U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES

            FOOD AND DRUG ADMINISTRATION

       CENTER FOR DRUG EVALUATION AND RESEARCH

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                    COMMITTEE FOR

            ADVANCED SCIENTIFIC EDUCATION

                   SEMINAR SERIES

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"The Use of Placebos in
Clinical Trials and the
Ethics of the Use of Placebos."

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                      WEDNESDAY

                   APRIL 21, 1999

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            The Panel met in Conference Room D, Third
Floor at 5600 Fishers Lane, Rockville, Maryland, at
1:30 p.m., Janet Woodcock, M.D., moderating.

PANEL MEMBERS:
      DR. ROBERT DELAP, FDA
      DR. PETER LURIE, Consumer Advocate
      DR. JAY SIEGEL, FDA
      DR. PAUL STOLLEY, University of Maryland
      DR. ROBERT TEMPLE, FDA
      DR. SIDNEY WOLFE, Consumer Advocate
                   C-O-N-T-E-N-T-S

                                                PAGE

Call to Order and Opening Remarks
  Dr. Kobayashi                                    3

Introduction
  Dr. Woodcock                                     6
  Dr. Wolfe                                       11
  Dr. Lurie                                       16
  Dr. Stolley                                     24
  Dr. Temple                                      28

Migraine Case Study                               46

Hypertension Case Study                           74

Major Depression Case Study                       93
                P-R-O-C-E-E-D-I-N-G-S
                                         (1:36 p.m.)
            Call to Order and Opening Remarks
            DR. KOBAYASHI:  Good afternoon.  I'm Ken
Kobayashi, speaking for the Committee for Advanced
Scientific Education, or CASE.
            I would like to welcome everyone here for
this very special CDER Seminar.  I know that we have
a number of people in the audience who have come a
long way, from as far away as Connecticut, and I would
like to say that we appreciate your interest in this
program.
            Please note that because of the amount of
material to be covered, today's seminar has been
extended and will conclude at 3:30.  If people come in
late, and there is lack of seating, we do have an
overflow room up in 13-B37.
            CASE rarely mounts a program of this
scale, and several people were instrumental in putting
it altogether.  I would particularly like to thank
Karen Zawalick, who came through with the ball on many
major last-minute requests and needs, Devota Herbert,
Joy Bennett and Sandy Coffin.
            Today's seminar will be transcribed,
videotaped, and video-conferenced to four locations. 
I thank See Lam and Dave Kausal, our technical
virtuosos, for their invaluable assistance with these
and other matters.
            I cannot thank Robin Huff and John
Senior of the CASE Committee for all of their help,
both in preparing for this seminar as well as others,
and last, but not least, I'd like to welcome and thank
our Panel members for their participation.
            I usually make the announcements at the
end of the question and answer period following the
talk, but I'll make an exception today, given the full
schedule and make a few announcements now.
            Next week's scientific rounds will be
given by the Office of Generic Drugs and will discuss
the issue of bioequivalence for inhalational drug
products.
            And we have an exciting line-up of
seminars to bring this academic year to a close.  Next
month we have Dr. Jane Henney, Commissioner of the
Food and Drug Administration, and Dr. Patrick Weir of
Smith/Kline Beecham, who will speak on predicting drug
class teratogenicity.
            In June, we have Dr. William Evans of St.
Jude's Children Research Center who is internationally
known for his work in childhood leukemia, speaking on
his work in developing a highly innovative and
successful treatment program for this deadly disease.
            Dr. Ezekiel Emanuel, who heads the
Department of Clinical Bioethics at the NIH, will
conclude the year with a talk entitled "What is
Community Consent and Consultation?"
            Dr. Janet Woodcock, who I think is the
Director of the Center for Drug Evaluation and
Research, who needs little introduction to this
audience --
            (Laughter.)
            -- will moderate today's discussion.  We
have a distinguished Panel assembled here today, Dr.
Sidney Wolfe, who is Director of the Public Citizen
and Health Research Group.
            Dr. Peter Lurie is a medical researcher
also at the Health Research Group.
            Dr. Paul Stolley, who is Professor and
Chairman of the Department of Epidemiology and
Preventive Medicine at the University of Maryland
School of Medicine.
            Dr. Robert Temple wears many hats here. 
He is Director of the Office of Drug Evaluation I and
of the Office of Medical Policy.
            Dr. Robert DeLap is Director of the
Office of Drug Evaluation V.
            We are pleased to have with us a member of
our sister center in FDA, Dr. Jay Siegel, Director of
the Office of Therapeutics, Research, and Review at
the Center for Biologics, Evaluation, and Research.
            Today's program will consist of two short
didactic presentations, followed by discussion of the
three cases.  Each case will feature comments by the
Panel members and will include an opportunity for
comments from the audience.
            After all three cases have been discussed,
Dr. Woodcock will conclude and wrap up the discussion.
And now, I will turn the meeting over to Dr. Woodcock.
            Introduction
            DR. JANET WOODCOCK:  Thanks, Ken, and
thank you for all your efforts.  This has been a very
successful seminar series this year and I think we are
all proud of it.
            I would like to welcome the member of the
FDA community, our invited guests, and outside people
who have come into our seminar.
            Our topic for discussion today is "The Use
of Placebos in Clinical Trials and the Ethics of the
Use of Placebos."
            One of the most interesting, I think, and
challenging parts of our work here at FDA, is the
extent to which judgment is involved, and the way the
different values and perspectives of different groups
influence their views of the issues that we deal with.
            The use of the placebo is one of these
issues.  It's something that has been the topic of
debate ever since their use was invented, and
currently, this is a very hot topic of debate in
various academic circles, as many of you may know.
            FDA oversees the conduct of many clinical
trials in the United States, and we are frequently
drawn into this controversy.  Our standards and our
guidances often drive the design of clinical trials in
specific disease areas, including the use of placebo.
            Since the ethical situation evolves with
changes in scientific understanding and with
development of alternative therapies, we have to pay
constant attention to the ethical implications of our
standards that we have developed, and our guidance.
            The purpose of the seminar today is
educational, because in our review and regulation of
clinical investigations, the FDA staff plays an
important public protection role in making difficult
judgements.
            It's extremely important for us to hear
the different perspectives, and to understand all the
points of view.  Only with an appreciation of the
variety of views, can we effectively and credibly
carry out our public health protection role.
            Given this, I am going to ask everyone
here today, both the audience and the participants, to
agree on some principles for our discussion.
            First and foremost, let's all acknowledge
that we all here work in the public health field for
the benefit of the public.  That's what we do.  And
that we in fact are united in our goal of helping
people, no matter what our differences are, about the
proper path to take.
            Therefore, please grant each other the
respect of their conviction and courtesy, and this
includes some ground rules.  Let's have no
interruptions, and let's try to keep to times, and I
will assist everyone in these endeavors.
            Now, what are these issues around the use
of placebo?  First of all, I think we have to
remember, although it's not a topic for discussion
today, that these issues are raised within a larger
context of concern that has always been present about
experimentation on human subjects.
            There is an inherent imbalance of power
that's perceived between the knowledgeable
investigator, and the less-informed volunteer, or the
dependent patient who has an illness.  And this has
long been a matter of concern for many people.
            Recently, we have to acknowledge that the
industrialization, so to speak, of clinical trials,
the reimbursement of investigators and their ties to
the pharmaceutical industry, have increased some
people's levels of concern.  So, this is a background,
I think, to this discussion.
            The use of placebo controls is a separate
issue, but it is linked in many people's minds to the
overall issues of ethics and clinical trials.
            Now, the goal of drug development is to
rapidly and efficiently characterize candidate
products, so the beneficial ones can be made available
to the public.  And I think we all agree upon this.
            From a strictly scientific point of view,
the most efficient and informative way to do this is
by using placebo controls, given the limitations of
our understanding of sources of variability in people. 
Nevertheless, it is widely agreed that use of placebo
is not ethical in cases where people would risk
serious or irreversible harm by taking them.  In these
cases, we must turn to the use of alternative trial
designs to get the information we need.
            In many cases, though, there is a gray
zone, as was discussed in the e-mail that was sent out
to everyone, and there are a couple of gray areas in
this.  What is harm?  How much harm is it ethical to
inflict?
            I mean, anyone who has ever vaccinated a
toddler knows that you're inflicting some harm upon
that person, that toddler, when you're sticking a
needle in their arm, but that's obviously a beneficial
thing to do.  Drawing blood from experimental subjects
inflicts a certain amount of pain and harm on them.
            So, the definition of harm is one area
that I've observed, where people have a disagreement
about how much, quote "harm" is tolerable.
            And then there is another area; there is
disagreement on the existing data.  And this gets to
the idea of equipoise in clinical investigations.
            There are many therapies where people have
an idea that they work, but it is not clearly known
whether they are effective or not.  And often, there
are great ethical debates about whether these should
be studied.
            Sometimes, such therapies have been
studied and it has been found that they are
ineffective, or even harmful.  And in retrospect, the
study seemed a very credible study to carry out;
however, the idea of how much is known about the long-
term effect, or the beneficial effect of an
intervention, impacts on how ethical it is to study it
and to omit it from people's care.
            This seminar today is designed to explore
this frontier of the ambiguous areas, or the areas
where there isn't agreement of what is ethical and
what is not ethical in clinical trials.  So, without
further ado, I am going to introduce Dr. Sidney Wolfe,
who will start out with one perspective on this issue.
            Dr. Wolfe.
            DR. SIDNEY WOLFE:  Thank you.  I would
like to thank Dr. Woodcock, one of the I'm sure many
geneses of this meeting was a discussion that Dr.
Lurie and Dr. Sasick, who is on our staff, and Dr.
Woodcock and I had last year, about problems in the
area of placebos, and she obviously took it very
seriously, and we are very hopeful that this seminar
will be instructive.
            I have already learned a lot by reading
some older papers that I hadn't seen before, and I
think that inevitably, the influence of the seminar
will be to move things forward.  I can't imagine that
what will be learned here will not affect FDA policy,
and as Dr. Woodcock alluded to, define maybe, or
refine some of the guidances that exist.
            One way of describing the purpose of the
seminar is to focus on how to reduce harm to patients
in clinical studies by a case-by-case elimination of
certain placebo trial designs, which inflict
gratuitous violence, pain, suffering, or permanent
damage including death to patients.
            By gratuitous, I mean at least one of the
dictionary definitions which is:  unwarranted by the
circumstances; unnecessary.
            The FDA is just one of a large number of
decision-makers who have the potential to say no to an
unethical clinical trial.  The list includes the
researchers; obviously, the funders, be they the drug
industry, or device industry, or the government; the
Institutional Review Boards, or the non-Institutional
Review Boards, the for-profit Review Boards that are
overseeing some of the non-institutionally-based
trials conducted by for-profit clinical trial
companies; the FDA, as another partner, as I
mentioned; and then medical journals.
            There are at least some medical journals
that have made a statement that they will not publish
an article whose clinical design is unethical in their
view, although at least two of them that I know of,
having said that, have published studies that are
pretty clearly unethical.
            Weak links in this chain of decision-
makers reverberate, and frequently, when a study that
is at least later, if not earlier, deemed to be
unethical is done, the people in the linkage will say,
Well, it must be okay, because the IRB approved it;
or, It must be okay because the government funded it;
or, It must be okay, because the FDA allowed it to go
forth.
            I would like to mention a few examples
that sort of crept through this entire chain.  I do
not know whether all of them -- I know some of them --
did go through FDA.
            One, are these studies in which HIV- and
PPD-positive people in Africa, after a time when it
was clear that isoniazid, INH, would prevent the full-
blown development of TB, were enrolled in a randomized
placebo control clinical trial
            Another, which Dr. Lurie and I have
focused on a lot in the last few years, which did at
least in part go through FDA, were studies in which
HIV-positive pregnant women were given placebos after
a time when it was clear that AZT prevented it.  And
it was after a time when it was crystal clear that a
shorter dose of therapy worked.
            Another example is SYST-EUR, a study done
in Eastern Europe, in which, for a number of years
after it was clear that isolated systolic hypertension
was successfully treated in terms of clinical
endpoints by diuretics and so forth, more people were
enrolled into a placebo control trial.
            By definition, all of these studies
cleared the funders, the researchers, the
Institutional Review Boards, and in some cases, the
FDA.  And one question we have, which is not
rhetorical, we will ultimately try and get answers to
it is, How many times has the FDA refused to accept a
placebo control trial because they believed, in those
instances, that it was unethical?
            We must point out that we do believe that
there are some placebo control trials that are okay,
but I have no idea what the answer to the question is;
we may be asking it at some point in the future.
            As mentioned before, there really isn't a
specific, a drug-specific policy on what you do with
respect to different therapeutic classes, as far as
placebos are concerned.
            First and foremost, as I mentioned at the
beginning, we need to protect patients.  That is the
primary concern in a clinical trial.  Yes,
immunization hurts, and that is a circumstance,
assuming that the vaccine is effective, where you
trade off some risk for some benefit, but a number of
the cases that we have been concerned with are much
more than just mild pain.
            I would just like to finish, and then turn
it over to Dr. Lurie, by talking about the benefits
and risks of the trial design itself.  We are all
familiar with looking at a drug in terms of its
benefits and risks, but one of the problems with the
benefits and risks of the trial design, is that the
benefits may go to one party, and the risks may go to
another, and there could be problems.
            Is there a difference between the group
which benefits the most from a certain trial design,
and the group which is at risk the most from the same
kind of trial design?
            One example in terms of a trial design, is
that in a number of instances, an equivalency study
