17. Áà######ÁATTENDEES (Continued)
FOOD AND DRUG ADMINISTRATION STAFF:
MOHAMED ALOSH, Ph.D.
JONCA BULL, M.D.
BRENDA CARR, M.D.
MARKHAM C. LUKE, M.D., Ph.D.
JOSEPH PORRES, M.D., Ph.D.
JONATHAN WILKIN, M.D.
ALSO PRESENT:
JOANNE M. FRASER, Ph.D.
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EVIDENCE OF EFFECTIVENESS OF ACNE PRODUCTS
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THE AMERICAN ACADEMY OF DERMATOLOGY CONSENSUS
CONFERENCE REPORT ON ACNE CLASSIFICATION
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PHYSICIANS' GLOBAL SEVERITY SCALE:
WHAT CONSTITUTES
SUCCESS AND THE UTILITY OF AN INFLAMMATORY ONLY SCALE
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CONSIDERATIONS ON SUCCESS CRITERIA IN ACNE TRIALS
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78. Á#######ÁÁ#######ÁDR. TEN HAVE: Yes. I'm the third statistician here. I guess
I should probably make a comment.
Á#######ÁÁ#######ÁBut getting back to this issue of the normal distribution,
there's another related issue and that's this variability issue which has come
up a number of times in today's conversation, in addition to your consistency
comment. And I have a couple of questions.
Á#######ÁÁ#######ÁOne is, you mentioned the difference in variability between
the active arm and the vehicle arm, and that also has consequences obviously for
your test statistics. And that's related to whether they're normally
distributed or Poisson distributed or whatever.
Á#######ÁÁ#######ÁBut there's a second issue which is probably more difficult to
consider and that's should variability itself be a measure of efficacy. You're
looking at differences in mean scores or mean counts. Should you be considering
differences in variability whether one is more consistently better than the
other across patients but also across time within patients?
Á#######ÁÁ#######ÁDR. ALOSH: That's definitely a good argument. I think in the
morning we had an example in which a drug was approved for the indication and
the other drug not approved. What we look for is collective evidence. We look
for consistency of finding across centers. So, for example, one might get an
application which barely makes it. We could go back. We don't take just this p
value. We look for consistency across centers what you see. Definitely at one
point in time, we were looking at the final assessment. We are going back here
to look at the repeated measurement approach whether we see some kind of a
plateau reached, whether there's a consistent finding or not.
Á#######ÁÁ#######ÁI would agree both with you and Dr. Kilpatrick. There are
many assumptions underlying the statistical test which I presented here about
the generalized linear model or repeated measurement. What's the type of the H
matrix you need, et cetera. So there is a lot behind those p values which are
reported here.
Á#######ÁÁ#######ÁBut I want to make the point, definitely we look for
consistency across centers. If there are outliers, we'll go and investigate
back.
Á#######ÁÁ#######ÁIn the second presentation, I'll be fitting a model and I'll
discuss exactly how far we go to see if there is an outlier and how we dealt
with that.
Á#######ÁÁ#######ÁDR. TAN: Yes. I just want to add just one point to the log
linear model here. I noticed on your slides, you already mentioned the
generalized linear model. I think nowadays all those models are falling into
this generalized linear model. That includes the log linear model. And it's
readily available. I agree with --
Á#######ÁÁ#######ÁDR. KILPATRICK: I think the term "general linear model" --
Á#######ÁÁ#######ÁDR. TAN: Generalized linear model.
Á#######ÁÁ#######ÁDR. KILPATRICK: But to me generalized linear model involves
the Nelder -- I call it Nelder generalization of the general linear model. Dr.
Kligman, are you with us, sir? Okay.
Á#######ÁÁ#######ÁDR. TAN: Yes. That would include what is called a log linear
model into that.
Á#######ÁÁ#######ÁBut actually I have another question. You said for the
repeated measures analysis -- I actually have a different view from what we
talked about this morning. You talked about the inhibition of the new, emerging
lesions. We all agreed in the morning that it is important to see the
consistent improvement throughout the course of this treatment. There are
certain defined periods. So, therefore, the success really should be defined as
not just at one shot. It should be at maybe 8 weeks and 12 weeks. So instead
of you increase your power, you actually have less power. You need to have more
patients in this way. You should have the improvement both at 8 weeks -- maybe
not 8 weeks -- maybe 6 weeks. At two points maybe.
Á#######ÁÁ#######ÁActually in the cancer research area, people have been using
this because patients who have cancer respond to a new therapy and then come
back again. So people now redefine responses. The tumor has to be shrunk by 50
percent at two time points. And this would capture that emerging new lesions.
Á#######ÁÁ#######ÁDR. STERN: That was exactly the point I was trying to make,
that rather than combine, it's probably more appropriate to do multiple,
independent testing, and you've got to pass both tests as opposed to combining
105. careful with this. I think that sometimes it's better just to talk about
efficacy and especially side effects.
Á#######ÁÁ#######ÁDR. WILKIN: Yes, these products are approved with that level,
but you have to remember there's a certain artificiality in a phase III study.
In your office, you never ever give someone a prescription and say, this may
work for you, or half of the people that get this prescription, they're not
going to get anything active and the other half are.
Á#######ÁÁ#######ÁThere was an abstract that was presented at the ASCPT meeting.
It must have been about 5, 6, 7 years ago now. They looked at the efficacy for
a product when it was compared against an active control and showed that it was
a much higher impression of efficacy than when that same product would be
compared with its vehicle or placebo. So I think there are enormous differences
between what happens in phase III and what happens in the clinical setting. So
you might actually get more. You do more for your patients than just give them
a prescription. You give them all sorts of other things to do.
Á#######ÁÁ#######ÁSo I feel that our approval of products that may only change a
couple of lesions at the end of the day is consistent with what we've heard from
clinicians in the past in terms of something that they find useful and
meaningful. And as Dr. Leyden said, not all those products make it on the
market. The market can be more Darwinian than the FDA. Nonetheless, I think
it's a level of efficacy that we should feel comfortable with. That's my
impression.
Á#######ÁÁ#######ÁDR. STERN: It's now 5:30 and I'd like to hear a motion to
adjourn the meeting, and we'll begin again at 8:00 tomorrow morning.
Á#######ÁÁ#######ÁDR. KING: So moved.
Á#######ÁÁ#######ÁDR. RAIMER: Second.
Á#######ÁÁ#######ÁDR. STERN: Thank you.
Á#######ÁÁ#######Á(Whereupon, at 5:30 p.m., the committee was recessed, to
reconvene at 8:00 a.m., Tuesday, November 11, 2002.)
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