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Uh I certainly didn't know what to
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expect in coming to this meeting. And
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I'm still not sure what to expect is
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that an ultimate the as the penultimate
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speaker I have two particular goals to
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to to accomplish and they will want is
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the the unlike any everybody else I
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intend to be completely non
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controversial. And the other is we will
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be finished at three thirty for the
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coffee break and the Eric and will
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start on time and the the the remote to
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my my two goals now having said that
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Thomas I feel that the in in the last
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hour I think at least a milligram about
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Emily and I am complaining of an amulet
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mode I can feel it and that's one thing
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and second the reason we don't have
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these databases is because the only
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risk of the databases won't give them
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are not because of the the we could we
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could discuss that later but the that
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is that is the reason. Um oh this you
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know I've put this up especially
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because I don't want to be picked up by
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by the FBI and and sent to a a to a
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dark prison hold and and it's it's
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fairly required a problem over to to
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disclose their our error complex but
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also put it up as a way of introducing
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might want to view what in what I'm
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about to what I'm what I'm about to
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discuss. And quality is that I come at
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this others as a long time clinical
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trials methodology stands statistician
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a to run those rumours studies and and
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deals with the needing really in the
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bias sees it the that are involved in
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the study and most importantly we have
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been doing work with matted databases
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with cool clinical trials a decisive
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modelling and simulating the trials and
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that doing little tweaks to to the
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assumptions and methods in order to
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better understand the the studies and
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as a result I I really do have a very
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different view these studies than than
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many of my my colleagues and you'll
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you'll hear that is well and finally
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the serves the purpose that the I
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decided that my audience here I really
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didn't know what to expect but my
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audience here is I intended be I
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intended to be necessarily people and
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so I'm speaking to to you as well as to
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to everybody else and that's based on
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on some conversations I had with the
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with the nest officers and the leaders
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recently as as an element of shameless
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self promotion on the editor in chief
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of the new journal called alzheimer's
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and dementia translational research and
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clinical interventions which the US old
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timers us situation and we're inviting
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well contributions this is what I'm
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going to to speak about and in about
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twenty five or so minutes I'm I'm going
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to discuss briefly the original FDA
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guidelines they serve as historic and
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meaningful guidelines in terms of in
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terms of developing no drugs I have to
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mean type tactic on a that like that to
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the goals here and that is to to to to
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fill you we where to give you a better
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appreciation of what we need we talk
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about drama lead the early eighty more
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preclinical a ID and then I want to you
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you feel for the outcomes that are used
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in in these studies and especially what
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we mean when we talk about something
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called a composite outcome this is
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important because these are as the the
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these these these these serve as a
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regulatory barriers. And a and and
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things that that we have to do in order
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to to get a drug approved for all
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timers does use they're they're
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actually more difficult than than than
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we we think and then finally I will