comparing a known effective treatment with another,
will lower the risk for patients, as opposed to a
placebo control trial, but it will increase the risk
for the drug company.
            A drug company, if they can, would much
rather conclude, as is usually the case, if not always
for hypertensive agents and others, that their drug is
better than a placebo, than risk the notion that their
drug may not be as good as the standard existing
therapy.  So, that's a risk that the drug industry
would take, which might, and would likely, benefit
patients.
            I'm now going to just turn this over to
Dr. Lurie for the middle part of our discussion, and
then Dr. Stolley will make some concluding remarks,
and then Bob will take over.
            DR. PETER LURIE:  I'm going to start off
by talking about what I hope are agreed-upon
principles between both us and FDA, and what we are
really going to be talking about I think is, not so
much these principles, but the interpretation of them.
            So, let me go through the principles which
would help one to decide whether the use of a placebo
is acceptable.
            The first principle, or first question is,
Do prior placebo control trials demonstrate
effectiveness?  And I think that we are dealing today
with no examples of medications in which there is no
drug proven effectiveness.
            So, as a general matter, the answer to the
first question will be yes for all three examples
today.
            If the answer is no, we would not object
to the use of placebo, and I want to be very clear on
that.  We are really talking about situations where
known effective therapy exists.
            Of course, what is effective is in the eye
of the beholder, or the interpreter, and how
convincing is that evidence, is the next question. 
And some evidence is more convincing than others; it
comes from better or worse done studies, or case-
controlled studies versus clinical trials, versus
those with poor follow-up or good follow-up, and to
the extent that the evidence is stronger, it makes the
provision of placebos all the more unacceptable.
            What is the magnitude of the benefit that
has been shown in prior studies, if the drug is
minimally effective, to the point that one is not
really that certain that it works at all?
            Well, to the extent that weighs in the
direction of being able to provide a placebo, this is
obviously tied into the first point.
            Now, how severe is the disease?  If the
disease is some trivial condition, unless one has one
right now, like a cold, then we think those kinds of
conditions can justifiably be studied with a placebo,
but as the disease becomes more and more severe, as
subjective symptoms become worse, or there is risk of
irreversible morbidity or even mortality, it becomes
more and more unacceptable to use a placebo.
            And importantly, Do alternative study
designs exist?  And it's incumbent, I believe, upon
the researcher to really honestly go through all of
the possible alternatives before concluding that the
placebo is really the only way to go.
            There are arguably some conditions where
the duration of the study is critical; studies where
it might be acceptable to provide placebo for a short
period of time, but not for a longer period of time.
            Will the most severe patients with a
disease be enrolled?  To the extent that the patients
are sicker, I think that that argues against the use
of placebo.  And to the extent that there are good
data on historical controls, that weighs in favor of
not providing placebo.
            Is the placebo effect for the condition
very variable?  Conditions like mild pain, that are
both not severe -- answering a previous question --
and which have a substantially variable placebo
response, we think that providing placebos, even
though obviously known effective medications exist,
would be acceptable.
            Finally, is there equipoise over drug
effectiveness in this population?  And if there's
reason to think that efficacy shown in another
population may not extend to the present one, that may
argue for a placebo control trial in the new
population.
            Now, it is worth reviewing the legal
status of the FDA's placebo practices, and some of
this comes from regulation, and other parts from
legislation.
            Active control trials are to be used,
quote "When the condition treated is such that the
administration of placebo, or no treatment" -- here is
the critical language -- "would be contrary to the
interests of the patient."  And I suppose that is part
of what we will be arguing about today.
            The Food, Drug, and Cosmetic Act does not,
as is sometimes assumed, require placebo control
trials.  What is required is adequate and well-
controlled investigations.  And by regulation, the FDA
has described these as: placebo control; dose-
comparison studies; no treatment concurrent controls;
active treatment concurrent controls; and even
historical controls.
            So, there is a place for interpretation
and a certain amount of flexibility.  I think out
there in the real world, the impression that people
have is that the FDA is really insisting on the first
of these, under almost all circumstances, and then
people feel obligated to echo the FDA practice,
something that Dr. Woodcock I think correctly pointed
out is, in fact, what happens.
            Importantly, there is no formal FDA policy
on placebo use at all.  And what we hope will come out
of this is the beginning of some kind of FDA policy,
which is condition-specific, and I think that that's
important.
            What we are glad about today's discussion
is that it's not going to be, we hope, one of
exchanging platitudes, but will rather be a discussion
of condition-by-condition, because it's really
condition-by-condition guidelines that are necessary.
            Now, this lack of FDA policy on placebo
use has contributed to some confusion among FDA
medical officers, and as some of you know, many of you
were surveyed by us in the Fall of last year, and we
asked people about the provision of placebos in
situations where known effective therapy existed, and
we got some of these comments back:
            "We had internal agreement that it was not
proper to conduct the placebo studies, but the
industry chose not to follow our advice."
            So, clearly, it's not only the FDA that is
at fault, by a long shot; sometimes the industry will
choose not to follow the advice of the Agency.
            Somebody else said, "Very difficult issue
and very situationally-dependent."
            My point again, it is situation-by-
situation, condition-by-condition guidelines that are
necessary.  There are situations, such as short
duration, proof of concept studies, where placebo
control would be appropriate, but in a long-term
study, approved active control would be preferable.
            Now, there are four underlying issues
here, I think.  The first is the ethics of placebo use
and the requirement under all existing ethical codes
to provide maximum protection to patients.
            Clearly, what is in effect being said, or
what is in part up for debate over here is, what
degree of suffering is acceptable to patients or, what
degree of risk to patients are we willing to tolerate?
            And that's part of what, that's one of the
issues.  So, the ethical protection of subjects is one
element of it.
            The second issue is the clinical
usefulness of the data that are generated, to doctors,
to patients, and to payers.  And we would argue that,
as a general matter, active controlled trials in
circumstances where known effective therapy already
exists, will provide information that is more useful
to doctors, patients, and payers.
            The average physician who has somebody
coming in with hypertension, does not so much ask
themselves, Do I provide Captopril or nothing?  They
ask themselves, Do they provide Captopril or
hydrochlorothiazide, or any of the other 60 drugs that
are on the market?  And there is a dearth of this kind
of information.
            Part of that, not only because of FDA, but
part of it comes from the FDA's continuing efforts on
the need for placebo control trials.  Of course,
studies that provide no useful data, are not useful
and shouldn't be conducted, and so, there is a need to
be able to draw useful inferences.
            And finally, there is a balance between
the so-called needs of regulators in the
pharmaceutical industry, which as Dr. Wolfe has
pointed out, often weigh in favor of placebo control
trials, versus the needs of patients, doctors, and
payers, who would probably be better served by more
active control trials.
            The issue here is the balancing of these
clinical usefulness issues and the ethical issues
against the needs of others, and we tend to put the
ethical issues and the needs of the patients ahead of
the needs of the pharmaceutical industry and
regulators.
            The issue really, when we come down to it
is, the differential incidence of harm.  The question
is, what is the difference in the incidence of some
serious outcome, like a stroke or a cardiovascular
event, or patient discomfort, like severe pain or
migraine, between the placebo group and the treated
group, in previous clinical trials?
            And from that, we should be able to, since
there will in general be previous placebo control
trials that precede the study that we will now be
discussing, you will be able to estimate what the
absolute value of the difference is between the
treated and the untreated.
            What is needed then is a determination of
the threshold for the differential incidence of
serious outcome, or patient discomfort, above which
the placebo becomes unacceptable.
            And in part what I think we need to do is
start making an agreement upon what that threshold
might be.  And that I think will help us to develop
disease-by-disease guidelines.
            Finally, as Dr. Wolfe pointed out, it is
not enough to say that informed consent was obtained,
or that IRB approval was obtained, and therefore, the
study is ethical.
            The medical literature is littered with
wholly unethical studies that were obtained with
supposedly good informed consent, or that went through
Institutional Review Boards.
            Sure, informed consent and Institutional
Review Board approval are necessary, but it is the
responsibility of the investigator and those in the
regulatory community that help those investigators to
design their studies, to act independently and to make
sure that, not only is informed consent and IRB
approval obtained, but that the studies themselves are
ethically designed.
            DR. PAUL STOLLEY:  Well, thank you for
inviting me.  I have sort of a bag of miscellaneous
comments that I would like to bring to you.
            I think the goal of a study is probably
the most important thing that drives the design, and
the FDA and the Sponsor want to know, is the drug
efficacious?  Does it work?
            The practitioner, once that is
established, really would like to know, How does this
drug compare to others in its class, and should I
choose it over its competitors for the same
indication?  And that of course would take a different
kind of a design, a head-to-head design, usually.
            In terms of the use of placebo, when you
get into the grey area, I think people of goodwill may
disagree, and one way of trying to get over that
disagreement is to try to quantitate the amount of
suffering that somebody on the placebo might endure,
and see if the different people who are arguing the
case can agree as to the amount and type of suffering,
and then whether it is acceptable.
            One of the things we haven't discussed is
unblinding in trials.  Unblinding occurs a lot more
than we would like to think.  The one of the few
trials that showed that Vitamin C was effective in
preventing the common cold was a trial in which the
subjects had unblinded it by biting through the tablet
and getting that acidic taste of Vitamin C, and all of
the benefit, when they reanalyzed it, were in those
that unblinded themselves, and knew they were taking
Vitamin C.
            The trial was repeated, and that flavor
was given to the placebo as well, and the benefit
didn't show up on repeating it, so unblinding can be
subtle, and very damaging.
            Bradford Hill tells the story of a
crossover trial in which they went from Drug A to Drug
B, and one of the subjects came up to him and said,
"Dr. Hill, did you change the drugs on me last month?" 
And he said, "Why do you ask?"  And the answer was,
"Well, last month when I threw them in the toilet,
they floated, and now they sink."
            (Laughter.)
            And going back and reading Bradford Hill
is always edifying, because, as I was preparing for
this, I was reading the defense of the use of the
probability value of five, for efficacy, or for the
decision rule, because it is just generally accepted
by the scientific community, but in preparing an
article on how Sir Ronald Fisher got to be on the
wrong side of the lung cancer, cigarette-smoking
controversy, I read a lot about him, and he is the one
who sanctified P=.05, and you know, there is no
rationale for that.  He just selected it because it
sounded reasonable.
            That's the entire theoretic rationale for
that choice.  There is no reason why that can't vary
depending on circumstances having to do with the
toxicity of the drug, need for therapy and so on.  And
a number of other issues.  Perhaps even Sir Ronald
Fisher, who never liked to change his mind, might
agree with us.
            And then I guess my final remark is that,
the balancing of statistical efficiency and the
maximal informativeness of a trial, reducing human
suffering, is a problem we face here.  And at times,
being able to do a quick, decisive trial using a
placebo, might cause less suffering than a very
lengthy trial where you don't, and the opposite of
course is true.
            So, some way of quantitating the human
suffering that is involved in placebo trials is
needed, and must be discussed.
            I think perhaps patients could be brought
in on this decision.  I still treat patients and it's
kind of amusing to me, a little amusing to me, to have
a patient come in and describe a mild headache that
they get in the front, but it disappears when they
take one Tylenol, and now as I am listening to them,
I have this migraine, you know.  And it's just, can I
finish the hour out?
            And you know, so there are headaches and
there are headaches, and I think we have to try to get
the patients involved.
            Thank you.
            DR. WOODCOCK:  Bob?
            DR. ROBERT TEMPLE:  Okay, I want to go
quickly through a few important concepts: briefly
discuss the ethical issue as I see it; address in more
detail what's been considered so far, why this issue
is important.  Why do you need a placebo?  Why can't
you just do an active control?
            Discuss a few practical considerations,
basically ways to design around the ethical problem,
if there is one.  Finally, how to make the case that
an active control trial would be informative in a
particular instance.
            I want to make it clear.  The issue about
placebo versus other designs is fundamental to
demonstrating that a drug is effective.  I will argue
that certain designs, active controls, are not
informative in certain situations.
            If they are not informative, that means if
we were to rely on them, we would put ineffective
drugs into the marketplace.  Nobody wants that, I
know, but that's what the consequences of this
discussion are.  It's not only about what would be
nice; you can't do a trial that hurts people, but you
do have to have a trial that is informative.
            So, sometimes if you can't do a placebo
control trial, you just can't get there from here.  We
can't approve the drug at all.
            Anyway.  Let me give a few more details. 
The ethical issue, as you have heard is, if there is
known effective therapy for a condition, when is it
ethical to deny this treatment to some patients in a
clinical trial?
            You have heard about the Declaration of
Helsinki, but the most extreme view expressed by
Rothman and Michaels some time ago is that, "If there
is effective therapy, you can never deny people that
therapy in a clinical trial."
            Now, I understand there may have been a
phone conversation where he might have changed his
mind a little bit on that, but that is the -- slightly
-- but that was the position.  And he really meant it. 
I've been on stage with him.  He meant, you can't do
placebo control trials in baldness, because we have
Rogaine.
            You can't do seasonal allergic rhinitis
control trials, because we have lots of effective
antihistamines, et cetera, etceteras.
