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`stimulant drugs. We don 1 t know about the
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`cutuplectic narcoleptics who weren,t. So, I wanted
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`to reflect whut we actually looked at, the
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`scientific evidence.
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`DR. KATZ: And, would that be the basis
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`for your no vote as well?
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`DR. SIMPSON: Well, mine is really thut
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`they reduced cataplectic events.
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`I guess my
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`understanding of treating it is that they couldn 1 t
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`sort of cure it.
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`DR. PENN: May I just clarify?
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`I didn 1 t
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`12 mean cure. My motion was not cure, nor did I say
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`13 monotherapy.
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`DR. KATZ: Right.
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`From the point of view
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`of an effect, you know, that sort of language only
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`being applied to a cure, the vast majority of
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`things we treat and give claims for in indications
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`are for symptomatic, non-curative treatment. So,
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`it is perfectly acceptable for us -- and I think i.t
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`was implied in Dr. Penn 1 s motion that to vote yes
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`you wouldn 1 t necessarily huvc to conclude that tr.e
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`drug cures it or wipes these attacks out, but just
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`tb.at there is a decrease in these attacks compared
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`2~
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`to the control.
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`DR. FALKOWSKI: And you can call it
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`stimulant drugs. We don 1 t know about the
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`cutuplectic narcoleptics who weren,t. So, I wanted
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`to reflect whut we actually looked at, the
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`scientific evidence.
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`DR. KATZ: And, would that be the basis
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`for your no vote as well?
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`DR. SIMPSON: Well, mine is really thut
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`they reduced cataplectic events.
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`I guess my
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`understanding of treating it is that they couldn 1 t
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`sort of cure it.
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`DR. PENN: May I just clarify?
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`I didn 1 t
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`12 mean cure. My motion was not cure, nor did I say
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`13 monotherapy.
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`DR. KATZ: Right.
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`From the point of view
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`of an effect, you know, that sort of language only
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`being applied to a cure, the vast majority of
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`things we treat and give claims for in indications
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`are for symptomatic, non-curative treatment. So,
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`it is perfectly acceptable for us -- and I think i.t
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`was implied in Dr. Penn 1 s motion that to vote yes
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`you wouldn 1 t necessarily huvc to conclude that tr.e
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`drug cures it or wipes these attacks out, but just
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`tb.at there is a decrease in these attacks compared
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`2~
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`to the control.
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`DR. FALKOWSKI: And you can call it
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`monotherapy but what the S'.Jbjects were in these
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`studies were subjects with the condition that wer~
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`already under medication for this condition. So,
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`to take that leap to say, well, therefore, if you
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`have people with this condition who are not on
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`stimulant drugs, docs that follow?
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`I don't believe
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`it does.
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`DR. KATZ: We will take that under
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`advisement.
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`DR. KAWAS:
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`The next question, has the
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`sponsor demonstrated efficacy of Xyrem for the
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`proposed indication to reduce excessive daytime
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`sleepiness in patients with narcolepsy? The floor
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`is open for discussion on this point.
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`At the risk of putting myself back in tht<"~
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`same place as last time, I would summarize what. we
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`have seen today with regards to excessive daytime
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`sleepiness that the~e was one study, in a
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`double-blind fashion, that showed subjective
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`changes in sleepiness with the Epworth Scale, and
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`that would be the GHB-2 study. The other study
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`which is being held up as a pivotal study with
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`regards to daytime sleepiness was the Lammers
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`study, which is a small study. Otherwise, I feel
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`that the evidence wit.t: regards to daytime
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`sleepiness was very weak at best, in particular,
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`the only study that proactively made daytime
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`sleepiness the primary outcome measu~-e as w·~ll us
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`using objective measures with the MSLT was, in
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`fact, negative. All the other studies were open
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`label. So, here I have a little more
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`considerably more difficulty actually seeing that
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`the sponsor has demonstrated efficacy for daytime
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`sleepiness. So, what are the committee's thoughts
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`on this? What arc the committee's comments on
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`this? Jerry?