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give some examples of of all Alzheimer
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disease trials and make a comment about
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the current a current draft legislation
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in a number of you here are from
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california. And you probably have
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immediately thought this is a map of
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California all the rest of you have no
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idea what talking about and some have
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even thought that this is actually a
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demographic map of democrats in
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California because we all live within
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five Miles of the the ocean oh but this
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is one hundred thirty one not not
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however many you mentioned Thomas but
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one hundred thirty one phase two and
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phase three clinical trials all this it
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in don holland registered in clinical
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trials not got of between two thousand
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and two thousand a fourteen and also
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shows that online and the duration
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roughly a a little bit of time to talk
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to to do these trials it only goes up
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to two hundred two two thousand
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fourteen. I she point here though is
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for all practical purposes all of them
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showed no results other than maybe some
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exceptions but that they they were in
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some on underpowered study another key
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point is that the methodology for these
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studies where essentially or identical
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rather straightforward highly refined
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parallel group trials randomise arrow
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group trials in which samples of
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convenience were obtained on the number
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of fairly straightforward
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characteristics and afterwords a post
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hoc subgroup analyses we're going on
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other other characteristics outcomes
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were largely the same remote control
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before the entire goal though a lot of
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these trials blasting list to aspire to
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get an outcome looks something like
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this. And that is on the car that as
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such as the gas card that the remote
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will be a better one and a have ones to
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two points better than then placebo. So
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all these one hundred thirty one trials
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a aspire to to get a minimal minimal
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that I circled here at the bottom of
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the last few trials are around two
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thousand or two thousand the fourteen
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and that projected into two thousand
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seventeen just to indicate that both
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the density of these trials and that
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they are nearly all trials directed at
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more they're all essentially anti more
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interrupts this is important this is
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the regional basis for I've read your
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guidelines for FDA approved drive bay
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where essentially put into place around
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nineteen eighty eight with the second
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hacker in a clinical trial the the
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guidelines and are are actually quite
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minimal on the consistent with other
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therapeutic areas requiring I'll only
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the enough patience be exposed to the
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drug for safety it there's enough to
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teach a ton taller ability in drug
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interaction a studies done to ensure a
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rag in relative safety and knowledge of
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the drug and then in a typical approval
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process and for all timers disease it's
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perfectly reasonable to have a fees to
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study of twelve weeks up or study to
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attend the proof of concept in some way
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and the face three need only to either
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confirm effectiveness or establish
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effectiveness with practically speaking
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only about four hundred to seven
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hundred that patients in one or two
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studies in alzheimer's disease our
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identification of the illnesses is very
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straightforward mild to moderate
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alzheimer's disease by make and
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criteria they're really straightforward
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and many mental states scores between
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ten and twenty six such that patients
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can be tested with this with the study