            As I said, that is the most extreme view. 
I would say, my view is, and our view generally has
been, that if we assume careful, informed consent, and
appropriate review by an IRB/IEC, patients can be
asked to participate in a placebo control trial, even
when there is existing therapy, when the risk of lack
of treatment is only discomfort, even fairly severe
discomfort.
            We will get to this later, but a
migraineur knows what a migraine feels like; who would
be better prepared to describe whether they are
willing to defer therapy for two hours, than someone
with the disease?  They know.
            If they are willing, and it has been
explained to them, and if they know they can get out
of the study if it gets too bad, I would allege that
it is ethical.
            That doesn't mean that patients are going
to be willing to enter the study.  That's a different
question.  But I think it's ethical.
            For that reason I would consider most
psychiatric conditions, outpatient depression,
obsessive-compulsive disease, panic disorder, anxiety,
angina, seasonal allergies, lots of other things,
acceptable.
            This presumes -- I want to emphasize this
-- that the patient has been properly informed, knows
that there is existing therapy, and all that stuff is
done properly.  You have got to assume that; if that
is in doubt, fix that.
            Now, it is completely clear; we do not
disagree on this at all, that if there is adequate
evidence that available treatment improves survival,
or prevents irreversible morbidity in the intended
study population, and the treatment is available --
            We'll get to this, maybe a little bit
later.  I think the question of what you can do in
another country that doesn't have therapy is a
complicated one.  Sid referred to that.  I'm not going
to go into that, now.  But talking only about the
United States, where presumably all the therapies that
are available to people are available, if you know
that there is improved survival, or something like
that, you can't do placebo control trials.
            We agree, and I'm sure we don't have the
lists, Sid, but I can guarantee, we have told people
they cannot do certain trials they wanted to do, and
have argued about them, gotten modifications, and so
on.
            DR. WOLFE:  How many times in the last
five years?
            DR. TEMPLE:  Yes, see I can't tell you
that, but I know -- Sid wanted to know how many times
in the last five years.  But he was just kidding.
            (Laughter.)
            DR. WOLFE:  No, he wasn't.
            (Laughter.)
            DR. TEMPLE:  I don't know.  A lot of
times, you don't get an application like that, Sid,
because they already know we wouldn't accept it.  A
lot of times they already know we wouldn't accept it,
because we've told them.
            So, you can't do placebo control trials --
you can't do placebo control trials with
thrombolytics, post-infarction beta-blockers, post-
infarction aspirin, post-infarction ACE-inhibitors, at
least in patients with ventricular dysfunction.  You
can't do antibiotic, placebo-controlled antibiotic
trials in dirty surgery.
            You can't not treat patients with
childhood, acute lymphocytic leukemia, testicular
cancer.  You can't do a long-term trial of moderate to
severe hypertension anymore.  We know there's a clear
benefit.
            An interesting case is, we don't think you
can actually do congestive heart failure trials
anymore, because ACE-inhibitors have been shown to
improve survival in virtually every phase, so maybe
for a day or two, but beyond that, you are getting
into territory where you can't do it.
            I need to remind you, however, that just
because you can't do a placebo control trial, doesn't
mean an active control trial is informative.
            An active controlled, beta-blocker, post-
infarction trial is uninformative.  Thirty out of the
35 trials, approximately, that have been done in that
condition have failed to distinguish drug from
placebo,  So, what is it going to mean if you don't
distinguish one drug from another?  A point I will
return to.  So, in those cases, you just can't do it.
            There are a lot of situations in which the
risk to patients could be debated.  There is a current
debate going on about whether you harm schizophrenics
by taking them off active therapy, or by delaying
therapy.  That bears discussion.  There are
sophisticated people on each side.
            The data on the benefits of treating very
mild hypertension, 90 to 95, are quite weak; some
people might decide that could still be studied, some
people probably would not.  And there are many
examples of that; I'm not going to try to do them all.
            Now, the next point is, Why does this
matter?  Why can't you just do an active control
trial, show no difference, no significant difference
between the two treatments, and say, Ah-hah.  I win. 
I'm as good as the other drug?  And that's what I want
to explain.
            I should mention here that the crucial
difference is between trials that show a difference
between treatments, and trials that show no difference
between treatments.
            The difference could be, again, placebo;
it could be an active drug; it could be dose-response. 
Those are all informative.  The problem arises when
what your goal, is to show no difference.
            And the problem is, the question of assay-
sensitivity.  In order for failure to show a
difference to mean anything, you must know that the
trial had the capacity to distinguish between an
active drug and an inert drug.  That is, an active
drug and placebo, if there had been a placebo there.
            That's called assay-sensitivity.  The
ability to detect differences.  Unfortunately, for a
wide variety of drugs that we know are effective, you
cannot make that assumption about any given trial.  I
will give just a small number of examples.
            So, what is the problem with equivalence
trials?  There is the historical assumption of assay-
sensitivity.  When you do an active control trial, you
don't have a placebo.  You don't show that a drug
beats placebo in that trial, you have to deduce it,
from experience in the past, or something else.
            Now, that is unless you do a nice study
called a three-arm trial, in which you use placebo,
active control, and new drug, which gets you
information about the comparison, and also does it in
a way that is informative.  That's a very good design. 
Very common in depression.
            So, one assumption is, you have to assume
that there is assay-sensitivity.  You don't measure
it.  I'll talk about that a little more.
            The second is, that there is a lack of
incentives to study excellence.  When you are trying
to show difference between treatments, you have to be
on good behavior.
            If you are trying not to show a
difference, there are a variety of things you can do
that would undermine the study, or fail to make the
study sensitive to showing drug effects, and you don't
have to be unduly cynical to think that that is a bad
kind of incentive to give investigators and drug
companies.
            We will leave the third one out; that's
not really critical.  Okay, so, in active control,
equivalence trial where the goal is to show no
difference, there is an often unstated, not always
recognized assumption, which is that the active drug,
the control, was effective in the particular study in
question.
            That is not necessarily true, and it's not
testable, and it means that these trials are
historically controlled trials, in a sense, and we
know what we think of them.
            We put this in regulations -- let me give
you one example.  There are an infinite number one
could do.  These are the results of six controlled
studies, three-armed trials, of a new antidepressant,
Nomifensine, no longer with us because it causes
hemolytic anemia, but it is an effective agent;
Imipramine, standard antidepressant; and placebo.  You
don't see the placebo there.
            The trials measured the HAM-D.  They were
all at four weeks, and they did an analysis using
common baseline, we don't do that very much anymore. 
And what you see under New and Imipramine, is the Ham-
D at the end of four weeks, and you can see there was
a change of about ten points on the HAM-D.  A typical
response for an active drug.
            And you can also see that the new drug and
Imipramine are right on top of each other, every time;
13.4 versus 12.8; 13.0 versus 13.4; they are all
essentially identical.  If you were to believe the
equivalence trials, this would be the case you would
believe in.
            Now you see the placebo arm.  In five out
of these six trials, the trials lack any ability to
even hint at a difference between an active drug and
a placebo.  The only trial that was able to
distinguish between drug and placebo was the fourth
one down, a trial with seven people per group.  I
mean, talk about ridiculous.  No one would take that
seriously.  But it was the only trial that had assay-
sensitivity, and readily distinguished placebo from
the two new active drugs.
            The other trials couldn't tell anything
from anything.  If we had developed this drug, I mean,
you could take a completely inert substance, like the
placebo, and win by comparing it with active drugs, in
trials of this kind.
            As far as we know, there was nothing wrong
with these trials.  They were a little small, although
30 is not that small, but it makes the point.  This is
the experience that has been observed in depression,
and other illnesses, over and over again; it's not
unique.
            I'm not going to go through this, but I
went through the last three years of trials in
depression, in psychosis, in OCD, and in panic; about
a quarter to a third of the trials, and they are
decent-sized, 40 to 80, couldn't distinguish drug from
placebo.
            That is the nature of the drugs we have. 
There is no doubt that the drugs work.  They are more
effective than placebo, far more than the one in 20
that you would get at a P-value of .05; it's close to
a third.  They work.  They just don't work all the
time.
            We don't even know if it's the drug's
fault.  In some cases, people just got better by
themselves.  There are a lot of reasons for a study to
fail.
            Well, they are not small.  They are 40 --
these -- I'll go back.  Some of these are very large
trials, in fact.  I guess you can't go home again.
            One of them on Quetiapine at the mid-dose
had 200 per group.  That's the largest trial I have
ever heard of in psychosis.  Still couldn't tell
anything.
            The Olanzepine trials were 80 and 50. 
Those are absolutely typical.  You don't know that a
larger trial would do it.  You can't tell that, until
somebody goes and does larger trials and proves it,
and nobody has the incentive to bother to do that.
            Anyway, if you can't be very certain that
a positive control in the study would have beaten the
placebo group, had one been there.  The fundamental
assumption of the positive control study can't be
made, and you can't use that design to reach an
effectiveness conclusion.  And if you can't reach an
effectiveness conclusion, we can't rely on it.
            Just as a throw-in.  If you want to know
how one drug compares with another, you have got the
same problem.  A study that can't tell drug from
placebo can't accurately compare two drugs.  If you
want to know whether the two drugs compare, you need
a placebo, also.  And that's a very good design.  We
like those a lot, even though we don't insist on them.
            Briefly, about the incentives.  Certain
kinds of sloppiness widen the confidence interval, and
will not lead you to a false conclusion about whether
a drug is equivalent to another.
            For example, if you have a lot of
measurement error, you might not reach a false
conclusion.  But there are some things you can do that
will not increase variance, but that will obscure
differences.
            For example, you can mix up the drugs. 
Now, you may think that doesn't happen often, but ask
people at a drug company, and they know it does.
            You can have very poor compliance.  You
can have people who all get better spontaneously.  You
can have people who don't have the disease, because
the diagnostic criteria weren't very good.
            All of those changes guarantee that you
will be equivalent to the drug you are comparing
yourself to.  That is not a good set of circumstances
to give people, and you don't have to be unduly
cynical; I'm not that cynical, but -- to think anybody
would do that on purpose, but you might be.
            (Laughter.)
            Anyway.  It's not a good situation.  When
you are trying to, all of these examples, the example
I showed you and the many others I could, of where
effective drugs don't beat placebo, all were in
situations where people were trying as hard as they
knew how.
            They were having wash-out periods, they
were assuring compliance.  They were yelling at people
to take the drug and try not to mix up the drug.  And
they still couldn't do it all the time.
            Now, if you wanted to do an active control
trial, because you think the circumstances are right,
here is what you have to do.  You have to show that
placebo control trials regularly allow a detection of
a difference between drug and placebo.  We have never
defined what regularly is; it means, almost always.
            Then you have got to use a design,
endpoints, sample size, all those kinds of things,
that is pretty close to that, so you know that it is
relevant.  You can't -- well, you can't take a
different endpoint and think you know anything.
            And I will leave the third one out,
because that goes to how you actually do equivalence
trials.  So, you have to make this statement sort of
historically.
            Now, can active control trials be
credible?  Of course they can.  Most bacterial
infections are studied in active control trials.  We
accept them with thrombolytics on the basis of an
analysis that Jay can tell you about.  The treatment
of deep vein thrombosis, it's easy to tell drug from
placebo.
            Many stages of HIV infection, highly
responsive tumors, anaesthetic agents; most people
stay awake until they get the anesthetic, there are
exceptions.
            (Laughter.)
            Beta agonists and bronchospasms, you get
a prompt, you get an immediate response.  It's pretty
easy to tell, and we do utilize active control trials,
so they are appropriate.
            Do I have another two minutes?  Okay. 
Just a couple of practical considerations.  I think
this is of interest to everybody.  Sometimes, you just
can't do a placebo control trial.  What can you do, in
that case?
            One of the best things you can do is you
do an add-on trial.  Everybody gets the standard
therapy, and you test the new therapy, added onto the
old therapy.  That only works when the drugs are
different pharmacologically; that's how anti-epileptic
drugs are done now, that's the only way.  You don't
have drug versus placebo; people are uncomfortable
doing that; they don't want to.
            Heart failure, that's how you do it.  You
take the standard therapy, diuretic, ACE-inhibitor and
so on, and you add something new.  Now, you're
probably going to have to take a beta-blocker in
addition.
            This gives no data on monotherapy, but at
least it shows you the drug works in some environment,
and that's better than nothing.
            You can beat the standard, tPA, b-
streptokinase.  Winning is always good.  It could even
be an imperfect dose of the standard and still be
informative.  That might be ethically questionable.
            Dose-response studies, if ethically
acceptable, are also informative.  Now, you can't
cheat.  You can't give a trivial dose and pretend
you're not giving the placebo.  That's no good.  That
doesn't solve any ethical problems.
            You can study a population subset not
known to benefit.  I think that was mentioned before. 
It's interesting to think about the SHEP Study.  That
was a study in isolated systolic hypertension in the
elderly.  What we had known for 20 years by then, that
treating hypertension was good for you and improved
survival in other things.
            Why was that okay?  Because no one had
ever done a study in isolated systolic hypertension in
the elderly.  The epidemiology says it looked at the
other situations, but everybody is pretty comfortable
with that, and I totally agree with Sid.  You couldn't
do SYST-EUR in this Country.  Whether you can do it
somewhere else is a different debate.
            Yes.  Well, we would -- if someone came to
us with that, which no one did, we would have said,
No, you can't do that study.
            It's okay to study nonresponders to
standard treatment; then you're not depriving them of
anything.  Clozapine was developed that way; Deprenyl
