of Cardiology - we\'re now
investing a huge amount in our professional society in internet
communications, and now that continuing medical education will require
continuous updating, using the same internet system, practitioners in
that specialty will go that site hopefully everyday.

And what we hope to do is to put the real scoop about what they need to
know from the label in that information source. It won\'t require any
funding by the manufacturers. It\'s simply a part of their professional
responsibility. I think up until practitioners begin to use common
internet sites as a professional responsibility, it\'s hard to
\[require\] - you\'re stuck in much the way that you described.

DR. GALSON: Great. Paul.

DR. SELIGMAN: Dr. Califf, you answered my first question already - thank
you - about the label. My second question then had to do with the
development of risk management plans and the statement that such
development should not include just the negotiation between the sponsor
and the FDA, but should involve pharmacists, physicians and consumers.
And I would like to hear a little bit more about how one would engage
other groups in that discussion and at what point one could engage a
wider audience in the development of those plans, since traditionally
that has been essentially a conversation and a discussion that has
included just the sponsor and the Agency?

DR. STEIN: The way we envisioned it at ASHP is if the FDA sees a need in
terms of a restricted drug distribution system for a particular drug
pre-approval, then that manufacturer and the FDA and the health care
provider should get together at that time prior to approval to develop
what that risk management scheme should be and perhaps even do a
demonstration project prior to the approval.

MR. MENIGHAN: I don\'t disagree, and would just add that oftentimes the
decision about how a drug would be distributed occurs fairly late in the
process of drug development and approval and marketing and distribution.

And I think if we began now to build the common elements, standard
elements that say if a drug test is required of a patient, how is that
going to happen commonly in a standard way across any drug that needs
that versus waiting till the drug comes along and then figuring it out
in these one off programs with everyone being slightly different.

So I would think more strategically we need to rise above the current
problem and think broadly and strategically about how that should
happen.

MR. WIRTH: May I add that one mechanism would be to look at the current
high risk medications that are on the market and try to put together the
system that could apply appropriately across all of those so that when
the next one comes along, you have a concept and a database, a system in
place, that you can just apply to the medication. I think it\'s an
extension of his comments. Let\'s put the system together now before
we\'re faced with having to develop a new one.

DR. CALIFF: I also might add medical economics in Practice 101. If you
have a drug that\'s identified truly as a becoming a standard of care,
which might not apply to everything that is approved by the FDA, but if
that were so, it would be very important and useful to get the payers
involved early because if practitioners were reimbursed for doing what
needs to be done to prescribe the drug safely, and that was the method
of reimbursement, it\'s likely that it would happen more effectively.

But again I would argue strongly that early on patients affected and
practitioners of all types need to be involved, something like a panel
that could bring people together. In the end, the decision needs to be
made by the people responsible for distributing the drug and regulating
it, but without that input, I think you\'re missing an important
component.

DR. GALSON: Anything more? Anything from the other table? Okay. If there
are no more questions, I think we\'re going to take a break. We have
still three public commenters who wish to talk for a few minutes after
the break. So it\'s 3:15. We\'ll meet back here at 3:35.

\[Whereupon, a short break was taken.\]

DR. GALSON: Okay. Welcome back, folks. The last part of the meeting is
to hear from members of the public who may be interested in sharing
their thoughts with us and we have three such folks.

The first one is Mukesh Mehta, and I want to remind those of you
speaking that we\'re going to keep it to about five minutes, and if you
could come up to the podium here and make sure to introduce yourselves.
Thank you.

MR. MEHTA: Thank you. Good afternoon. My name is Mukesh Mehta. I\'m the
Vice President for Thomson Medical Economics, the publishers of PDR. I
would like to thank you for this opportunity. I was not surprised today
when several times the PDR was mentioned in the different presentations.
I would like to make a couple of comments on several points made today.

One, this morning, Dr. Korn mentioned about the MedWatch form that\'s
not accessible or physicians don\'t know where to find one. I would like
to point out that ever since the inception of MedWatch program, PDR has
been printing the MedWatch form without any cost to the taxpayers and
distributing it to the practitioners and other health care
professionals.

So, in turn, it\'s close to a million copies of MedWatch forms have been
printed and distributed to the practitioners every year. Also, the
Vaccine Adverse Event Reporting System form is also included in the PDR
every year.

The other point I\'d like to mention is in the area of risk
communication and what PDR has done over the last several years. One is
an innovative program that has been instituted for the past 14 years
called PDR Addendum Program, which is a direct mail program which is
sent out on behalf of the pharmaceutical companies. What this program is
is a cover letter. It\'s a nonpromotional cover letter, along with a
package insert of the prescribing information formatted into the PDR
page format.