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with a with the tests such as the as
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the despot then there is a requirement
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that there be two outcomes one
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apartment of outcome that is of course
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significant and then another either a
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functional or global outcome which is
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interpreted as a test of clinical
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meaning. So one establishes that the
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drawing drug as a cognitive fact and
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then with the functional or global
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outcome one establishes that the effect
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is quote unquote meaningful this is the
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extent of the at the is regulatory
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regulatory guidance here these
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guidelines are important as well
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because this is the basis on which for
00:10:09
drugs were five drugs actually work
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proof from marketing. And in and and
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for those five drugs yeah but the cut
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the effect on the part of the testimony
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that card after six months was about
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three point sometimes a little more
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sometimes a little less and use it in a
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small of that on the on the subject
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costly CSCGIC which established at the
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clinicians more often than not could
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value dedication to improve that's it
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fairly straight forward this is guided
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not clinical trials ah but it this is
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guided that clinical drug development
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but it on the I'll only for the
00:10:52
diagnosis of alzheimer's disease
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dementia. And does not particularly
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allow for for other aspects of either
00:11:02
dementia were thought of alzheimer's
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related I illness. So how on they'll
00:11:10
just talk about newer criteria that
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that research diagnoses for early stage
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alzheimer's disease so the the term
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early stage becomes a becomes important
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because it's subsidised these concepts
00:11:24
such as preclinical alzheimer's disease
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programmable Summers as user M ceiling
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due to old simon's use which which are
00:11:32
that's under under most circumstances
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essentially the same for the concept of
00:11:37
early eighty or my old lady which
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operationally is really old timers
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disease dimension for the many mental
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state between twelve twenty and twenty
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six a lot of this is is really fairly
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concrete because we clinical trial
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assured fairly concrete and and simple
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and we want to be able to operational
00:11:59
noise things as best as possible but
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there are issues. So here is is kind of
00:12:05
the nomenclature or spectrum of what
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I'm calling a clinical phenotype but if
00:12:11
that at the end of the various names
00:12:13
that we use for alzheimer's related
00:12:15
this disease. That attended a DD for
00:12:19
for autopsy supported clinical dementia
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possible and probable lady from the
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original nineteen eighty four Mccann
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criteria and then as I mentioned the
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concept of early stage illness a weary
00:12:35
and MC all I do while timers disease is
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rather specific and you'll you'll see
00:12:42
this in a minute when we talk about MCI
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we're not just talking about somebody
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who may have a memory complaint or
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we're not sure what is happening but
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but it's a red there's specific and
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severe a syndrome and as I mentioned
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roughly equivalent to to program more
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all timers disease. And then the
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concept of preclinical alzheimer's
00:13:02
disease the idea that you have to have
00:13:05
something before you have proved wrong
00:13:07
or eighty so that should be called
00:13:09
preclinical and you'll see in a moment
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how that has been operational eyes for
00:13:14
better or for worse but they keep in
00:13:16
mind the other the other causes of of
00:13:20
the other associations or cognitive
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impairment in like life as well as the
00:13:25
other prompted not the to use that may
00:13:27
be involved in in cognitive impairment
00:13:31
in in like life and realise that that
00:13:33
we really are not very very sadly at at
00:13:38
using the part of some of these
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technologies little moan a let alone
00:13:43
etiology is out of particular
00:13:46
importance of more with preclinical ED
00:13:50
has emerged the state of not having
00:13:53
preclinical lately which itself is
00:13:56
developing the names start and snack
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part to relate that to to refer to
00:14:02
primarily related how a pithy and snap
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suspected non Amway pathology that she
00:14:09
points here is worked a restart to talk
00:14:12
about the mentioned syndrome or
00:14:15
cognitive impairments syndrome that is
00:14:17
specifically defined by not having
00:14:20
found one one of our issues is this we
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make our diagnoses by consensus I'm
00:14:27
usually a by having a meeting over a
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day or two writing paper getting people
00:14:33