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`DR. WOLINSKY: As I tried to point out
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`before, I think this is such an enriched patient
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`population for purposes of the endpoints that were
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`studied, it is hard to know that one could
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`population of narcoleptics. So, I agree thut the
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`data is weak and it is also in a very enriched
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`population.
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`DR. KAWAS:
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`: am not sure I understand.
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`For clarification, en:-iched with what? You mean
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`enriched for cataplexy?
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`DR. WOL1NSKY: Er:riched for cataplexy
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`which is not present. in all narcoleptics and js not.
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`always present at this frequency. So, I don't
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`think that we would know.
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`I would not know as a
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`clinical that if I had a narcoleptic with sleep
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`attacks or daytime sleepiness but no cataplectic
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`attacks whether I could expect the drug to work or
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`not, and I saw no data to tell me that 1 could.
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`DR. KAWAS: Any other comments? Any other
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`thoughts before we call the vote on this question?
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`DR. PENN:
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`1 move that the company has not
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`provided information to prove that daytime
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`comment on my motion, that if the company sees this
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`as an important thing they can do a post-approval
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`study on that specific item and that would be
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`appropriate.
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`I was leaning at the beginning of
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`doubt, but considering the potential for abuse in
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`better be quite strict. on this.
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`DR. KAWAS: Can you make that motion
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`comment.
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`DR. PENN: No, no, the adde~dum is just my
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`DR. KAWAS: Good. Give me the short
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`2 motion.
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`DR. PENN: They didn't p~ovc their point.
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`DR. KAWAS, The language is has the
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`sponsor demonstrated efficacy of Xyrem for. the
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`proposed indication to treat excessive daytime
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`sleepiness in patients with narcolepsy? So, a vote
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`of yes the way I just worded it would suggest that
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`the company has shown efficacy, similar to the last
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`vote. A vote of no would suggest that the company
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`has not shown efficacy for that particular
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`indication. So, all in favor of yes, the company
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`has shown efficacy for the indication of daytime
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`sleepiness, please raise your hand.
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`[No show of hands]
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`All if favor of no?
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`[Show of hands]
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`Let the record show that it was unanimous.
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`It might be the only time today.
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`DR. TITUS: And enter nine names please
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`into the record.
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`[Drs. Penix, Van Belle, Penn, Kawas,
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`23 Wolinsky, Romun, Falkowski, Simpson and Lacey voted
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`DR. KAWAS: Now, the second question that
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`the FDA has asked us to vote on is has the sponsor
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`established the safety of Xyrem when used for th~
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`proposed indication for which substantial evidence
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`of effectiveness has been submjtted?
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`Now, given our previous vote, we are
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`talking about substantial evidence for the
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`effectiveness to treat cataplexy, and I want to go
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`ahead and put in here that I think most of the
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`committee members have been of the opinion that the
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`substantial evidence is almost exclusively in the 9
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`g dose range. So,
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`I think we are talking about has
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`the sponsor established safety of Xyrem when used
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`for cataplexy at a dose of 9 g per day, for the
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`14 most part. The floor is open for discussion on
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`this question.
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`DR. SIMPSON: Could one of the physicians
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`put the adverse events that one can see i.n t.he 9 g
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`in perspective?
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`DR. KAWAS: Let me let Dr. Katz and Dr.
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`20 Mani answer the question. Dr. Katz?
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`DR. KATZ: Yes, this is why the dose which
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`you think is effective is important.
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`It might be
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`useful, before you decide whether or not. the .safety
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`has been established at 9 g, to have a look at what
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`the total exposure at the 9 g dose is and whether
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`or not you think that is acceptable, as a first
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`step, independent of whether or not it seemed to
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`have been tolerated, with enough people at 9 g with
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`sufficient duration. So, I don't know if the firm
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`could put up a slide.