was developed that way.
            One thing you can do if the duration is of
interest, is provide early escape.  If you are doing
a short-term hypertension study -- we'll talk about
those later -- and people's blood pressures start
going up, and you're worried about it, get them out. 
Maybe that makes you comfortable doing a short-term
hypertension study when you wouldn't have been,
otherwise.
            Sometimes you can treat people for a long
time with active drug, do a randomized placebo control
withdrawal at the end, and as soon as their disease,
whatever it is, comes back, you take them out of it,
count them as a failure, and note the difference
between the two.
            That may be ethically comfortable, whereas
a long-term, you know, a six-month study in
hypertension is out of the question.  You can't do
that.  But you can treat people with an active
control.
            Take the drug away, and then they're a
little hypertensive for two weeks.  Many people would
accept that; we'll probably talk about that later.
            Okay, well, you've heard the conclusions. 
We'll pass that one.
            DR. WOODCOCK:  Thank you, Bob.  All right,
we have heard people's take on a wide variety of the
issues relating to the placebo.  From one hand, the
imperative not to do harm to people, but from Dr.
Stolley we heard the issue of, you know, how much harm
is harm?  And we're always drawing blood from people
and harming them in different ways.  What is tolerable
in studies?
            To the other side, which you heard mainly
from Dr. Temple which is, well, we can't -- it's also
unethical to studies that are completely
uninformative, because then you are exposing human
subjects for basically no purpose.
            And so, how do we wind our way between
these?  And to illustrate some of these issues, we
want to talk about three case studies, and is it all
right with the Panel if we start with the migraine? 
We can dispense with that fairly quickly, perhaps, and
I think it does illustrate some of the issues?
            Migraine Case Study
            DR. WOODCOCK:  All right.  We wondered how
people got their e-mails.  Let me just read briefly. 
"There's an element that causes symptoms, but little
likelihood of causing long-term harm.  Existing
treatments are effective in treating symptoms, but
don't have an impact on reducing the possibility of
long-term harm or effects."
            Migraine is going to be the first one of
these we discuss.  And what I would like to do is
start with the questions.
            The first question for migraines is, "Can
a placebo control study design be used ethically?  If
so, under what circumstances, and with what
limitations?"  And any people who want to contribute
on what would be the best design.  Who would like to
start off on this?  Yes.  All right.  Dr. Lurie
            DR. LURIE:  I understood the process
slightly differently, but that's fine.  As you said,
it's an example of a condition where a patient's
symptoms are all that's really relevant.  There's no
long-term risk, as there is with hypertension, for
example.  So, the question, as I said earlier, becomes
How much patient suffering is acceptable?
            And we have said a certain amount is
acceptable for mild pain, cold symptoms, allergy
medications, but if anybody has suffered a migraine in
this room, and I suspect there are many, perhaps from
hearing us speak before, the two hours of intense
suffering, as with migraine, we think is a very
substantial discomfort to patients, and an early
escape, as FDA seems to be doing these days, after two
hours, does not seem acceptable to us.
            I went back and looked at some of the
recent migraine studies, and noticed several things;
one was the absence of any attempt for a meta-analysis
or any kind of review, the way one finds in some of
these other conditions we'll discuss.
            And the studies that I looked at, at
least, were numbingly and consistently positive, and
again, just the recent ones.  But, the placebo
response was reasonably uniform.  It works out to be
about a third of people who respond, if you define
responding as moving from a moderate or a severe
headache to one that is mild or not present at all.
            What is interesting in looking at these is
that alternative designs have been used.  One was a
study in the Academic Emergency Medicine from 1998,
which was an equivalency or a positive control study,
one can't quite tell, but compared to IV Ketorolac to
IV Prochlorperazine.
            It showed that Prochlorperazine was
better, and that I think is very useful clinically for
physicians.  The problem is, of course, it's a risk to
the drug company, and if IV Ketorolac's sponsor was
the sponsor of this trial, they would probably be
quite disappointed by the results.  Patients, on the
other hand, would benefit greatly.
            There were also some interesting dosing
studies that I think are also alternatives, for
example, an article by Klausen in Headache in 1997
looked at Naratriptan at a number of different doses,
and at the highest dose, there was a 60% response
rate, followed by a 50% response rate at a little bit
lower dose, but the two lowest doses had 35 and 32%
response rates, and the placebo was 34%.
            I think that that's the kind of dosing
study that would be helpful, because anybody at the
top three doses would have said, 60% versus 50%, well,
that's a lot better than what we assumed the placebo
response rate to be, about a third, which in fact is
what it turned out to be, in this particular study,
and even if they hadn't made that assumption, they
would have seen a drop-off at the third dose, from 50%
down to 35%, and they said, we wouldn't have used
that.
            So, I think that, again, for us, the
important element here is to not downplay the severity
of two hours of unnecessary migraine that some one-
third of people will experience, and to look at the
fact that there are some alternative designs that can
be informative.
            DR. WOLFE:  Just a little quick follow-up
on that.  I mean, I agree with what Bob said before,
was that one should not mask in what appears to be
just a dosing study, what may be de facto, a placebo
arm.
            I think that once you have been through at
least a few drugs in this category, you have a better
idea of how to design a dosing study.  I mean, unlike
the hypertension example which we will get to, where
you use a surrogate, here you have got intense pain,
and you should be able, with a dosing study that is
honest and based on what you knew from the
pharmacokinetics of the drug and from the other drug
in its class, you can design one that can get you all
the information you need, without resorting to a
placebo.
            DR. WOODCOCK:  Dr. Stolley.
            DR. STOLLEY:  Well, I've been an authority
on migraines since age 13, and the reason I think a
placebo trial is permissible is that you can put
people to sleep after two hours.  You can give them a
hypnotic, and often that's the only way to help
somebody with a very severe migraine, is to give them
a hypnotic so they can sleep.  So, I think that that
protects patients.
            DR. WOODCOCK:  Dr. DeLap?
            DR. DELAP:  Yes, I think this is a very
interesting discussion.  I think, one, I would like to
pick up on just a couple of things from the
introductory discussions by Dr. Stolley and Lurie,
pertaining to bringing patients into the process as
much as possible, and the fact that something that
passes an IRB and an informed consent screen, that's
not necessarily reassurance that it is the right thing
to do.
            I think investigators of course have
different -- well, I would say, two primary
motivations in getting involved in clinical research. 
One is to provide treatment for their patients, and
the other is to study the new treatments as they are
administering them.  Those are not necessarily the
same goals, sometimes, and there can be some
conflicts.
            Patients come to the experiment with, on
the one hand, a hope of benefit.  They really, I don't
think anyone really wants to get an inactive treatment
for something that is causing them serious problems,
but patients also I think bring some understanding of
the research process, and certainly, some, what I
would describe as, beneficence or altruism to the
process, as well.  And their understanding of the
necessity for clinical research to advance the field.
            Now, of course, the investigators and
companies who are developing products oftentimes know
'way more about the underlying disease process and
about the drugs that are being tested.  The patients
know a lot more about symptoms that they are
experiencing.  And again, I think that's one of the
really relevant points in the migraine case.
            I think if the patient has the sense, that
understanding that they are going into a placebo
control trial and they know their migraine, they know
their symptoms, they know what they are up against,
and if they want to agree to participate in a trial,
as opposed to taking some medication that they may
have taken in the past successfully, I think there,
they really know pretty much what they're getting
into.
            I mean, there aren't a lot of other
secrets.  They know that they might get a treatment
that's not going to work, and they might have whatever
discomfort they typically have, for that period of
time.
            And so, I would agree with Dr. Stolley's
comment, but I think as long as you have ways to, in
the end, ensure that the patient is comfortable, if
they're willing to endure that, then I think the
design is acceptable.
            Now, I think there are also other designs
that may be acceptable, and I think that's another
issue.  If someone wishes to set forth a design that
has an active control, and take into consideration all
of the historical information about placebos, and what
they do, and how many patients you might need to
study, and what the confidence intervals need to be of
the relief, to satisfy yourself that you have fairly
tested the new drug.
            You know, I think that kind of a design
can also be acceptable.  It may take more patients, it
may take longer to do, it may be somewhat less
definitive, unless adequate numbers of patients are
studied.
            DR. WOODCOCK:  Okay, so I think I'll call
on the rest of the people in a second, but let's sort
of review the bidding here.
            With migraine, what we have heard is,
there is some opinion that the pain that people, to
which I can personally attest is occasionally severe
pain that people are being asked to endure, and I
think Dr. Lurie expressed the view that, in fact,
given that in his point of view there are alternative
trial designs, it could be advanced that that would be
too much to ask people -- am I paraphrasing you?  That
that would not be appropriate to ask people to endure
those two hours of pain, because there might be
alternative ways to get this information.
            We also heard, though, that perhaps people
know what their pain is, patients can be involved in
these decisions, and an alternative view was, it's not
too much to ask people, since they really know the
whole story for their migraine.  They know what they
are getting into, and they are capable of perhaps, in
that view, deciding whether they would enter into this
trial or not.
            And I think this is illustrating a sort of
fundamental difference here which is, why subject
people to any pain, when it could be avoided by some
other trial design, versus well, people can make these
decisions.
            And I think underlying that issue is the
fact that, although these alternative trial designs
may work in some cases, they also have a much higher
chance of not being successful, and not getting the
information.
            So, if that's fair to all the
participants, that's where we are right now.  Do we
have more comments?  Jay?
            DR. SIEGEL:  Well, first I'd say, I would
agree largely with Dr. DeLap's comments.  I think
though that some attention has to be paid to the, and
probably there isn't time to address the critical
issues here, but to the questions that were raised
about the quality of the informed consent process,
because if you ask a patient to undergo this sort of
pain, the critical issue is, are you asking under any
coercive, or otherwise manipulative conditions?
            And I think that if you're not, then there
are many patients who really wish to be part of
medical science and a medical study, and ought to have
that ability, if all is done openly and fairly.
            So, I think significant attention does
need to be paid to that process, how it's done.   I
think it is a little bit, if you can ensure good
informed consent, then it's paternalistic to say that
patients shouldn't be allowed to make the
determination as to whether that two hours of pain is
worth enduring.
            A second issue that this and all these
questions raise in my mind, that I'm wondering about
is, are, the way we framed this question, can you ask
the patient to potentially endure this pain, is based
on a strong presumption that the active control will
work.  Because the active control design is also a
design in which significant numbers of patients are
not receiving proven effective therapy.
            And indeed, if you know that the active
control works, then you ought not be doing the trial. 
Well, at least, you might be doing it for other
reasons, but not to prove efficacy, if you know
efficacy.
            Presumably, if you are doing the trial to
prove efficacy, you don't know if the study works, so
you are in fact asking patients to take the risk of
having an ineffective therapy in either design.
            And then the active control does raise
some additional issues about the informed consent
process, because one of the concerns about informed
consent, in general, is that many patients in many
trials, after informed consent, despite perhaps being
told that it's unknown if the drug works, sign onto
the trial quite convinced that the drug works.
            And if you are to obtain true informed
consent, and tell the patients in fact that even when
you do the active control trial, what you are telling
the patient is, we have a proven effective therapy
here, but we want to enroll you in a trial in which
you may receive a therapy that doesn't work.  And I
think there are important differences, but some of the
ethical issues are the same, and we need to guard
against that presumption, that all experimental
therapies work.
            DR. WOODCOCK:  As we well know, to bitter
experience, is not true.
            DR. WOLFE:  Just a quick comment on that
which is, I think that the implication was not simply
that the patient needs to be involved, as a patient,
in the informed consent decision, as to whether she or
he participates in the trial.
            I think that if we took a roomful this
size of people who had had one or more, or ten or more
migraine headaches, and explained to them that the
only alternative was not a placebo versus a new active
drug, but that an alternative design was the active
control design, assuming that the active control was
something that had previously been found to work,
versus the placebo, which we were at a point, years
ago with these kinds of drugs --
            And fully inform them.  I agree with Jay
that you need to explain that in the placebo control
trial, there's a certainty that the placebo won't
work, and that there is at least some hope that the
other will work, whereas in the active control, you
know that one of them has worked, and you don't know
yet whether the other one works.
            But, I think you might get a different
kind of decision as to which of the two trial designs
would be preferable, if you involved people who have
actually experienced a headache.
            Now, this is possible because it is the
effect, or the effect of not being treated is right
there, very immediate, measurable on their part.  One
can get some quantitative measurement and compare them
for themselves when they start using the drug an hour
or two later and so forth.
            So, I think that we might get different
design trials, particularly now, and maybe ten years
ago it was different, but there is an enormous amount
of data which Dr. Lurie mentioned is just
extraordinarily repetitive when you look at it, trial
after trial, with the same general kinds of findings,
that when the next one of the drugs in this family
comes up, I think that a group of patients might
choose to have an active control trial, if they were
allowed to.
            DR. WOODCOCK:  Yes.  Could I just comment
on, just from an outsider's viewpoint, and not a
member of the Panel?
            But, Dr. Lurie, didn't you say that in
signing up for a placebo, you diminish your chances of
50% being better at two hours, to about 30%?