to sign onto it and offering up
00:14:36
criteria that we still have not
00:14:39
validated much of I and then of course
00:14:42
we re at exactly the time we've gotta
00:14:45
running the cache catcher planes back
00:14:47
to California or Paris so oh oh one of
00:14:52
the things we don't do very well. This
00:14:55
we don't validate and part of
00:14:57
validating the diagnosis is not showing
00:14:59
correlations with the criteria and
00:15:03
Goldsmith diagnosis but also being able
00:15:05
to not diagnosed to show the people who
00:15:08
do not fulfil these criteria. Indeed do
00:15:11
not have the illness a tape that we're
00:15:14
concerned about and we don't do that
00:15:16
well okay here are the share the
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criteria we have been using it for
00:15:22
better or for worse again in current
00:15:24
clinical trials we divided this into
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the concept of preclinical EDMCI
00:15:30
associated with the D again the same as
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a as from drama lady. And alzheimer's
00:15:36
disease dementia the in advance in the
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newer criteria to newer dress criteria
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from two thousand eleven was the role
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of by a markers wisely each of these
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conditions would be further defined or
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even a greater level of competence by
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adding a buyer marker a and and on
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validated by a marker as as it happens
00:16:00
innocent as it continues. So
00:16:02
preclinical in order to have
00:16:04
preclinical all all all timers disease
00:16:07
you must have any data by consensus one
00:16:11
must have been any data I'll a positive
00:16:14
thought positive by a marker for MCI to
00:16:18
do AD or from from from a lady again
00:16:21
and eight B to buy a marker is it is
00:16:26
absolute minimum a preclinical eighty
00:16:29
is then staged further top levels of
00:16:32
alleged levels of competence of stage
00:16:34
one two and three depending on not only
00:16:36
whether you depending on what you have
00:16:38
a data by marker alone whether you have
00:16:41
one with a positive so called the road
00:16:45
generated by a marker which by
00:16:47
convention in definition is possibly a
00:16:51
tell positive tell by a marker a a
00:16:55
small volume one on one MRIO or a
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particular decrease in in glucose
00:17:02
uptake pattern on or one day and then
00:17:06
stage three is having the above but
00:17:08
also having a very slight amount of
00:17:11
cognitive impairment that does not like
00:17:13
qualify for MCI do ADC if you can see
00:17:16
the rationality in here even as you I
00:17:19
think you can also appreciate these
00:17:21
things can be very difficult to not to
00:17:24
die to diagnose but the common element
00:17:28
in the take home message is new
00:17:29
criteria require one of these by
00:17:33
markers and you can also I think that
00:17:36
there are other by more considered that
00:17:38
to see the light of day that may have a
00:17:41
role in a in a in these criteria but
00:17:46
but not yet. So I don't want to just
00:17:48
continue that being to point out now
00:17:52
what and what and see I do a few years
00:17:55
and make the point that in CI due to AD
00:17:59
is I was here in illness as my all they
00:18:03
did when you look at the operational
00:18:04
criteria that we adopt ah you see that
00:18:07
the difference is that the the
00:18:09
essential similarity to a is that
00:18:12
people have memory complaints. And they
00:18:15
had an episodic memory or they memory
00:18:19
recall of a certain level and that's a
00:18:22
certain threshold level here. It's
00:18:24
we're taking a remembering only eight
00:18:27
of twenty five story elements are in
00:18:30
logical memory is the ceiling threshold
00:18:33
for MCI do the way the war for old
00:18:35
timers systems. So people problems like
00:18:38
we had it sinks threshold a and memory
00:18:42
impairment or ten of memory impairment
00:18:44
has severe as as people with
00:18:47
alzheimer's disease. Then the essential
00:18:49
difference becomes the clinicians
00:18:52
assessment of health functionally
00:18:54
impaired that person is do I feel that
00:18:57
this person is so functionally impaired
00:19:00
that I can provide a dimension
00:19:03
diagnosis if I can he has mildly D if I
00:19:06
can't oh we say MCI do do eighty the
00:19:11
next level to this as I mentioned is
00:19:13
well is the is the by a marker but I
00:19:17
wanted to make that point because
00:19:20
there's nothing my all about mild
00:19:22
cognitive impairment to you in the in
00:19:25
the way we use the term ah yeah
00:19:28
obviously there has to be something in
00:19:30
front of MCI do eighty and that is now
00:19:36
the preclinical IED concept that the
00:19:40
the we've been using that we're
00:19:41
starting to use in clinical trials and
00:19:44
here you can you can tell the I I
00:19:46
telegraphed part of part of that
00:19:50
concept I'll get to that I don't get to
00:19:52
in a minute. But fundamentally is a
00:19:56
having on memory complaint. And be able
00:20:01
to have an episodic memory score
00:20:05
anywhere from the impaired to the non
00:20:08
impaired a range and a clinical
00:20:11
observation of having a couple
00:20:13
dimensional rating scale of zero but
00:20:16
most importantly you've got to have the
00:20:18
E bay to buy a marker if you process
00:20:21
this another way what this basically
00:20:24
comes down to be is I have a memory
00:20:26
complain I get enamel like pets and I
00:20:29
have a certain level of them avoid yeah
00:20:32
in my brain. And that's what I have is
00:20:36
preclinical a old timers these that
00:20:39
family blow done complaining about
00:20:41
them. And so here is a graphic showing
00:20:46
a showing the severity of the
00:20:49
equivalent severity of thought and see
00:20:52
I do do way D and timers disease items
00:20:57
you guys blue all timers disease is
00:20:59
green you see the logical memory cutoff
00:21:01
score eight and of course they are all
00:21:04
either ball no but the functional
00:21:07
assessment on the Y axis you see that
00:21:10
in general the ED patients have more
00:21:13
functional impairment higher scores and
00:21:15
in general the MCI patients happen or
00:21:18
functional impairment. But there's a
00:21:21
lot of overlap and the overlap is due
00:21:26
to the vagaries of the of the positions
00:21:28
them a judgement. So another look at
00:21:32
preclinical lately and what is not
00:21:35
preclinical L eighty so I went through
00:21:38
this before the preclinical concept is
00:21:41
having a memory complain having a
00:21:43
positive a beta by a marker either I
00:21:49
either had scanner or or or CSF and
00:21:53
then and then whether or not you have
00:21:57
in your degenerative marker or you have
00:21:59
some degree of of of cognitive about
00:22:02
the point it that that you can make
00:22:04
sure this is what we use in the eighty
00:22:07
four study va for soulmate only use a
00:22:10
minute study for for entry. Now. So in
00:22:13
order to have this thing you have to
00:22:15
ask the question what would you do with
00:22:16
somebody who's got a memory complain
00:22:18
and not and a positive eighty by market
00:22:21
what you do with forty percent of
00:22:23
people who who don't screen in for
00:22:26
preclinical a day and that's where
00:22:29
where the with the concept the snap. So
00:22:32
since suspected non and Amway pathology
00:22:35
I suspect you suspect hunting brain
00:22:38
pathology they're not family positive.