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`I think Ranjit has an
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`overhead.
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`DR. KAWAS: Slide 67 from the company,
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`updated ISS database, summary patient exposure by
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`dose. By my calculations we are talking about 60
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`years, person years of exposure on the 9 g dose
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`from the integrated data set.
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`DR. MAN!:
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`I am sorry, I don't believe it
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`is patient years, is it? It is the number of
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`patients.
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`DR. KAWAS: Well, I calculated it because
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`there were 13 patients who had been on it for 2
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`18 months or more. So, it was just 2 times 13 plus
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`34. That is the way I cam to the 60 person year
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`estimate.
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`I actually didn't give them any credit
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`for the 6-month exposure.
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`Actually, I have a question to ask of the
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`company, do each years subsume t~e others? So, the
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`13 individuals who were in the 2-yea~- category, are
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`they also included in the 62 who are in the 6-month
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`category and the 34?
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`DR. REARDAN: Yes, I believe that is
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`correct, Dr. Kawas, the 13 patients would be
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`included in the 34, and the 34 would be included in
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`the 62.
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`DR. KAWAS:
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`So, the math is more
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`complicated than I made it out to be, actually.
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`It
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`still comes to about 47 patient years of exposure
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`by my calculation.
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`I believe that the standard
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`generally if it is considered acceptable is
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`considerably higher than that. Perhaps Dr. Katz
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`would like to comment on that, particularly in the
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`case of an orphan drug with a relatively small
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`patient population.
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`DR. KATZ: Yes, the typical mir.imum
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`requirements for an application for a st.andard drug
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`that is not an orphan -- we will start t:here
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`because we have such standards written, is at least
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`1500 patients total or subjects total, with at
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`least 300-600 for 6 months for a chronic disease
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`and at least 100 for a year. That is thP. standard
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`ICH minimum data package for safety.
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`As you point out, this is at: orphan
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`condition.
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`I guess the company estimates the
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`prevalence of narcolepsy patients with c~taplexy is
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`about 25,000 or 24,000, something like that. And,
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`we had agreed prior to the submission of the NDA
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`a fairly small prevalence, that they wouldn't
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`really have to have the full data set that a
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`typical NDA would have, and we agreed that a total
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`of about 500 would be in the ball park.
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`It is
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`understood that at least some significant
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`percentage of those patients should be at a
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`therapeutic dose because the safety accrued at the
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`dose that is less than therapeutic isn't
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`particularly contributory.
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`So, while I don't believe -- the company
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`can correct me if I am wrong, but I don't believe
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`we set in stone what would the minimum numbers be
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`that would be sufficient for either 6 months or a
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`year or total active therapeutic dose.
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`I don't
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`believe we signed a contract about that, but I
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`think the implication is that a big chunk of the
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`data ought to be at therapeutic dose. So, I can't
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`give you an absolute answer but I will throw it
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`back to yoi.l and ask would you think that the
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`exposure at the therapeutic dose that you have seen
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`is sufficient to characterize the safety profile
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`would adequately inform prescribers u.bout what thf~
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`panoply of risks is at 9 g?
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`DR. ROMAN: Could that be solved with a
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`post-release very strict follow-up on these
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`patients, Dr. Katz?
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`DR. KATZ: We really have to be assured
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`that the drug is safe in use at the time of
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`8 marketing. We cannot rely on post-marketing data
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`use. We have to make a decision about. whether it
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`is safe in use as described in labeling, whatever
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`that is going to look like, at the time of
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`app~·ovul. There may be additional information we
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`would lik0 to have in Phase IV but the fundamental
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`DR. ROMAN: A second point that I would
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`like to mukc is that probably you can say that up
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`recommended to start with a lower arno~1nt and
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`increase according to tolerance and effects, but it
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`is up to 9 g per day. That is sort of the upper
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`limit.