            DR. LURIE:  Yes, 50 to 60%, down to about
30%.
            DR. WOODCOCK:  Okay.  So, about half the
people may not get any relief, anyway?
            DR. LURIE:  Bob is saying -- Bob is
saying, Big deal.  And I think that actually is a big
deal.  I personally am not a migraine sufferer, and
I'm happy for it, and I would feel differently --
            I mean, an informed consent form would
state not only the things that Sid has said, but it
would state, Because we are using a placebo control
trial instead of an active control trial, which very
often can provide useful information, you will with
certainty, if assigned to the control group, have a
30% greater likelihood of having migraine for two
hours.  And that's what a truly informed consent form
would say.
            Now, as a general matter, they don't say
that, because everybody knows that if you really
disclosed that, some people would sign up, I think
that's true.  But if you really said that, I think
people wouldn't.
            And especially with the direction in which
clinical trials are going these days, where there is
sort of a decentralization of clinical trials in
doctors' offices, and very often it's the doctor,
himself, who is enroll -- or herself, excuse me -- who
is enrolling the patient, and acting as the
investigator, it is very difficult for a patient to
say no in a circumstance like that.
            DR. TEMPLE:  May I?
            DR. WOODCOCK:  Okay, let me go in order
here.  Bob, first.
            DR. TEMPLE:  There are a few
misconceptions that need to be corrected.
            DR. WOODCOCK:  Speak into the microphone.
            DR. TEMPLE:  There are a few
misconceptions that need to be corrected.  The example
of the Ketorolac-Prochlorperazine study was
successful, because one drug was better than the
other.
            If that study had shown no difference
between the two drugs, it would have been completely
uninformative.  You wouldn't have learned a thing.
            It's not true, you should know this, that
sponsors do not particularly prefer to do placebo
control trials.  One of the reasons we told people
that they had to do them was that they were eager not
to.
            It's very easy to win in an active control
trial.  And people do active control trials in Europe
all the time.  Europe is finally getting the idea that
they need to add a placebo group to make them
informative, but these trials happen all the time.
            In the example you gave, the very results
you described would have been uninformative about the
value of the low doses, completely uninformative if
you didn't have a placebo to know that the placebo was
doing about the same as the low doses.
            It is of interest to know what the lowest
effective dose is.  It's particularly of interest in
these drugs, because there is a little concern about
coronary artery spasm, and you want to use the lowest
dose you can.
            So, it's not trivial to want to know what
the dose response is.  Some people might want to start
on a lower dose, if they are --
            DR. WOLFE:  But you can do that without a
placebo.  You can do a dose response curve without
involving the placebo.
            DR. TEMPLE:  But you won't learn whether
the low dose works.  If you've got a 40% response rate
on the low dose, and no placebo, what would you know? 
Did it work or didn't it work?  You don't know,
because you don't have a placebo.
            DR. WOLFE:  But you would have a good idea
from the previous trials.
            DR. TEMPLE:  No, I don't --
            DR. WOODCOCK:  Okay, Jay --
            DR. TEMPLE:  -- agree at all.  Finally,
last point.  I have got to say, migraine is the purest
possible case where the patient knows exactly what she
or he is getting into, and I agree with Jay's use of
the word, paternalistic.
            I'm perfectly content to let Paul decide
whether he wants to be in this trial, and you don't
need to take a vote of this room to do it.  He can
figure it out.  You know what a migraine is.  You have
had them.
            DR. STOLLEY:  I want to be in the trial
and I want the placebo.
            (Laughter.)
            DR. WOODCOCK:  You've had the treatments,
right?
            DR. WOLFE:  So you need to have your head
examined.  All right.
            (Laughter.)
            DR. WOODCOCK:  We'll finish up with Jay,
and then we're going to take some questions from the
floor, or comments, on this particular example which
is a fairly pure, I think, balancing of the issue of
the interpretation of the amount of harm that comes to
subjects in a very pure case, for a short period of
time and so on, versus the issues of what we can learn
and how informative other trial designs might be.
            Jay.
            DR. SIEGEL:  Yes.  I'd just like to
comment on a substantial note of agreement that I
heard, that may have been missed by some in the face
of disagreement.  Not so much on the ethical part, but
on the informational part, or the ability to draw
inferences, which is that Dr. Temple noted that the
times when you can draw inference from an active
control trial, are times when your drug would reliably
perform better than placebo by a determinable amount.
            And Dr. Lurie noted that, in this case,
and I'm not arguing specifically the merits of this
case, but in this case, what the informed consent
should say, the word to use is, with certainty.
            That, with certainty, if you are
randomized to placebo, you will have an outcome that
is 30%, or one-third, or whatever the number is,
inferior to the outcome you would get had you received
an active control.
            And I think we probably do have some level
of agreement that these standards of, that the active
control is better than placebo reliably, or with
certainty -- with certainty may be a somewhat higher
standard -- but are similar.
            So that if in fact we -- you know, and not
arguing the merits of migraine per se.  But if in fact
we have a situation where we can say with certainty,
that under the conditions of the trial, the patient
would do worse with placebo than with active control,
we have a situation where we can draw inferences from
an active control trial.
            DR. WOODCOCK:  Agreed.  I think there's
agreement on that.  All right.  Well, why don't we
move to -- There's not?
            Okay, why don't we move to questions from
the audience.  Come up to the microphone, or if you
have a comment.  Maybe we have some migraine sufferers
in the audience, who would like to give some editorial
comments.  Dr. Johnson.
            DR. JOHNSON:  I'm not a migraine sufferer,
but I am interested in the quantitation of this notion
that, if there is an alternative design and an active
control design, and let's say you determine that it
requires ten times the number of patients, is somebody
looking at the global ethical perspective here?
            Is that more unethical if you have to
enroll ten times the number of patients with an active
design, rather than one-tenth the patients with a
placebo control design?
            DR. WOODCOCK:  I'll have Dr. Lurie answer
--
            DR. LURIE:  Well, there's -- that sort of
ratio of active-controlled to placebo-controlled
sample size requirement is a kind that is frequently
bandied about, but generally not supported by what is
actually necessary.
            Generally, the increment in the sample
size requirement is nothing like ten times greater. 
It's generally some much more modest amount; 50%
greater, or what have you.
            In the Africa studies for example that we
looked at, it was about a 20% incremented studies, and
I think -- in sample size.  In the others, it depends
on the particular tolerance that you are willing to
take in an equivalency study, et cetera, et cetera. 
But, as a general matter, it will not be enormously
greater.
            Let's put all of this in the context of
the drug approval process, which as you all know, is
long.  And you know, you have to put it in the overall
context of that, and particularly, in the context of
a situation which we're talking about here, which is
there already are effective drugs on the market.
            I think that, you know, where there is no
effective drug on the market, well, it's a
straightforward shot, and there's a rush to the market
and you can use the placebo control.
            But I think that, again, just to
emphasize, I don't think that you very frequently are
going to run into a ten times greater sample size
number.
            DR. WOODCOCK:  Okay.  Two more questions -
-
            DR. TEMPLE:  May I comment on that one?
            DR. WOODCOCK:  Briefly.
            DR. TEMPLE:  In an active control trial,
you have to presume, you have to choose as your
estimated effect, the lowest values you encounter. 
And that will lead you to get larger sample sizes, as
a rule.
            I need to mention one other thing.  We're
all presuming that people entering these trials are
true migraineurs.  It's perfectly possible to screw
that up and put in people who have different kinds of
headaches, and your active control trial then becomes
utterly spurious.
            You have got to remember that.  There are
a lot of problems when your obligation is to show no
difference.
            DR. WOODCOCK:  Two more questions, or
comments.  Go ahead.
            DR. YAES:  Yes, Bob Yaes.  There's
another ethical issue which I think has been sort of
touched on, but not really gone into, and that is,
suppose you have a new drug, which is more effective
than placebo, but less effective than currently
available treatment.
            Is it ethical to bring such a drug to
market?  Now, one would hope that a drug company, you
know, if they had an inkling that this was what the
situation was, that they would throw the thing in the
trashcan and that would be that.  They'd go onto other
things.
            But, it's conceivable that they might
decide, you know, well, we can get it approved because
we can show it's better than placebo, and then maybe
we can effectively market it.
            If they don't do a comparative trial, then
there is no way to show that that drug is less
effective than drugs that are already on the market.
            Now, with migraine, I mean, that's a
slight problem.  I mean, it would mean that, if
patients don't know that this new drug is less
effective, then they'll suffer more pain, because they
won't know that the other thing is better.
            But when you get into more serious, life-
threatening diseases, like cancer and AIDS, then I
think this consideration reinforces the idea that you
don't want to use placebo.
            You don't want to use placebo because it
would be unfair to the patients in the study, but you
also don't want to use placebo because if you are
dealing with an illness like AIDS or cancer, which
kills you, I mean, then you don't want to let out any
drug that is not at least as effective as drugs that
are already available.
            DR. WOODCOCK:  Okay.  Well, let me just
use the Chairman's prerogative and answer this, or the
Chair's prerogative, or whatever.
            I think we don't have placebo controls,
ordinarily, in life-threatening diseases that have
successful therapy available.
            The issue of less effective drugs for the
other range of treatments is a complicated one, which
I don't think we can fully address here, today, and
maybe we could take it up at another seminar, because
there are things like a lower toxicity and so on that
might make a less effective drug acceptable, or to a
niche of the population.
            Final question here.
            DR. ANDREA SEGAL:  I'd like somebody to
talk about the influence of variability of placebo
rate, and how this affects.
            It appears to me that I recall reading a
study by a man named Beecher, and I believe this is
where the original one-third placebo rate was drawn
from, where the placebo variability I believe was from
15 to 58%, and there are many studies of sham
procedures, such as cutting the internal mammary
arteries to treat angina, that show that placebo rates
can be as high as 70%.  Maybe there is literature that
shows that it goes even higher.
            And I would like somebody to comment on
how that possible variability in placebo response can
make an impact on non-placebo-based trials.
            DR. WOODCOCK:  Dr. Wolfe.
            DR. WOLFE:  This -- I'm not meaning to
defer your question, but this issue is really right in
the middle of the whole discussion of the third case
that we have, which is depression, because clearly, as
a function of whether it is three-day old reactive
depression to a death or something like that, or two-
year old serious, endogenous depression, there is a
huge difference in the placebo response rate.
            One of the confounders in looking at all
of the literature on antidepressants is the failure to
clear out the different degrees of depression and so
forth and so on.  But I mean it's a very, very good
point, and I was, as I read through that literature on
depression, I was astounded at how long they have sort
of realized this, and it hasn't filtered down into
consciousness.
            DR. WOODCOCK:  Dr. Stolley and then Dr.
Temple.
            DR. STOLLEY:  Well, I'm glad you mentioned
the internal mammary artery ligation experiment that
was done back around 1958, where everybody woke up
thinking that -- they had an incision, and thinking
they had had the procedure, but when they opened the
envelope, it was ligate or not ligate, on a random
basis.
            And the placebo rate was not as high as
70%, but it was on the order of 30 or 40%, and this
showed that you could have a fairly striking placebo
effect, when somebody thought that they had the
surgical procedure, even though they didn't.
            It was partly this that led to the study
that has been designed for Parkinson's patients, where
they get a hole drilled in the skull, I believe, but
only some of them get the procedure, and there, I
would have to say that that's making too much of a
placebo effect, because when you have a disease like
Parkinson's Disease, where you may have diurnal
variability, and you use something as crude as what
they call the YAR Score, rigidity and ability to do
things quickly, and so on, which is kind of a crude
measure --
            Nevertheless, it's a downward course for
everybody.  It's an unremitting disease.  And I had a 
lot of trouble justifying a sham operation in that,
and was wondering how that got approved.
            (Laughter.)
            DR. WOODCOCK:  Okay, we'll move on.  Dr.
Temple, did you have a comment about this?  Can you
try and keep it brief?  We have about 35 minutes left,
okay, for the next two cases.
            DR. TEMPLE:  The only point I would make
is that describing the change in the placebo group as
the placebo effect is a misnomer.  It includes all of
the changes due to natural history.
            However, a variable response in the
placebo group is one of the hallmark features of
trials of situations where active control trials are
not very reliable, because the results are so
different.
            DR. WOODCOCK:  Right.  Bob, did you have
any --
            DR. DELAP:  Yes.  I think we have
sometimes a false sense of security, too, from the
active control trials.  People think that if you do an
active control trial, and Drug A looks like Drug B,
then they must be about the same, when in fact, all
you're really saying is that you have established
within a certain confidence interval margin, that you
can't tell them apart.
            Now, you know, oftentimes what that means
in practice is that Drug B could in fact be 30% worse
on whatever outcome they're measuring, and it still
turned out the same in this particular experiment. 
That's the simple statistics in the matter.
            DR. LURIE:  Yes, but that's really no
different than what you are seeing in a placebo
control trial.  You're saying, with some probability,
this drug is superior to placebo.
            So, that argument -- what you are saying
is true, but it really cuts both ways.  In the end,
one has to establish parameters of alpha values of
tolerance levels and the like, and go from there.  And
if you understand the statistical interpretation
correctly, you understand it.
            It's not certain that a drug that is
statistically significantly better than a placebo, is
better than placebo, it's 95% or more likely that
that's the case.
            DR. DELAP:  Well, yes, this is true.  I
think, again, a lot of our drugs are not terribly
effective to begin with sometimes.  I mean, you may --
migraine is an example of a situation where we do have
drugs that do have effect for the majority of
patients, but they're not always effective.
            So, there is a treatment effect of both
placebo and if you are giving away 30% of the effect,
you may be giving away most or all of what was there.