00:22:42
But they may be positive one what we
00:22:45
consider a neural degenerative marker
00:22:47
pen FTV pet. So the alright volumes or
00:22:51
worked hell. So a and a you meant time
00:22:56
I will detail I want to I I want detail
00:23:01
this this to to a too shore degree that
00:23:05
only when out that this concept then of
00:23:09
suspected non animal like pathology
00:23:12
yeah is a the user group that can be
00:23:14
identified by for instance more
00:23:16
hippocampus volumes by not progressing
00:23:21
a either in their example volumes were
00:23:24
in their cognition as much as some of
00:23:28
the other some of the other groups this
00:23:31
graphic I I'm going to skip the intent
00:23:35
here was to take this further and to
00:23:38
show that from a the come by a more
00:23:41
perspective as you start to compare the
00:23:43
preclinical with the proved wrong or
00:23:46
you start to see that so the promos are
00:23:51
positive are positive the eight dated
00:23:54
the preclinical or positive the the
00:23:59
their a their some cognitive impairment
00:24:03
in the perjure almost as a little bit
00:24:04
less in in the preclinical the they the
00:24:10
the the boundaries are are fuzzy and
00:24:12
I'll leave it at that and and just
00:24:15
summarise by by by by pointing out the
00:24:20
severity of MCI do do AD that concept
00:24:24
to snap. And to be where that the that
00:24:27
these are consensus a criteria as a
00:24:30
word about outcomes currently used in
00:24:33
trials. Well some of you are familiar
00:24:36
with this but I'm assuming many or or
00:24:38
not I basically been the same over the
00:24:41
last twenty years we use the a desk
00:24:43
here that's "'cause" it fairly
00:24:45
reasonable come up a battery of of test
00:24:50
by adding a to a three extra test to
00:24:55
them by adding a executive function
00:24:59
these is digits and and deleted we call
00:25:04
you could then take in a lot and use it
00:25:07
across a across a spectrum you discard
00:25:10
continues to be commonly use the other
00:25:13
instrument is the clinical dimension
00:25:15
rating scale. And then a in most of our
00:25:20
larger studies we're we're using in
00:25:22
their psychological test battery
00:25:24
similar to very similar if not
00:25:27
identical to what me ahead presented
00:25:29
before most of the test batteries are
00:25:32
are really similar like five or the
00:25:34
same areas are usually with the same
00:25:36
tasks but but sometimes with different
00:25:39
equivalent S the big news here is the
00:25:42
idea or the concept of composites. And
00:25:46
the the willingness we are desire to
00:25:48
use a composite made up of available
00:25:53
tests that we've been using before to
00:25:55
substitute as little one primary
00:25:58
outcome in early stage old timer
00:26:01
disease studies. So various groups had
00:26:04
in a sense invented composites by
00:26:07
taking cohorts existing code words are
00:26:11
old clinical trials data. And
00:26:13
processing it in and I'm sure go away
00:26:17
to look for the ideals that that are
00:26:20
more associated with children
00:26:22
progression then mother on items that
00:26:25
will be the greatest enough that chi
00:26:28
divided by standard deviation of change
00:26:32
us for that one can find and what what
00:26:35
you see rather interestingly is that
00:26:38
when independent group start out to to
00:26:41
make composites. They end up with just
00:26:44
about the same thing and so I
00:26:46
highlighted in blue the the the right
00:26:49
three columns are independent composite
00:26:51
S so you see that they all consist of a
00:26:54
delayed memory test orientation from
00:26:57
either many mental state it be a desk
00:26:59
all and orientation from from the CDR
00:27:04
this basically reduces to orientation
00:27:07
and that and number. I need you take a
00:27:10
closer look and deconstruct one of
00:27:13
these composites you you seem typically
00:27:16
made up of about sixty one percent is
00:27:19
of the composite is a CDR a a twenty
00:27:22
percent eighty percent is the new
00:27:24