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`It happens to be the most effective one and
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`sort of therapeutic dose but probubly yo"J. would
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`like to start with the lowest possible amount.
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`DR. KAWAS:
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`I think the company shares
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`your ir.terest, but my take on this is we don't want
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`to put out there that a drug is efficacious at one
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`dose and safe at another.
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`I mean, I think it is
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`incumbent on us to feel confident that both of
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`those characteristics go with whatever dose we
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`think is appropriate.
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`In response to your question, Dr. Simpson,
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`and I don't know if I understood it correctly but
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`you said what is the clinical significance, is that
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`from the perspective of a clinical?
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`DR. SIMPSON: Well, that is part of it.
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`Just speaking as a statistician tho~gh, the safety
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`evidence isn't there with those kind of numbers,
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`obviously.
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`I mean, I think everybody knows that.
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`DR. KAWAS:
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`I think that is really more
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`the question that is on hand here --
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`DR. SIMPSON: Yes.
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`DR. KAWAS:
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`-- because from the
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`perspective of a clinical, this drug actually
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`you know, if you didn't tell me what the drug was
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`and just showed me ten safety profiles that have
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`gone by this committee in the last decade, or
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`25 whatever, I suspect this would look like one of the
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`best ones. Nobody died from it. No major
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`laboratory abnormalities wei·e detected. But it is
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`very, very, very few subjects that we are talking
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`about, and I think that is conside~·able concern to
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`us.
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`DR. SIMPSON: There actually was one
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`suicidP. which could be attributed to this.
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`DR. KAWAS,
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`It still puts it in probably
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`the best of the ten. Dr. Katz?
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`DR. KATZ: Dr. Racusin, on our safety
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`team, ·just reminded me of sort of a simple rule
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`that we use to decide what sort of size of a risk
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`you car. cap with a given exposure, it is called the
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`rule of thirds, but basically with a cohort of 60
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`patient years you could be comfortable with ruling
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`out a risk of no greater than 1/20, which is
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`--what? -- 5 percent. So, in other words, there
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`could be a rate of 5 percent of something bad with
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`a cohort. of 60 that you would not. have even seen in
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`that cohort. So, just to sort of give you an idea
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`of what .sorts of potential risks ar·e there that we
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`22 might not have seen yet with tr.is cor.ort size.
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`DR. VAN BELLE:
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`Just a small correction,
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`Dr. Katz.
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`I believe that it sb.ou!d be 3/60, which
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`is 15 percent rather than 20 pP.l·c:ent.
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`DR. KAWAS: Do we have any other commenL:;
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`before we give a shot at tryir.g to vote on the
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`safety~:'
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`DR. WOLINSKY:
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`I very much share your
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`conce~-r1 about approving the drug at one effective
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`dose and then saying the safety is really at a
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`lower dose than what is effective. On the other
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`hand, I do think that we have some reasonable data
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`or. the E"!fficacy side that says that the dose ranged
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`DR. KAWAS:
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`I agree with that comment, Dr.
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`15 Wo1insky, but I really would want to point out that
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`a:most <1ll of the SEs appear at the 9, not at the 6
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`ranqe. So, you know, you are stacking the deck a
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`little.
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`DR. WOLINSKY,
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`I thought actually, as I
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`su.w tht~ listing of the adverse reactions, they
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`21
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`23
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`clustf~red in two modal distributions. One was at
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`t.h'= high range and one was, su~·prisingly, below 6.
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`DR. KAWAS' Actually, maybe we will take a
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`.looJ.: at t!1at. Could Xyrem put up slide number 70
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`for us, updated ISS database does distribution of
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`[Slide]
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`I think that is what you are talking
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`about.
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`It is not a perfect dose response.
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`I meun,
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`something pops up in the middle, the 6 range
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`actually in terms of SAEs at 12 percent for the 6 q
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`dose.