The statistics that all the studies we have done show that over 90
percent of the physicians who receive this PDR Addendum tend to open the
envelope, and there\'s a blue strip attached to the package inside of
the formatted page, and 70 percent of the physicians take time to take
the blue strip off and put it on the page number that\'s included on the
letter. So this is a very effective program to communicate prescribing
information to the practitioners, especially in the times when
physicians receive hundreds of direct mail pieces from manufacturers or
other organizations.

And another thing that was mentioned today was information technology.
In that area, there are two initiatives that have been going on. One is
the PhRMA Labeling Initiative. That\'s directed for the dispensing site
and PDR has been working with PhRMA for the past three years in this
area, and I would like to mention that the system that we have
developed, which will be alpha tested in about a month or so in the
Washington, D.C. area pharmacies, is a system that does not involve
computer, per se, but it only takes an outlet and a telephone line, and
there is a two-way communication between the central database and the
system itself.

And the good thing about this is there is acknowledgment received
everyday. If there is new information or change in labeling that was
sent to the pharmacy, it acknowledges back every morning that the
information was received by the pharmacy. This system can also be used
in other areas such as physician\'s office.

And the last thing is the PDR, the hand held devices, just this past
three weeks ago, we introduced mobile PDR, which can be downloaded on
the Palm operating system or the pocket PC-based platforms which allows
the manufacturers or the FDA to send out the alerts through this system
to the practitioners.

Thank you very much.

DR. GALSON: Thank you very much. The next speaker is Dr. Stephen
Goldman.

DR. GOLDMAN: I\'m Dr. Steve Goldman, managing member of Stephen Goldman
Consulting Services, LLC, and former Medical Director of MedWatch.

I wasn\'t going to speak today, but I couldn\'t contain myself from some
of the things that actually were said this morning, and I think there
are a couple of things that really need to be clarified about adverse
event reporting and the adverse event reporting environment, and I think
it\'s important. That\'s why I\'m here.

I find it interesting that many of the presenters this morning said it
was so hard to report and hard to find the forms and hard to find
availability. It\'s never been easier to report. You can report by
direct toll free number. You can send it in by fax. You have a form
online; you can download and you can send it in literally online.

And what\'s interesting is when you studied, as Dee Kennedy and I have
over the years, the reporting environments, you take a look at what
people weren\'t reporting 30 years ago, and the reasons given,
distressingly they\'re not much different than what you hear now 30
years later even though the mechanisms are so much better now than they
were 30 years ago.

Why am I mentioning that? We tend to be relearning the same things.
We\'ve had several mentions today of a program from the \'80s, the Rhode
Island AER Reporting Program, which did indeed, as Dr. Wolfe pointed
out, increased reporting in the state of Rhode Island 17-fold with no
commensurate increase in the rest of the United States. What was not
said about the Rhode Island program was it was a committed educational
program. It wasn\'t a hit or miss type thing. It was a dedicated
program. It was directed particularly to physicians, and it showed great
results.

And, of course, as Dr. Kweder pointed out, funding no longer was there
for it. There was nothing wrong with the idea. MedWatch comes into
existence, uses some of the same basic techniques that the Rhode Island
Adverse Event Reporting Project did, but focusing on serious adverse
events.

So it\'s not the total quantity of reports coming in through the
voluntary system, it\'s the severity of the reports coming into the
system. And, of course, MedWatch covers drugs, devices, biologics,
special bionutritionals and dietary supplements. No longer veterinary
meds. So we\'ve got reporting environment concerns. We\'ve got
availability. We\'ve had several mentions about educating other health
professionals.

Well, in my experience with MedWatch, that was spotty in terms of the
support that one got for doing lectures on adverse event reporting at
national health professional meetings. I\'m a psychiatrist, and I have
to confess that I did two sessions for the APA on adverse event
reporting, and I am distressed to tell you that the attendance was
dismal compared to almost any other session that was there.

Yet the people who came enjoyed it and felt it was important. But
getting people to come and hear about it was a tough sell. Other
programs we found we were more successful. As a matter of fact, even
though it was barely mentioned this morning, we heard a lot about it
this afternoon, was pharmacist reporting. And actually through the
MedWatch program, at least when I was at MedWatch, the large percentage
of reporting came from pharmacists, not from physicians.

And I remember one of the programs that we ran at ASHP, we had
tremendous attendance. I think we had over 300 people there to hear
about that. So these are things that we have been plagued with. These
are things that we\'ve looked at. These aren\'t new ideas. It is a new
era, and risk management is jumping to the fore. But I think we\'re
dealing with some of the same difficulties we had over the past ten, 20,
and unfortunately 30 years.

I do want to point out two other points, because this was mentioned in
the Lasser article in [JAMA]{.underline} two weeks ago, and this was
mentioned this morning. That\'s not consumer reporting. I think it\'s
worth pointing out that the United States and Canada are among the few
countries that actually mandated that companies report consumer reports
they receive to the regulatory agency.