mental state and the and orientation in
00:27:27
memory items from the other side
00:27:29
contribute the other twenty two O
00:27:31
altogether orientation of memory will
00:27:33
make up about fifty percent of but of
00:27:36
these composites with essentially
00:27:38
border so back to the blessed Tomlinson
00:27:43
and Ros original all the coffee
00:27:46
cognitive assessment that they use to
00:27:48
of course correlated that's entangled
00:27:52
with cognition. So so and not on that
00:27:57
except to say that we've gotten to the
00:27:59
point where we can use a fairly basic
00:28:02
that composite in early stage up in
00:28:05
early stage starting so that's where we
00:28:08
are a it in terms of current the
00:28:12
current clinical trials we we take in a
00:28:16
drama lee D as a as a therapeutic the
00:28:19
target. And we are all into the idea of
00:28:23
preclinical eighty in one form or
00:28:26
another as a nother therapeutic target
00:28:29
in either case will try to use for the
00:28:33
most part a a composite similar to the
00:28:37
ones that you showed were we to L
00:28:40
common in which one will look at
00:28:41
cognition and activities of daily
00:28:44
living. So now some examples of early
00:28:46
stage trials. And and what they look at
00:28:50
what what they look like first I I
00:28:52
won't go through this this is the point
00:28:54
out the field is rich in proved promo
00:29:00
eighty trials mildly D trials and
00:29:03
others one ah there's one preclinical
00:29:05
trials we also have protection trials
00:29:08
Mia discussed a number of them but to
00:29:12
particular importance is the screen
00:29:15
using map study in PS one mutations in
00:29:18
you hear a columbia. And then the
00:29:22
people it his own trial combined with
00:29:26
the with the top forty eight O we and
00:29:29
each marker work predictor of a
00:29:34
response an outcome that's the tomorrow
00:29:36
study participants to go into that
00:29:39
study do not have a a or are
00:29:42
essentially cognitively normal and
00:29:44
would not qualify ordinarily for
00:29:46
preclinical old timers disease a a
00:29:50
typical MC like trial looks something
00:29:53
like this we we enrol people with
00:29:55
program ole D we said in age then it we
00:29:58
insist that they have a CD or point
00:30:01
five and it is backed up by a by a
00:30:04
marker it's a study will be eighteen to
00:30:06
twenty four months it can involve
00:30:07
twenty two hundred patients to be one
00:30:10
or two doses patients may or may not be
00:30:13
stratified on the on something like
00:30:16
that but we for at the beginning and
00:30:18
the outcomes or they're changing
00:30:20
cognition wanna see D or or on a
00:30:24
composite work point to conversion to a
00:30:28
old timers disease a dementia it's a
00:30:32
fairly basic the trial but what I want
00:30:34
to show here in the in the graphic
00:30:37
here's a spaghetti pot of about two
00:30:39
hundred people with the with MCID do
00:30:41
all alzheimer's disease. So that you
00:30:43
can visually see how over the course of
00:30:46
two years very very few people from the
00:30:49
speaker IE five point to you or
00:30:52
actually were sitting and those who
00:30:54
worse and worse and very very slightly
00:30:56
on the a desk all and the C you are
00:30:59
some boxes it's difficult to tell a
00:31:01
draw the that if some a a is patients
00:31:05
are not particularly were something but
00:31:07
the goal is as I showed be before is to
00:31:11
try over the course of the year and I
00:31:13
have to be able to show what a
00:31:15
difference a drug placebo difference in
00:31:19
the over the course of time now that
00:31:24
difference though is rather small and I
00:31:27
think you saw we definitely saw enough
00:31:30
in me is discussion of the figure study
00:31:31
how small the that were in the you're
00:31:35
here it's essentially the other studies
00:31:38
that are being planned for the outcomes
00:31:40
that are being planned for are about
00:31:42
that the or rather small finger maybe
00:31:45
maybe a little bit larger I want to
00:31:47
give you a flavour for the a for trial