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`DR. WOLINSKY: And if I heard correctly,
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`and I don•t know how they were distributed, at
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`least some of those serious adverse events were
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`cataplectic episodes.
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`DR. KAWAS: But even then, I mean, I would
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`point out that we are talking about a 3-fold
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`increase in discontinuations due to AEs in the 9
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`I mean, it is a 3-fold difference.
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`DR. WOLINSKY:
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`DR. PENN: On the other hand, once again,
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`that looks like a pretty safe drug to me when you
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`are only talking about 15 percent of people
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`dropping out for AEs, and the real-life situation
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`is that. these patients are going to be titrated up
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`to the 9 and, as we saw from that graph of the
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`unacceptable information from the standpoint of t:-te
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`study results, in experience over a number of year·s
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`I think that should be influer:cing ou1.·
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`opinion of the safety data.
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`DR. KAWAS: Thanks. Dr. Katz?
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`DR. KATZ: Yes, I think the critical
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`question here is not whether. those numbers at 9 g
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`are acceptable or not, although that is an
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`important question, but to me the question is
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`and you have certainly been talking about that, do
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`you have enough experience to be comfortable at the
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`dose you think is effective.
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`I think, I mean my
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`sense of what people are saying -- you didn't vote
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`on it yet, but my sense is t~at you felt that at 9
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`g there just isn't really that much data.
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`I don't
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`want to preempt your vote, but it sounds like the
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`general consensus was there wasn't enough data
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`showed, but there just wasn't enough to be able to
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`be comfortable that we have adequately
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`churucterized the safety at 9, which is what we
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`have to do. The only vote you took on
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`effectiveness was effectiveness at 9 g. So, if you
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`think it is useful to reopen a discussion about
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`23 whether or not you think there is effectiveness at
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`question because if yoa do think there is
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`effectiveness at a lower dose, it increases your N
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`from the point of view of safety. So,
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`I just throw
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`that out.
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`DR. KAWAS'
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`I actually think that is
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`10
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`probably worth our doing. With regards to
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`11
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`effectiveness at 6 g, what are the thoughts of the
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`12
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`committee?
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`I will start by saying that I suspect
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`13
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`that there is effectiveness for at least many
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`14
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`patients at 6 g, partly for all the reasons that
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`15
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`other members of the commit.tee have said, but also
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`16
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`because there appears to be o. fairly prominent.
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`dose-response curve not only in terms of AEs but
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`also in terms of efficacy. And, what isn 1 t
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`factored into a total dose is the levels of
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`particular patients, the weights of particular
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`patients or whatever, but t.hc data shows me that at
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`least a subset of patients appear to be responding
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`ut least in some of the trials to 6 g. Dr. Katz?
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`DR. KATZ: Study 21, the withdrawal study.
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`DR. HOUGHTON, That is the slide that I
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`DR. KATz, The dose there was 50 mg/kg, is
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`that correct? What was the distribution of doses
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`in that study?
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`[Slide]
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`DR. HOUGHTON: This is shown here. There
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`was an equal distribution of patients at the 6, 7.5
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`and 9 g and if you look at that paradigm of acute
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`9 withdrawal, the response to placebo randomization
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`is obviously very robust at 6 and 7.5 g, as it is
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`at the 9 g. The problem with the GHB-2 study is
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`that it is only a 4-week study and the slope of the
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`line hadn't plateau'd at the end of 4 weeks. When
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`we did apply that to open label, even though it was
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`open label we still saw the maximum nadir at 8
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`16 weeks. So, if you then take a group of patients
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`17
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`who have been on active treatment for a very long
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`18
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`19
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`time and are then randomized to placebo, if you
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`believe that is a support. for long-term efficacy
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`20
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`then efficacy is supported at 6 g and 7.5 g.
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`DR. KAWAS: Would members of the committee
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`like to comment on this data or any other data
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`showing efficacy or non-efficacy at 6 g? Yes?