            So, you know, again, if you don't have
assurance that you haven't lost the entire effect,
then you know, I'm concerned that you open the door to
having a drug out there that you would say from the
study, looks the same.  The practitioner will say,
well, this drug worked the same as the other drug in
the study, and can be used interchangeably, and yet,
it really isn't doing anything.
            DR. WOODCOCK:  All right.  Well, will the
Panel -- we have 35 minutes left, approximately. 
Would the Panelists like to move to hypertension as
the second example?  Yes.
            Let me just give the -- I think this was
a very illuminating discussion.  We see we have
different estimations of the degree of harm from
migraine, and that's one of the --
            And we also have different estimations of
the degree of informativeness of the different studies
that might be done, although there is more agreement
upon that.
            I like to use a simple-minded approach to
understanding part of this equivalence issue which is,
for the highly variable drugs with the small effects
that Bob was talking about, and you do an equivalence
trial without a placebo, the way to tell the lay
public about this, I think is, you don't know whether
both of them worked, or neither of them worked,
because in many trials, the active drug doesn't work. 
It doesn't distinguish itself from placebo.  I think
that's a sort of easier way to understand it.
            Hypertension Case Study
            DR. WOODCOCK:  Now, we are going to move
to hypertension, as in the -- right.  Hypertension. 
That's the one we want to do next?
            Okay.  As an example of an illness,
obviously, that can cause long-term harm if left
untreated or inadequately treated for a substantial
period of time.
            Of course, effective treatments are
available.  Limited periods of inadequate treatment
commonly occur in medical practice -- nobody is saying
that's you know --
            For example, when a hypertensive patient
comes in, presents originally, you may recommend diet,
exercise, what have you, salt restriction, and other
things, and not treat them with medication, and this
may not cause harm, but no one has really proven the
absence of harm.
            So, we are going to discuss hypertension
and why don't we start with trying to go through these
questions, telling whether or not they think the
placebo-controlled study design can be used ethically.
            As you saw in your handout, these are
typically short-term, 8 to 14 week, moderately short-
term, placebo-controlled trials, looking at control of
blood pressure.
            Who would like to start on this one?  Dr.
Temple, we'll let him go first.
            DR. TEMPLE:  All right, let's -- 8 to 14
weeks is actually unusual.  They are actually shorter
than that, more like four to six.
            DR. WOODCOCK:  That's what I thought.
            DR. TEMPLE:  I need to tell you that
hypertension trials occur that do not distinguish drug
from placebo.  There is a very large response in the
placebo group, 5 up to 10 mm Hg.  It could be digit-
preference, we don't really know.  We are exploring
whether automated cuff designs might not have that,
but the change in placebo is relatively large,
compared to the added effect of the drug, which might
be as little as 3 or 4 mm Hg.
            In addition, it is desirable here, as it
is in other cases, to know what the lowest effective
dose is, and the effect there can be quite small; it
could be 2 mm Hg, and I will allege that you cannot
properly learn these things from a trial that doesn't
have a placebo.
            It is totally clear that nobody is going
to, in this Country anyway, countenance long-term
trials with outcomes using a placebo, so let it be
clear, there is absolutely no disagreement about that,
but a trial of four to six weeks is consistent, as you
just said, with practice, and we think that there is
little evidence, little possibility, there could be
harm.
            We are in fact carrying out a study
internally of something like 100,000 people who have
been in trials, and will be back to tell you whether
there is any possibility of harm, but at least at
present, it seems entirely compatible with ordinary
practice to have a period of, say, four weeks or six
weeks.
            This is in people who are 95 to 105.  You
don't take your diastolic 130 and put them in a trial
like this.  That would never be done.  Never be
allowed.
            DR. WOODCOCK:  Okay, Dr. Wolfe.
            DR. WOLFE:  Yes.  I disagree.  But beyond
those two words, Dr. Lurie will just briefly mention
some of the evidence that the problems, as in the
worsened cardiovascular outcomes, are pretty linear,
and seem to go back to the beginning of these trials. 
So, that there is worry, even in a month or two.
            But I think, unlike the situation with
depression, or migraine, where we have a clinical and
measurable effect right away, here this is clearly a
surrogate effect.  We are looking at lowering of blood
pressure, and hoping to get people into a, quote,
"acceptable" range of blood pressure, compared with
what they were before, or what they were when they
were on another drug, and so forth.
            And the literature is filled with examples
of studies, randomized controlled studies, where there
wasn't any relationship between the extent of lowering
the blood pressure in these trials, and the eventual
outcome.
            A number of them have been published in
the last couple of years.  There's FACET, in which
amlodipine, which lowered the blood pressure more than
an ACE inhibitor, and had a much worse outcome in
terms of cardiovascular problems.
            On the other end of the spectrum, there is
the lowering too far of blood pressure, and there's a
study published in the JAMA, I guess a couple of years
ago, from the Group Health Cooperative of Puget Sound,
where they showed that, as you start inching down to
87, 75, 70 in the blood pressure, you have increased
risk of primary cardiac arrest.
            That's a case control study, not a
randomized study, but I think the difference here is
that, if one can agree that it is worthwhile  getting
someone's blood pressure into whatever range is
thought to be okay for them, is a function somewhat of
how old they are, because of the systolic blood
pressure, then yes, there are some examples where, in
randomized control trials, the antihypertensive agent
wasn't distinguishable from the placebo.
            But I think that in the overwhelming
majority, the drug, particularly when we are talking
with mainly classes that we already have examples,
whether it's ACE inhibitors or diuretics, or calcium
channel blockers, or whatever, we have multiple
examples already in each of those classes, where the
drug is more, and statistically significantly more
effective than a placebo.
            Peter, why don't you talk a little bit
about the linear outcome?
            DR. LURIE:  Well, earlier on, I made the
argument that what we really need is some collective
agreement about the amount of risk that patients can
endure, and there's the subjective elements, as we
discussed in the migraine case.  Here, patients are in
a sense asymptomatic, and therefore in a worse
position to be able to decide for themselves what it
would be like to have a heart attack in the future.
            If you look at the MRC, the SHEP Study,
and the SYST-EUR Study, three of the leading
antihypertensive studies, one thing that you notice is
that, the best one can tell, the divide between the
placebo and the treated arm begins right at the
origin, right at the beginning, in a sense, but it
goes more or less linearly out for as long as people
are followed.
            I make that point because I've also said
that we need to determine for these kinds of studies,
an incidence of adverse effects, an excess incidence
of adverse effects, which would become unacceptable
for the conducting of a placebo control trial.
            So, the diversion extends all the 'way
back to the first couple of months, and I went back to
the MRC, SHEP and SYST-EUR studies, and calculated the
excess risk of having a stroke or a major
cardiovascular event, during, say, the first two
months of therapy, and in the MRC, it's about .5 per
1000 strokes, or .7 per 1000 major cardiovascular
events, in that two-month period.
            In both the SHEP and the SYST-EUR, you get
about 1 in a 1000 additional strokes and 1.8 in
additional major cardiovascular events.
            Now, the question is, is 1 in 1000 --
let's take that as an outcome -- is a 1 in 1000 chance
of having a stroke or a major cardiovascular event
unacceptable?
            And obviously, in the great majority of
such studies, there will be no such event, or no such
excess event, because the studies will be considerably
smaller than 1000.
            But let's contrast that to levels of risk
that are otherwise accepted in society.  The Supreme
Court has ruled that a lifetime risk of 1 in 1000 of
occupational cancer is sufficient to mandate the
Occupational Safety and Health Administration to act
and regulate.
            That's 1 in 1000 in a lifetime to exposure
to a potential carcinogen.  We're talking about a 1 in
1000 in a two-month period.  So, I think that this is
certainly of the order of risk that leads to
regulation in the occupational area, and I think it
should lead to regulation, in this case, the
preventing of placebo control trials in this area.
            DR. WOLFE:  Just to comment on what Bob
said, which is that there is quite a literature,
again, something I learned by reading for this seminar
this afternoon, on comparing the placebo effect in
hypertensive trials, as measured by clinical blood
pressure monitoring and ambulatory.
            You sort of alluded to that, and it looks
as though there is still some, but it is considerably
less if you do the 24-hour ambulatory monitoring.  And
that actually looks sort of hopeful, because if you
can in some way diminish what appears to be a larger
placebo effect, then even more reason not to do a
placebo.
            DR. TEMPLE:  We agree.  And we also have
a study going on about that.  Peter, could you say
exactly how you made your calculation?  Did you assume
a linear effect over time?
            DR. LURIE:  Yes, that's what I said.  I
assumed a linear effect over time, because that's --
I mean, you know, the data are pretty much linear,
since we have these --
            DR. TEMPLE:  Okay, well, lucky for you. 
We really will have 100,000 people studied in four to
eight week trials, and we ought to be able to get an
answer on that.
            I can tell you, as the trials go by, and
they typically do have a couple thousand people in
them, you don't see anything like that.  But that's
not big enough to be fully reassured.  I mean, for any
given application with 2000 people randomized --
            DR. WOODCOCK:  Yes, Bob, you have to --
yes.
            DR. TEMPLE:  In any given application with
a couple of thousand people in it, you cannot see an
excess of those events in the placebo-treated group,
but those are very small numbers, as Peter said. 
You're not going to see very much.  That's why we have
to do the pooled analysis.
            DR. WOLFE:  Are you trying to encourage
more use of ambulatory monitoring, though, in these
trials?
            DR. TEMPLE:  Were trying to analyze the
data we have, to see if we can do that.  Yes.
            DR. LURIE:  I just want to really
compliment you on doing that analysis, because that is
the kind of analysis that's necessary.  I mean, by and
large, we do need to get to the point of quantifying
excess risk, and coming to an agreement about how much
is acceptable, and that's a very useful step in that
direction.
            DR. WOODCOCK:  Yes.  If we had more
resources, we could do more retrospective analyses of
these sorts.
            DR. WOLFE:  We've all supported larger
budgets for you.
            (Laughter.)
            DR. WOODCOCK:  You know, it sounds like
what we're getting to here is the issue, a different
issue.  Some risk is clearly unacceptable, we all
agree with that, and the issue here is, quantitation
of the risks that people are subject to, and Bob DeLap
and then Dr. Stolley.
            DR. DELAP:  Well, I have to confess to a
certain ambivalence about this.  I think it really
gets down to the details.  If you're talking about one
day, I don't think people would get too concerned
about one day of lack of treatment.
            If you're talking about, you know, 12
weeks, that's a different matter.  If you're talking
about a blood pressure of 105 versus 95 versus 115,
obviously, the degree of concern is different.
            One of the other -- well, there are two
fundamental things that really concern me though,
here, which is, one is, I do think that it's harder
for the patient to really appreciate what they're
signing onto when they sign onto one of these trials.
            It isn't like the migraine situation,
where the person has a headache and they know what
they've got, and they know what they are up against,
and they can fully appreciate what they may be signing
onto.
            Here, it's, of course, it's hard enough
for us to figure it out, I guess, but it's I guess
impossible for the patient to really fully appreciate
what risk they're assuming.
            And the other thing, in the real world, I
think we know how these trials are actually done, with
new blood pressure medicines.  There are people who
have clinical trial units around the Country, and they
have groups of patients who participate in trials, and
there is an aspect of kind of, in at least some study
settings, where people get washed out from their
therapy, and then they try the new drug.
            And then the next new drug comes along and
they get washed out from their therapy, and they try
the next new drug.  So, it's not necessarily, you
know, four weeks we're talking about here, but it may
be four weeks now and four weeks there months from
now, and four more weeks.
            So, over the course of time, for a
particular individual who has signed on with one of
these clinical research units, they are going to have
quite a number of weeks of being washed out and off of
treatment.
            DR. WOODCOCK:  Thank you.  Dr. Stolley?
            DR. STOLLEY:  One of the things it says in
the description is that, "Candidate drugs are not
required to show reductions in mortality or
cardiovascular events."  And that's the really
important question, a public health question, and the
question the doctor and the patient want to know is
not, Will you lower the number but, Will I live
longer?  Will there be fewer sequelae?
            And when the calcium channel blocker
controversy arose, nobody knew whether calcium channel
blockers actually were going to protect you from
stroke, and you would live longer, and with newer,
expensive antihypertensives coming on the market, and
no drug insurance under Medicare, and you have to take
them for the rest of your life, that's a key question.
            I don't know what you can do about it, but
that's the question we need answered.
            DR. WOODCOCK:  Dr. Stolley, I hear you
focusing in a couple of these examples, and your
original discussion, on really outcomes of medical
treatment, which is an even broader issue, and choice
within the armamentarium of the proper treatment, and
maybe we can discuss this at the end, is that the
proper role at the very beginning of drug development
when you're really trying to select candidates that
work?  Or, is this something that we just all need to
concentrate on getting done more, and sometimes --
            DR. STOLLEY:  Of course, that's not the
question you ask when you don't even know that the
drug has any effect on blood pressure, granted, but
that is the ultimately important question --
            DR. WOODCOCK:  Amen.
            DR. STOLLEY:  And it's the one that the
NIH usually winds up answering and funding.
            DR. WOODCOCK:  Dr. Temple.
            DR. TEMPLE:  Which fortunately they're
sort of doing in this case with the ALHAD Study.
            DR. STOLLEY:  Oh, good.
            DR. TEMPLE:  Which will be more
information we have, than we've had up to now, on
whether you can get an answer to those questions,
which I don't think is completely obvious.
            I want to give you a brief anecdote, which
I found sobering.  This is about a drug called
Carvedilol.  It's a beta-blocker with some alpha-
blocking components that you take twice a day.
            The reason you take it twice a day is that
in a study done in the United States, it was perfectly
clear that taking 25 mg, the largest dose you could
tolerate once a day, did not lead to adequate control
at the end of the day.  And we don't approve drugs
that don't give you 24-hour control.
            They had studied over 8,000 people in
comparative trials in Europe, because Europe likes