00:31:50
a day for trial is users only use map
00:31:54
to treat preclinical alzheimer's
00:31:57
disease a participants are given
00:32:00
infusions monthly and the follow up is
00:32:04
four years at tells impatience or being
00:32:07
recruited for the trial I gave you the
00:32:09
inclusion criteria earlier the outcome
00:32:12
is the EDVDCS which is a composite that
00:32:15
they should be for and the issue in the
00:32:19
trial is that large numbers of patients
00:32:23
we have to screen in order to find
00:32:26
those who filled the these criteria are
00:32:30
at our site for example we managed to
00:32:33
screen forty patients approximately to
00:32:37
enrol and and these screens or the
00:32:41
these are people who've done cats cats
00:32:43
so so we have about twenty five percent
00:32:45
hit rate on the on getting a positive
00:32:48
that's complications in our
00:32:50
participants in this trial but that's
00:32:52
the flavour of that that that study a
00:32:55
tomorrow is a prevention trial so it's
00:32:58
not an early stage fright but it is
00:33:02
interesting because it'll basically the
00:33:04
largest prevention trial I think pretty
00:33:07
sure with perhaps the most carefully
00:33:09
work top up artists. It's will be
00:33:13
followed for over four years especially
00:33:16
the earlier ones and version we're
00:33:18
looking for four hundred and ten it's
00:33:21
four hundred and ten outcomes which
00:33:23
will be conversion to MCID the way D or
00:33:26
two dimensional over this period of
00:33:29
time. So just think about the
00:33:30
efficiency here fifty eight hundred
00:33:33
what are too well to or four hundred
00:33:36
and ten events and in order to hope
00:33:38
that the the the part of the selection
00:33:41
criteria and the people is a real the
00:33:44
way up will delay a onset I want say
00:33:50
more about that. But I will move
00:33:52
quickly to targets just to make the
00:33:54
point you could take this up in any
00:33:56
review just to make the point that's
00:33:59
been made before out we don't really
00:34:01
know what all timers diseases in the
00:34:03
sense that we don't really know what
00:34:05
some of the therapeutic targets are and
00:34:09
if any of them are validated if we can
00:34:11
dream up this many potential targets
00:34:14
hamlet Al pathways eight but we for a
00:34:18
yeah please inflammation of
00:34:20
mitochondria functions separately that
00:34:25
post pose genetic defects well we
00:34:32
really don't have a handle so so that's
00:34:35
the the purpose of this might the
00:34:37
second for this is still this some of
00:34:40
the the vitamins and supplements that
00:34:44
that that have been tried the
00:34:47
alzheimer's disease now being fairly
00:34:49
specific I'll just skip this but this
00:34:53
is the density of the data of current a
00:34:57
beta anti H beta trials that are
00:35:00
ongoing most of the our resources are
00:35:03
devoted to a to a data here's a here's
00:35:06
a quick yeah a summary of cognitive
00:35:10
change in a number to supplement trials
00:35:15
and the the they're interesting from
00:35:17
the point of view of the variation what
00:35:19
they tell us about other trials and
00:35:22
about a and that they were largely not
00:35:26
the first one in the upper left hand
00:35:27
corner is with civil in eighty eight
00:35:30
that it matters little for the moment
00:35:32
what sue the need is but this was a
00:35:33
twenty four weeks study that was a cat
00:35:37
borderline positive we twenty four but
00:35:40
what what happened what fit over the
00:35:42
first twelve weeks until the second
00:35:44
outdated measure both groups improve
00:35:47
substantially then in order for there
00:35:50
to be an affect the placebo group had
00:35:53
to the control group had to essentially
00:35:56
make a right hand turn a sharp right
00:35:58
hand turn and stop improving well the
00:36:01
drug group but continue this is
00:36:03
illustrating a perhaps it's
00:36:06
illustrating the very important factor
00:36:09
the very important influence of
00:36:11
practise affects work study effects on