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`DR. SIMPSON,
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`I do think that this trial,
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`in fact, is very impressive.
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`I just want to remind
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`everybody of the caveat of t~is, that the people
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`that you were looking at long-term exclude all
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`those people who have dropped out for adverse
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`events.
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`DR. KAWAS,
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`I think that is a very good
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`point.
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`I mean, this was a study done in responders
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`rather than just random narcoleptics.
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`Individuals
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`in this group represented probably are individuals
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`who felt they were getting benefit or saw benefit.
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`DR. SIMPSON, And provided the drug is
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`safe, then in fact this might be a fair rule to
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`look at to say, yes, the drug is effective.
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`DR. MANI:
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`T would just like to point out.
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`that these comparisons are not of randomized
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`groups.
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`DR. KATZ: They are not randomized to
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`dose.
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`DR. MAN!: They are not randomized to
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`dose.
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`DR. KATz,
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`It is obviously a randomized
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`study. So, they are not randomized to dose in t.h'::'!
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`sense of typical dose response. These are doses
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`that presumably they had been responding to in open
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`experience, and there is not as balanced across t~e
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`25
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`doses, that is true. And, the numbers are quite
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`small on each dose. On the otr.er hand, you have
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`already decided that in toto it is a study that
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`demonstrates effectiveness.
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`DR. KAWAS:
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`I mean, I think even though we
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`all recognize these are responders, the fact that a
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`group of individuals on 6 g who, when withdrawn,
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`showed this effect at least told me that there was
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`a subgroup that did respond, as I said before, to
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`6. The question is how big is that subgroup, and
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`when we are talking about indications and efficacy
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`do we feel that on the whole 6 is a dose to which
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`people respond based on all the evidence that we
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`have seen so far?
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`DR. FALKOWSKI: And I would also like to
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`say I am a little uncomfortable with the idea of
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`saying that we have so many patient hours for most
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`drugs but, because this is orphan status, we have
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`it but we don•t have -- Dr. Katz' remarks
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`but. we
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`don't have any numbe~s. Well, that, to me, puts
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`the sponsor in a difficult situation about, you
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`know, what is adequate in trying to develop a new
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`drug and it makes it very difficult for us here to
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`try to reach a conclusion. Enlighten me, here.
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`DR. GUILLEMINAULT: Can we make a comment.,
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`25
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`as a sleep expert, on the issue?
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`DR. KAWAS:
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`I am sorry, who is speaking?
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`DR. GUILL~~TNAULT: Yes, can we make a
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`comment on that issue as sleep experts?
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`DR. KAWAS: Please. Yes, you are on the
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`air.
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`DR. GUILLF.MTNAULT: Okay. The comment
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`that I want to make is that currently there is no
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`drug for cataplexy which is at a fixed dosage.
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`None. Because there is a certain amount of
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`variability from patient to patient, and a patient,
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`for example, can respond at 20 mg of fluoxetine or
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`60 mg of fluoxetine.
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`In general terms, it is
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`unrealistic to believe that there will be a single
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`dose which will control all cataplectic attacks for
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`15
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`all narcoleptic patients. So, you have dose
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`ranges, and I think that that is what these studies
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`are showing. Looking at the data that you have,
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`efficacy for some patients is at 6 or for some
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`patients at 9. And, that is the clinical
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`is the best that you are going to get. So, your
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`efficacy for some is 6 and for some is 9. All
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`DR. KAWAS: Thank you. Dr. Katz, would
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`you like to comment on Dr. Falkowski's concerns
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`about
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`the orphan status?
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`DR. KATZ:
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`The only written rules that I
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`am aware of which talk about numbers that are
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`adequate, or are potentially adequate,
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`for an NDR,
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`or for a typical NDR,
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`there are no numbers written
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`down anywhere as policy or guidance.
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`So, as I say, had agreed that a total of
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`500 was appropriate -- we,
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`the company and the
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`division.