As you know, in Europe, that is not the case. There is no mandate to
send \[reports\] in the European Union, there is no mandate to send
consumer reports into the agencies. You can do it voluntarily as was
pointed out. But they talk about medical validation. Well, the United
States has no such concept.

And consumer reports are treated like other reports. If you want to get
technical about it, they\'re all consumer reports because a consumer has
to tell their physician or their pharmacist or someone else that they
have an adverse event and it goes on from there. So I find it
interesting that this initiative keeps coming up, and yet we have the
environment in the United States, and certainly with MedWatch, where
consumers were encouraged to report to either the FDA directly, to the
companies, or both if they chose to do so.

So I just thought it was important to mention a couple of these points
in the interest of clarification. Thank you.

DR. GALSON: Thank you very much.

MR. MAYBERRY: Thank you. Yes, I am Peter Mayberry and I\'m here on
behalf of two groups, the Health Care Compliance Packaging Council and
the Pharmaceutical Printed Literature Association. In listening to all
of the presentations this morning, I wanted to just very briefly mention
that I heard very little about the risks inherent under our current
paradigm of dispensing drugs based on repackaging of drug product.

I\'ve been active in a group within USP, which has formed a work group
on the risks associated with repackaging drug products at the pharmacy
level, and they have identified some two dozen different risks involved
in taking the product out of big bottles and putting it in small bottles
before handing it to the consumers.

And I just wanted to point out that FDA has established precedent under
GMP standards with iron for requiring the product be not repackaged but
to be dispensed in a unit of use or unit dose format from the
manufacturer to reduce the risk associated with iron poisonings. And I
would encourage you to consider this as you consider the entire risk
that patients face today.

If original packaging were adopted in this country as it has been
through so many other countries in the world, Europe, Asia, many other
countries within the Western hemisphere, the research is all there, the
experience is all there, that many of the issues that had been
identified today in terms of the patient, empowering the patient, giving
the patient information they need, could be solved by GMP requirements
that more products be dispensed directly in unit of use packaging by the
manufacturer with printed literature accompanying it so you don\'t have
the administrative problems that were cited of trying to find the Med
Guide for a handful of products.

If they\'re coming directly from the manufacturer in a unit of use
format with the written literature that will help the patient, I think
that many of the issues that were addressed today would go away. Thank
you.

DR. GALSON: Thank you very much. This concludes all of the speakers, so
I would like to just conclude with a few remarks. I think at great risk
probably to myself, I\'ve tried to jot down some summarizing comments.
It\'s very, very difficult to summarize what we heard today because
there was a real wide variety of views, but I\'m going to try anyway,
and if the other panelists want to add, feel free.

The first is that there are a variety of views. That\'s real easy, and
some of them are actually mutually inconsistent. So the Agency has got a
huge challenge in trying to figure out how to move forward. We certainly
can\'t move forward in a way to make everybody happy, but what we did
hear is that there is a strong willingness on the part of a lot of the
folks who spoke today to work more closely with the Agency as we develop
risk management plans on individual drugs and then on a more systemic
approach.

The second thing I think I heard globally is that there is an agreement
that we\'ve got some problems with the current system. Nobody really
thinks everything is working perfectly, and that helps us figure out
that we really do need to do something.

The third point is that we have heard that folks feel, in general, that
there should be a health system wide approach to this problem. A
piecemeal kind of a drug by drug approach or one that just focuses on a
certain segment of the health care population really doesn\'t work, and
we\'ve got to look at the whole system.

And the next step, we need more research. We need more research on the
effectiveness of risk management approaches. What works and what
doesn\'t. And I think that really concludes it in terms of my ability to
generalize and summarize what we heard in terms of broad brush points.

There are a lot of other details that we heard that I won\'t be able to
summarize right now. Does anybody want to add anything else in terms of
overarching themes?

DR. KWEDER: I would just add one, Dr. Galson, and that is any changes to
the system or any large programs that we would develop really need a
sustained commitment and not just short-term funding or short-term
commitment as some of the ones that were described today that enjoyed
some success, but then went away. We\'re never going to move forward,
we\'ll be destined to be here five years from now, ten years from now
having the same conversation if we don\'t develop something that can be
maintained over a long period of time.

DR. GALSON: Any other points, comments? Okay. Well, I want to thank our
transcriptionist in the front of the room; Chris Bechtel and Lee Lemley
who worked hard to set this whole meeting up and have it run smoothly;
our colleagues from the Centers for Biologics and Office of General
Counsel who were here with the folks from the Center for Drugs; and all
the panelists sitting up here. Thanks a lot, folks. Bye-bye.

\[Whereupon, at 3:50 p.m., the hearing was adjourned.\]