comparative trials, that did not include a placebo. 
And the dose they studied was 25 mg once a day.
            They showed in those 8,000 patients, no
difference between known effective once a day
therapies and their drug, which we know from the U.S.
study doesn't work.
            It's a bad incentive to have to show no
difference.  People can't handle it.  You wouldn't
expect them to, it's not in their interest to, and you
don't want to approve drugs that don't work in
hypertension.
            You wouldn't want a drug that didn't work
for the full 24 hours.  Doctors don't necessarily
measure that.  They wouldn't know about it.  You have
got to be very careful before you start accepting
active control trials in settings where you are not
quite sure that they can show the difference.  Just a
reminder.  Eight thousand patients and the wrong
answer.
            DR. WOODCOCK:  Dr. DeLap and then we'll
sum this part up.
            DR. DELAP:  I just wonder if we might
further consider the possibility of add-on kinds of
designs.  I mean, if you are studying these kinds of
drugs, there are plenty of patients out there that
have not quite adequate control of their blood
pressure with one pill, and it's a reasonable thing to
think of what to add next, and what people think about
taking a person who is on a therapy, their blood
pressure is already under some control, maybe not
quite enough, and now you're going to add another
drug, or a placebo, but you're going to keep them on
the drug they're already on.
            DR. WOLFE:  I think that's a good point. 
I mean, in SYST-EUR because the drug company wanted it
that way, they started out with a new calcium channel
blocker, it was Isradipine, I think is what it was.
            DR. TEMPLE:  Nitrendipine.
            DR. WOLFE:  Nitrendipine, and then --
            DR. TEMPLE:  A new old one.
            DR. WOLFE:  -- only added on diuretics and
beta-blockers for those people that didn't respond. 
I think that the reverse kind of study would be very
useful, which is what you're talking about, which is
to have, for protection and so forth, people taking
now as we know effective low-dose diuretic and then
seeing whether these additional ones are going to
confer any benefit.
            I think that the place that one might be
going in terms of -- even though it's a longer-term
outcome with hypertension may be, as Bob was
describing before for seizure disorders.
            I mean, given that we have something known
to be effective, which happens to be extremely
inexpensive, and we really should be asking, can we
outdo that, rather than risking people even for four
weeks or six weeks or whatever, with no treatment in
the placebo --
            DR. TEMPLE:  Sid, can you make the design
here clear?  If you wanted to do a trial in people who
don't respond adequately to diuretics, what would you
then do?
            DR. WOLFE:  Well, I was saying, take
people who do respond to diuretics.  I'm knocking the
design of the Nitrendipine study.  I'm just saying
that, if the question is, can we do better than
diuretics?  You might have people taking diuretics,
and see whether you were going to protect them
anymore, long-term, by adding another drug.
            DR. TEMPLE:  The trouble is, all
hypertension outcome trials don't study a single drug. 
They study an approach, that starts with one drug,
adds another, adds another, until they get to some
degree of control.
            DR. WOODCOCK:  Bob, get to the microphone.
            DR. WOLFE:  But the sequence of adding is
sort of drug company-driven, as opposed to --
            DR. TEMPLE:  Well, that's true.
            DR. WOLFE:  That's the problem.
            DR. WOODCOCK:  Okay.  Well, I think we've
heard a variety of opinions about this issue of
hypertension studies.  Number one, we heard that there
is difficulty in quantitating, or extrapolating the
amount of risk people are signing onto, when they
would enroll in one of these trials.  And explaining
it to them.  Because we don't really understand that. 
But we're doing some studies, fortunately, to try to
quantitate that.
            Number two, the ethical issue is added to
because, as Bob DeLap said, we are pretty sure that
patients wouldn't know what risk they were signing
onto, even if they were signing onto some risk.
            We can't quantitate it, but we're sure, in
people who are healthy and taking a preventative, that
they really can't imagine what a risk of stroke or MI
might be, a remote risk, and so that complicates it.
            We've heard from Bob Temple that head-to-
head trials of certain drugs have been quite
uninformative in hypertension, about their failure to
be effective in a situation, and that's very
concerning, because putting ineffective drugs on the
market could be a problem.
            And we've heard of some alternative trial
designs, either short-term for effectiveness, or long-
term for outcomes, that people feel could be employed.
            So, do we have any questions from the
floor?  We're going to have to move right along.
            DR. JOHNSON:  Quick technical question for
Peter and also for Bob Temple.  Have you, or can you,
or could you, or would you develop a confidence
interval for that 1 out of 1000 figure that you
calculated?
            And what you guys are doing, Bob, will it
yield confidence intervals?
            DR. LURIE:  So, is it yes, no, yes, and
no?
            (Laughter.)
            DR. JOHNSON:  Have you, and if so, what is
it, and if not, will you?
            DR. LURIE:  I didn't do that, but I
imagine it could be done.  I took, you know, my
calculation came out of the estimates of the
differential risk at the end of five years in those
particular studies, and there are confidence intervals
around them, at least at the five-year point, and I
suppose one could bring it back down to one year.  I'd
need some help, but it could be done.
            DR. TEMPLE:  We'll put a confidence
interval on it.  The number of events is like, even
with 100,000 people exposed, the number of events
altogether is like to be quite small.
            DR. WOODCOCK:  If any.
            DR. TEMPLE:  So, you know, you won't have
more than you have.
            Major Depression Case Study
            DR. WOODCOCK:  All right.  Well, I'd like
to move on to the example, if that's okay with the
Panelists, and talk about major depression.  This is
a very interesting example.
            We've categorized in, "The illness that
causes symptoms, but has little likelihood of causing
long-term harm."  That might be a subject of debate,
actually, amongst the Panel.
            "Existing treatments are effective, but we
don't think they have impact, really, on reducing the
possibility of long-term harm."
            So, why don't we go ahead and get people
to talk about the use of placebo controls in
depression trials?  Who would like to start?  Dr.
Wolfe would like to start.
            DR. WOLFE:  We were able to get a copy of
the -- I guess it hasn't been fully published yet --
AHCPR funded a massive study on looking at the
effective effectiveness of antidepressants, both old
versus new, and new versus placebo, and so forth.
            And we just want to show just a couple of
overheads, just taken directly from that.  The main
findings were that, very consistently, and we're
talking about major depression, as I mentioned earlier
in response to the question for someone --
            The less severe and the shorter duration
the depression is, the much more likelihood that it
will have a placebo response.
            DR. WOODCOCK:  Dr. Wolfe, can you talk in
the microphone, please?
            DR. WOLFE:  Yes.  Right.  These were the
meta-analyses in this study funded by AHCPR, Agency
for Health Care Policy and Research, and I think if
you bring it down a little, I think those are the
placebo versus -- what is it on the top -- it's the
SSRIs.
            And what you can see is pretty
consistently, the point estimates are all to the
right; in other words, improved outcome, and maybe
half of them have confidence intervals that do not go
below 1.
            The next one is placebos versus
tricyclics, I think, is that what it is?  Newer
antidepressants.  Sorry.  Versus placebo.  And again,
one sees that these are all for serious depression,
effective.
            And finally, the last one was the one that
concluded that there really wasn't any difference
between the old and new drugs, and you can see with
remarkable adherence to the one, and you see the
studies are just -- and it lists study-by-study, that
they reviewed them.
            Anyway, the point is, from all of this and
from what we knew before is that, for major depression
at least, antidepressants are very effective.  For
minor depression, particularly in the situational
variety, there is a huge placebo response rate.
            One of the other things I learned was
that, in a meta-analysis of 101 studies, they failed
to find out, to show, that a wash-in phase really made
any difference.
            They said that the placebo run-in does
not, quote, "One, lower the placebo response rate;
two, increase the drug-placebo difference; or three,
effect the drug response rate, post-randomization,
either inpatients or outpatients, for any
antidepressant drug group."
            As I mentioned earlier, the main point of
confusion, I think, in looking at the effect of drugs
on depression, is the failure to stratify by severity.
            One study involved 146 depressed
outpatients, who met the criteria for inclusion. 
Eighty received placebo; 27 Imipramine, and 37
Alprazolam.
            And what they found was that, the
hypothesis was that the shorter the duration, the more
of a placebo response rate there would be.  And what
they found was that, people who were depressed for one
year or longer, the placebo effect was 22.5%, whereas
people who had not been depressed as long, it was
44.9%.
            And there is study after study in the
literature, that compares either in terms of duration
of the depression, or the severity initially, as rated
by the Hamilton Scale, or the presence or absence of
an acute precipitating event, that there is a huge
difference.
            Their description, which is just three
sentences long in this AHCPR Study of depression is,
"Detrimental effects on personal productivity" -- and
we're talking again about serious, endogenous, DSM-,
I guess, now 4, Depression, Major Depression --
            "Detrimental effects on personal
productivity, interpersonal relationships, and the
ability to perform usual daily activities are
pervasive.
            "Studies examining the effects of
depression on health-related quality of life,
demonstrate decrements that equal or exceed those of
patients with chronic medical illnesses, such as
diabetes mellitus, or ischemic heart disease."
            Now, I'll just summarize by saying that,
given that we know that for major depression, that we
have a large number of antidepressants that work; that
there really does not seem to be any important
difference between them; that to relegate people,
particularly to a wash-out, which despite this meta-
analysis seems to still continue, and to another
period of time without the drug, is really cruel.
            And I would strongly disagree with Bob's
initial slide, saying that for psychiatric illness, be
it psychosis, or depression, that as long as patients
were informed, which itself is a problem because of
insight, and it's been taken up by the National
Advisory Commission on Bioethics, in terms of the
vulnerability of such a population to informed
consent.
            But, aside from that issue, this is
inflicting a lot of pain for a benefit that is really
very questionable.  We have not really gained, other
than the difference in adverse effects, which
obviously can be measured in a comparative study, we
haven't gained, really, a lot.
            You are trading one set of anticholinergic
effects with the tricyclics and tetracyclics for a
very high incidence of sexual dysfunction and so forth
with the SSRIs.
            So, I think that, whether it is
withdrawing someone from an antipsychotic drug in a
wash-out period and allowing them to become psychotic,
or putting them in a placebo group, and having them
become psychotic, or relegating people with serious
depression, which as was said, is equal or in excess
of those people with diabetes or ischemic heart
disease.  I don't think that a placebo control design
for this kind of serious depression, is indicated.
            For more mild depression, for a mild
depression, the placebo response rate is so high that,
from a practical perspective, one would wonder,
assuming that these people are not suicidal, because
you can be suicidal, even without the other criteria
for DSM-4 Depression, I would wonder why people
wouldn't be tried on non-pharmacologic therapy at
first, rather than doing more clinical trials with
mild depression, which according to the review of the
AHCPR, result in very confusing kinds of results.
            DR. WOODCOCK:  Dr. Temple?
            DR. TEMPLE:  I think -- I'm really
stunned.  I think you're saying, it wasn't worth
developing any of the newer antidepressants, because
they're not more effective than tricyclics.
            I'm positive there's someone in the room
and they can speak to that, but no psychiatrist
believes that is remotely true.
            Attempts to -- you -- it's perfectly true
that you get one kind of side effect on one, and one
kind on the other --
            DR. WOLFE:  In terms of effectiveness in
treating major depression?
            DR. TEMPLE:  No.  No.  In terms of
effectiveness, they're all the same.  That's
absolutely right.  That's --
            DR. WOLFE:  Well, that's what I said.
            DR. TEMPLE:  That's very important.
            DR. WOLFE:  And there are different kinds
of adverse effects, I'm sure.
            DR. TEMPLE:  That's right.  But, you
needed to know that the SSRIs were effective.  You had
to have a study design that would show they're
effective.  And an equivalence design could not do it,
for reasons that I showed you, nobody's contradicting
that.
            DR. WOLFE:  Let's assume we're talking
about now.  We're not talking about five years ago. 
We now have two, three, four classes that have been
developed and at this point, the question is -- which
is the case that's presented today -- do we need to
keep doing placebo control trials for major
depression?  That's the one I'm answering no to.
            DR. TEMPLE:  Only -- only if you want more
antidepressants.  If you don't believe you need any
more drugs, then you don't have to do it.
            DR. WOLFE:  If you want more that are no
more effective, as is likely to happen, from the ones
we have now --
            DR. TEMPLE:  Right.  It's extremely clear
that nobody is going to be able to distinguish one
antidepressant from another.  They've been trying for
decades.  They all have roughly the same effect,
within the limits of these studies to detect them.
            But they differ enormously in their side
effects.  And if anybody thinks that SSRIs are the
sort of ultimate and optimal therapy, they just
haven't talked to --
            DR. WOLFE:  Well, using your own logic --
            DR. TEMPLE:  They just haven't talked to
the women who --
            DR. WOLFE:  -- the ability to distinguish
between the classes, in terms of adverse effects,
would be very clear.
            I mean, certainly, the nature of, and the
degree of adverse effects with SSRIs versus tricyclics
or tetracyclics is pretty clear, and you don't need a
placebo control trial, if that's what you're
postulating, for the next class that comes along.
            DR. TEMPLE:  No.  You need to know it's
effective.  You have to find out it's effective, and
you cannot do that without a placebo control trial.
            DR. WOLFE:  I disagree.
            DR. TEMPLE:  So, if you -- you disagree? 
How do you disagree?
            DR. WOODCOCK:  Wait, wait, wait --  Let's
get to the technical issue.  Dr. Wolfe thinks, I
gather, that it's unethical to withdraw people and
wash them out, and expose them to placebo, who have
major depression, okay.
            And Bob thinks -- I'm summarizing
everybody -- that it's impossible to determine whether
a new agent is effective, unless you do a placebo-
controlled trial of it and depression.  Is that true?
            Okay.  But they disagree with that --
there's a disagreement about that conclusion here. 
Dr. Wolfe, you believe it is possible to determine the
effectiveness of an antidepressant --
            DR. WOLFE:  With severe depression.  I
mean, again, we're not talking about where there's a
high placebo response with mild or kind of depression,
severe depression --
            DR. WOODCOCK:  With a head-to-head trial,
is that what you're -- wait, let's see what