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`DR. FALKOWSKI:
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`So they came up short.
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`DR. KATZ: Well,
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`that is the question we
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`are asking. There was, on our part,
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`that at least
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`a big chunk of that would be at a therapeutic dose.
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`So that is why we are asking you whether or not you
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`think it is adequately chararacterized.
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`I just want
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`to make one other comment with
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`regard to the 6—gram effectiveness and to ask the
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`company just
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`should make this explicit, although
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`I
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`think Dr. Trout said it a couple of times.
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`In Study 2,
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`the p-value for the 5-gram
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`versus placebo contrast was 0.0529. or 0.053,
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`I
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`believe.
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`That was including a correction for
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`multiple comparisons given the three doses.
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`so you have one study which, basically,
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`has a p—value of 0.05 at the 6—gram dose; right?
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`And then you have what you have seen.
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`So I just
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`remind the committee of that.
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`DR. FALKOWSKI: And that was the four—week
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`study,
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`the GHB-2 study; right? Okay.DR. KATZ:
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`i
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`DR. KAWAS: Any final comments before we
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`take a vote on the sponsor establishing the safety
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`of Xyrem when used for the proposed -- well,
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`actually --
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`DR. SIMPSON: Would it be appropriate to
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`do a revote on the efficacy?
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`DR. KAWAS: Not revote, but we can do
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`another vote on whether or not
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`the panel thinks
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`that there was efficacy demonstrated at --
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`DR. SIMPSON:
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`A dose between 6 and 9.
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`DR. KAWAS: Well.
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`I think we will have to
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`say either a dose of 6 or a dose of 7.5 or
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`something like that.
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`DR. KATZ: Well,
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`if you conclude it is
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`effective at 5 and you have already concluded it is
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`effective at 9, it would be sort of odd if it
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`wasn't effective at 7.5.
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`So,
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`if you just want to
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`vote it at 6. we will
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`take it from there.
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`DR. KAWAS: Okay.
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`We are voting on 6.
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`Has the sponsor demonstrated efficacy of Xyrem for
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`IU
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`the proposed indication to treat cataplexy at the
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`dose of 6 grams per day? All
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`in favor? All who
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`agree that the efficacy has been demonstrated.
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`raise your hand.
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`[Show of hands.]
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`DR. KAWAS: Let's start and identify
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`yourself as we are going around.
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`DR. SIMPSON:
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`Simpson.
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`DR. ROMAN:
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`Roman.
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`DR. WOLINSKY: Wolinsky.
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`DR. LACEY: Lacey.
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`DR. KAWAS: All who do not feel that the
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`company has demonstrated efficacy at 6 to treat
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`cataplexy, raise your hand. Start
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`identifying at
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`that end.
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`DR. PENIX:
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`Penix.
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`DR. VAN BELLE: Van Belle.
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`DR. PENN:
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`Penn.
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`DR. KAWAS: And I am the lone abstention.
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`I
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`think.
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`DR. FALKOWSKI: Over here.
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`DR. KAWAS: Oh; and Falkowski.
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`so we have
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`a split committee for you on 6.
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`If I vote,
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`I break
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`it. Actually,
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`I am fairly convinced that there is
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`efficacy at 6.
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`So Kawas.
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`Now, safety.
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`We are now talking safety
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`between 6
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`to 9. We are now talking about a lot
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`more patient hours, patient years.
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`The floor is
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`open for discussion for safety between 6 and 9
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`grams a day.
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`DR. PENN:
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`Can the company give us the
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`number of patient years exposure 6, 7, 9,
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`total
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`because we can't do it from your data that we have
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`seen here.
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`How close to the magic 500 are you?
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`Patient years; excuse me.
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`DR. KATZ: Not patient years.
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`250
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`patients greater than six months,
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`if I added that
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`up correctly. That is without Dr. Scharf.
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`This is
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`now with, so the numbers are bigger. Without Dr.
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`Scharf,
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`I calculate about 250 patients for at least
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`six months.
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`Is that about right?
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`DR. VAN BELLE:
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`I got 399.
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`DR. KATZ: Greater than six months?
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`DR. VAN BELLE: Yes.
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`DR. KATZ: At 6 and above? We can just
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`split the difference.
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`DR. VAN BELLE:
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`How many Ph.D.s does it
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`take to add nine numbers?
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`DR. KATZ:
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`I am not a Ph.D.
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`T can't be
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`expected to.
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`Can you put the slide back without
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`IU
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`Dr. Scharf?
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`DR. KAWAS:
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`I come to about 150 patient
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`years of exposure just looking at the individuals
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`who were on at 12 months or more.
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`DR. REARDON: This is the data without Dr.
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`Scharf included from the ISS.
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`DR. KAWAS:
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`I think it is important that
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`we know exactly what we are looking at so thank you
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`for pointing that out to us.
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`On the other hand,
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`I
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`will say that it is to -- my personal
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`impression
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`was that Dr. Scharf's data, although it was the
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`most extensive and the longest
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`term, was collected
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`the least systematically. Given some of the other
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`issues that were brought up about it, it is
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`probably to your advantage to stick with this
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`dataset
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`in terms of AEs.
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`Okay;
`
`then the vote is about
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`to be called
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`for.
`
`If the sponsor has established the safety of
`
`Xyrem when used for the proposed indication at the
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`dose of 6 to 9 grams per day. All who think yes,
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`raise your hands.
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`{Show of hands.]
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`DR. KAWAS: Wait a minute.
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`Something very
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`funny just happened here.
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`It seemed like more
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`people were willing to say it was safe at 9
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`than
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`are willing to say it is safe at 6 to 9? Let me
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`try again.
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`who thinks it is safe, raise your hands
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`now.
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`end.
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`[Show of hands.]
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`DR. KAWAS:
`
`Identify yourself from that
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`DR. ROMAN:
`
`Roman.
`
`DR. WOLINSKY: Wolinsky.
`
`DR. PENN:
`
`Penn.
`
`DR. KAWAS: Kawas
`
`in there. Anyone else?
`
`who does not
`
`think it is safe, raise your hands,
`
`that safety has been demonstrated. established
`
`safety at the dose from 6
`
`to 9 raise your hand now?
`
`[Show of hands.]
`
`DR. KAWAS: Has not been demonstrated to
`
`your satisfaction.
`
`Falkowski, Simpson. Lacey,
`
`Penix? Anyone else?
`
`DR. VAN BELLE: Van Belle abstains.
`
`DR. KAWAS: And one abstention. We are
`
`really helping a lot.
`
`DR. KATZ:
`
`I didn't Count. was that a
`
`split?
`
`he1ping.
`
`DR. KAWAS: Right down the middle. Really
`
`10
`
`ll
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`23
`
`24
`
`25
`
`VV0ckhardt1003
`
`Wockhardt 1003
`
`
`
`The third question that the FDA has asked
`
`P.)
`
`us to consider is the adoption of a risk management
`
`plan necessary for the safe use of Xyrem.
`
`I would
`
`like to focus us on that question. First.
`
`in a
`
`yes/no way rather than the details of whether or
`
`not, of what belongs in a management program if we
`
`think yes, or what doesn't belong if we think yes.
`
`DR. FALKOWSKI:
`
`I
`
`thought part of our
`
`discussion was going to be different elements of
`
`that.
`
`DR. KAWAS: That is the next part. First.
`
`let's decide do we need a risk—management program,
`
`yes or no.
`
`And then.
`
`if we do, what should be the
`
`elements.
`
`Jerry?
`
`DR. WOLINSKY:
`
`I
`
`think there are really
`
`two issues here.
`
`I wish there weren't, but there
`
`are two.
`
`One is th
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