alternative trial do not -- a head-to-head trial
versus an active control approved antidepressant.
            DR. WOLFE:  Right.  Right.
            DR. TEMPLE:  There's just no track record
in those.  Those studies are actually severe
depression, you know, with suicidal and everything,
scares everybody off.
            No one wants to study those, and we have
relatively little experience.  However, I can tell
you, when inpatient studies are done, you have huge
placebo responses, just the same as here.  Tom
Laughren is here and he can attest to that.
            All of the people in these trials meet the
diagnosis for major depression.  They're not
absolutely the most extreme, but they're all major
depression.
            A typical response is that you get a
change of 10 or 12, I mean, I just showed you six of
them -- 10 or 12 in the placebo group, and if you're
lucky, on a good day, the drug adds three points more.
            That's a set-up for not being able to tell
anything in an active control trial, and you couldn't. 
If we were to reach the conclusion, and one could
reach that conclusion, that you cannot --
            DR. WOODCOCK:  Talk into the microphone,
Bob.
            DR. TEMPLE:  If you were to reach the
conclusion that it is not appropriate to take people
off their current therapy, and that the only people
you could study, for example, are people who don't
respond to other therapy, you could probably work up
a drug that way.
            Whether it would be successful or not is
not clear, but I would say, if you were to decide that
it's unethical to ask people to endure a period of
depression, even though they say it's okay with them,
you are going to have trouble developing any new
antidepressants, and I would allege that the current
crop is not so good, that that's a very, a price we
should accept very willingly.
            DR. WOODCOCK:  Dr. Stolley, yes.
            DR. STOLLEY:  I think one of the problems
here has to do with the severity of the disease.  The
thing that nobody wants to study is the thing that
requires the most treatment.
            DR. WOODCOCK:  Please speak into the
microphone --
            DR. STOLLEY:  And these are the people who
have a major depression; who lose 15 to 20% of their
body weight in four to six weeks; who either become
highly agitated, or immobile; who have a 15% suicide
rate over a six-month period; and if you want some
idea of how much they suffer, you can read William
Styron's account of his depression, which became a
bestseller.
            These are the people who have to be
studied and have to be helped.  On the other hand,
having them use a placebo would probably be cruel.
            DR. WOODCOCK:  Bob DeLap.
            DR. DELAP:  I think this is a very
difficult situation for me to evaluate, too.  I'm not
a psychiatrist and haven't been involved in using
these products.  I recognize that they are very
valuable products, and they are very helpful to people
that have this particular kind  of life illness.
            And I do think there are some issues about
informed consent in this situation, that have to be
thought through.
            Part of it is, expending effort to develop
kind of more of the same.  Of course, one outcome that
we would be delighted to see would be a head-to-head
trial, we'd be delighted to see a head-to-head trial
that would show the new drug was actually superior to
the existing drug, but you know, again, I think we are
not really expecting to see that, based on historical
precedent.
            We're thinking that the new drugs that
come along will turn out to be, at best, kind of as
good as the existing drugs, with maybe some advantage
in side effects.  So, we are left with this efficacy
question.
            But if we did have, again, some trial that
showed a new drug was clearly better than a
comparator, I think we would accept that.  We'd be
delighted to see that, in fact.
            DR. WOODCOCK:  All right.  Well, this
sounds like it is a dilemma.  Let me take some
questions from the audience, and then we're going to
have to close up.  Tom Laughren.
            DR. TOM LAUGHREN:  Can I just make a
couple of comments?
            DR. WOODCOCK:  Yes, you may, if you speak
into the microphone.
            (Laughter.)
            DR. LAUGHREN:  I think one of the problems
pervading the entire discussion is that, it seems that
folks from FDA see a different set of trials than
folks who are not from the FDA.
            And I think that's most apparent with the
depression example.
            DR. WOLFE:  The ones that don't get
published.
            DR. LAUGHREN:  Right.  Dr. Wolfe focused
on the AHCPR Report, which is based on published
studies.  At FDA, we see all the studies that fail. 
And we see all the negative studies.  And I think for
that reason, we have a much better sense of how much
extraordinary variability there is, in placebo
response rate, across different trials.  And these are
all patients who meet diagnostic criteria for major
depressive disorder.
            Now, these are not the kind of, these are
not the endogenous patients who have to be
hospitalized.  And so, it's true, you know, we're not
studying probably the patients who most need
treatment.  But there is, you know, for this
population of major depressive disorder patients,
there's enormous variability in placebo response.  And
that's why it's so difficult to interpret a trial
which shows no difference.
            There's another point I just want to
follow-up and make and that is, you know, it seems to
me that one of the issues here in terms of ethicality
is how much clinical trials differ from what's done in
clinical practice.
            And I can tell you that it's not uncommon
in clinical practice for patients who have mild to
moderate depression, who meet diagnostic criteria for
Major Depressive Disorder, to be observed for some
period of time, before treatment is initiated.
            So, what we do in trials, in terms of
giving patients placebo, is not so different than what
is done in clinical practice.
            DR. WOLFE:  The question I have for you,
Tom is, let's assume that we had figured out what the
most optimal dose is for a known placebo-proven,
existing antidepressant.  And we do a randomized
control trial of that, with severe, endogenous
depression, people above a certain level, with a new
drug.
            I mean, why do you think -- I mean, I
agree with Bob, even though I haven't seen the
unpublished studies, that there isn't much experience
with that, but I mean, one of the reasons for the
seminar is to think about encouraging new kinds of
experience.
            Why do you think that it isn't possible,
from such a design, to get a useful answer?  Assuming
that the population is at least somewhat similar to
the population that the control drug was originally
studied against, in terms of --
            DR. LAUGHREN:  Even for severely depressed
patients, as Bob pointed out, in hospitalized trials,
in patients who were hospitalized, you still see a
fair amount of variability in placebo response.  And
it's actually not surprising.
            DR. WOLFE:  This is a randomized study,
though, so you sort that out in a randomized study,
yes.
            DR. LAUGHREN:  Maybe I didn't understand
your question again.
            DR. WOLFE:  No, I'm just saying, why with
a drug proven to be effective, you're using it at the
right dose, with a population that is similar if not
identical to the population in whom it was shown
effective against the placebo, you now take that drug,
at the right dose, with the same group, kind of
people, generally, randomize them to that, versus a
new drug.
            Why would you not, Bob seems emphatic that
you would never get any kind of useful information
from a study like that.
            DR. LAUGHREN:  It's not predictable. 
That's the problem.  Here's the problem, the same
diagnostic criteria are always used.  You always use
DSM-4 Criteria for Major Depressive Disorder.
            You apply those criteria in a standard
way, despite that fact, I mean, you would hope that
you would get a predictable placebo response when you
apply those criteria, but you don't.  And you know,
despite anything you said about being able to predict
a placebo response from this based on severity or
duration, all of that falls down.
            I mean, there was a conference on this
some time ago, and it basically falls down --
            DR. WOODCOCK:  But, Tom, are you saying
also that you can't reliably distinguish active, good
treatment from placebo, is that what you are saying? 
In a trial.
            DR. LAUGHREN:  You cannot reliably do it. 
Again, as Bob pointed out, about, you know, a third of
trials, maybe 40% of trials, fail to distinguish
drugs, standard drugs that we know work, from placebo.
            DR. WOODCOCK:  Even in that setting.
            DR. LAUGHREN:  Even in that setting.  And
again, it's an issue of those data not being available
more widely.  But we see them, because they come in as
part of an NDA.  You don't see them, because they're
not published.
            DR. WOODCOCK:  Well, I would like to find
some way to make these data available.  That's one of
my missions.
            DR. WOLFE:  The Conference Center would be
glad to receive them, I'm sure.
            DR. WOODCOCK:  I think Peter Lurie and
then Jay Siegel.
            DR. LURIE:  Okay, a couple of points.  One
is, I don't think that we, meaning Sid, I, and Paul
have adequately emphasized how much we agree with Dr.
Temple's earlier statement that three-armed studies,
even if you have to have a placebo, can we at least
agree that three-armed studies would be better than
two-armed ones?
            DR. TEMPLE:  In depression?
            DR. LURIE:  No, no, in depression, I
understand you're talking about in depression.
            DR. TEMPLE:  In depression there, that's
what's almost always done.
            DR. LURIE:  Okay, what -- that --
            DR. WOODCOCK:  Wait, wait, wait, wait. 
Finish, Dr. Lurie, please.
            DR. LURIE:  I'm just saying, I'm not
saying that that is not the case in depression.  All
I'm saying is that that needs to become much more
common in all areas of FDA regulation, particularly as
there become vanishingly few conditions for which
there is no available therapy, and most of the time,
we're talking about me-too drugs that are very likely
to be better than placebo, because they are in fact,
you know, some minor chemical modification on known
effective therapy.
            The second point is, there agreeably might
be times where you have, say, a particular study which
doesn't, you know -- it can't show differences, Bob,
but when you go back and you look at only the
publishes studies, even, on depression, what you see
is there have been a large number of studies.
            And what you're really doing is you're
looking at the family of studies, and interpreting
them as a group.  And that a single, or even two,
quote, unquote, false negative studies, if you will,
can be interpreted in the context of the totality of
clinical experience.  The pharmacological data, the
toxicological data, animal data, you know, if relevant
to the condition, and the large number of clinical
trials that are often conducted.
            So, you have to put the whole packet
together, and one trial here or there, you know,
probably isn't going to sink or swim the drug.
            DR. WOODCOCK:  All right.  Dr. Siegel,
then our questioners, and then we're going to have to
wind this up.
            DR. SIEGEL:  I just wanted to comment on
the issue, the critical importance of an issue Dr.
Wolfe mentioned, the similarity of the population, the
similarity in the active control trial, to the
population in which the active control was initially
studied.
            In a case such as Dr. Laughren mentioned,
where active control works sometimes and doesn't work
other times, there may be differences in the
population that are not related to placebo response
rate, a variability we've talked about, but that are
related to responsiveness to the drug, that we are
unable to identify.
            In many areas, we don't know the co-
variates that account for the fact that people respond
or don't.  And one of the few areas where we've
successfully used active control trials, the area of
thrombolytics, we have the advantage of a database
generated from tens of thousands of patients in
placebo-controlled trials.
            In fact, when meta-analysis came around,
it was discovered and noted probably correctly by many
that we were doing placebo-controlled trials of
thrombolytics long after we had convincing P-values
with several zeroes that they saved lives.
            Well, obviously, assuming that's true,
that shouldn't have been done, but having been done,
we now have a massive database that we can look at,
and we know things, such as, if you do your study in
a country or a community that doesn't have emergency
medical services, or that doesn't have patient
education such that patients arrive within the first
two hours of their heart attack, the drug is not going
to make a difference.
            If you do it in a population enriched,
which can happen, for patients with inferior MIs, or
MIs with little ST-elevation, the thrombolytic is not
going to make a difference.  And what that means is
that if you were to do an active control trial of a
new agent to a known thrombolytic, even if that new
agent were completely inactive, and you were to do it
in those settings, either unintentionally or
potentially intentionally, you could pretty well
ensure that you would, by any statistical standard, be
able to prove that there aren't important, whatever
you set up as your margins, differences between the
two therapies, because in fact, the thrombolytic
doesn't work.
            So, this is the harking back to the
caution Dr. Temple made, but I think that where we
have a massive database, we know that there are
inferential problems based on certain co-variates that
react or respond.
            Where we don't have that database, but we
see variabilities in response, it doesn't -- I think
the important thing to keep in mind is, we don't know
why some people don't respond, but we do know in fact
that some people don't respond, and some trials don't
show responses, and that raises significant concern
about the ability to conduct an active control trial.
            DR. WOODCOCK:  But that's a very good
point, that as our science advances, that we will have
better ability in cases, and we will be driven, and we
will try to get that baseline data and those
predictors.
            DR. SIEGEL:  It's all genomic.
            DR. WOODCOCK:  Genomics.  Oh, jeez.  Don't
hold your breath.  Our last two questioners.
            DR. SCOTT WOODS:  Just to follow up on
that point of needing to do better.  We may -- my name
is Scott Woods.  I'm from the Yale Psychiatry
Department.
            We may not be at the point that Dr. Wolfe
thinks we may be at depression, while we could say
with perhaps 95% confidence that an active control
investigation, had it included a placebo, would have
been informative.
            We may not be there yet, but we should try
to get there, and think about ways where we might be able to,
and the sloppiness that people have talked about that
possibly would be encouraged in an active control
investigation, there ought to be ways to control that.
            I mean, we could, for example, just
instead, for patient selection.  You say, patients
might not really have the disease.  Well, there would
be a way of perhaps controlling for that.
            A videotape of the patient interview could
be submitted, instead of the rating scale, and the
rating could be done by someone who wasn't associated
with the study at all.
            So, we ought to try to get there, even if
we aren't there now, where we would be able to stop
using placebo controls in depression studies.
            DR. WOODCOCK:  Thank you.  The last
question?
            DR. JOHNSON:  Yes, we've been discussing
efficacy, and I'm curious to hear opinions on whether
active controls are comparable to placebo-controlled
studies, to assess adverse event profiles.
            DR. WOODCOCK:  We need monosyllabic
answers, please.
            DR. WOLFE:  A definite maybe.
            DR. LURIE:  A definite maybe.
            DR. TEMPLE:  No, they're not.  You don't
know whether a given rate is larger than the placebo
would have been.
            DR. WOODCOCK:  This is Bob's equivalent of
a monosyllable.
            (Laughter.)
            DR. TEMPLE:  No, no, no.
            DR. WOODCOCK:  Anyone else?  Substantial
disagreement on this point.   All right. Well, thank
you very much.  I really appreciate the audience's
tolerance for this long, and thank you to this Panel
for this good discussion.
            (Whereupon, at 3:45 p.m., the Panel
meeting was concluded.)

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