00:36:14
the efficiency of thought out of a
00:36:17
clinical trial to do these trials are
00:36:21
sufficiently incorrectly one has to
00:36:23
take that into account one has to
00:36:25
adjust for for that the right hand
00:36:29
studies RRDHA in the upper right hand
00:36:33
corner and vitamins I mean these
00:36:38
complex in the in the lower I put that
00:36:41
up it's easy studies done by the ADCS
00:36:43
ah ha each of them had four hundred try
00:36:47
a patience in patients had mild to
00:36:49
moderate eighty and as you can see we
00:36:51
saw nothing with the with DH a war with
00:36:56
with vitamin B twelve yeah there are
00:36:58
other studies other clinical trials
00:37:01
that to show what steps so this is
00:37:03
pointing L variability or inconsistency
00:37:07
in a fax that one would have that one
00:37:10
would have to deal with in order to be
00:37:13
able to demonstrate that the that these
00:37:16
two supplements are are are that this
00:37:21
again is their most optimistic case at
00:37:23
the moment for for for drug for
00:37:27
alzheimer's sound easy matt is it
00:37:29
danced into it's less space three study
00:37:32
this takes three study will be over in
00:37:34
November next year the entire trial
00:37:38
with twenty two hundred patients is all
00:37:40
aimed to show a one point two
00:37:43
difference some desk all fourteen I
00:37:47
should be successful and and show this
00:37:51
statistically significant that one the
00:37:54
drug may very well be marketing
00:37:56
marketed and to the fight well we'll
00:38:01
always start and will only be in there
00:38:03
because it will be a knock down drag
00:38:06
out dried out issue of whether or not
00:38:09
not that this small over the course of
00:38:13
eighteen months is clinically is
00:38:16
clinically worthwhile so like put the
00:38:18
first paper the first trial an
00:38:20
alzheimer's disease regulatory try all
00:38:23
of with attacker in that Thomas
00:38:26
referred to as a as a Leon balls and it
00:38:29
indeed was good by Leon and can pages
00:38:32
an open again so and and and number but
00:38:35
speak lost in that study over a over
00:38:38
three weeks we generally so every six
00:38:41
weeks assuming we generally saw four
00:38:43
point improvements that we we can
00:38:46
rationalise it in so many ways but it
00:38:48
but it by Mcculloch and not economists
00:38:50
will not be a impressed a this is my
00:38:54
are really my my my my my second to the
00:38:57
last slide. So all this comes down to
00:39:00
current FDA guidance if the A think is
00:39:04
really nothing but helpful in not
00:39:06
timers disease. And those work as hard
00:39:09
as it can to facilitate outcomes for
00:39:12
better or for worse and here in fact is
00:39:15
how the try to inform us sponsors of
00:39:21
how they might go about a getting a
00:39:24
drug approved for their preclinical
00:39:26
alzheimer's disease the concept here
00:39:29
being that you can identify people
00:39:31
along the way that I described it but
00:39:34
also that experts will agree that will
00:39:39
will agree with that definition and
00:39:42
then if you could show cognitive
00:39:44
improvement FDA will Walter accelerated
00:39:47
a provisional approval I about the drug
00:39:50
on the market all other things being
00:39:52
equal with post marketing surveillance
00:39:55
or the FD A.'s new guidance for program
00:39:58
all the the is a diagnosis along the
00:40:01
way that I described before they can
00:40:03
stay conceptualise for drama lady at
00:40:06
this stage in which the nation is
00:40:09
imminent this is important because
00:40:10
you'll never get a claim for preventing
00:40:13
dementia clean about it. If you go in
00:40:16
with the diagnosis of from drawn more
00:40:18
need the and here they very
00:40:20
specifically allowing composite to
00:40:23
serve as the primary outcome there are
00:40:27
some issues with the with the guidance
00:40:30
and the the there's some fine points to
00:40:32
it but as you can see the the the the
00:40:36
intent is to facilitate so Mike make
00:40:38
conclusions you the probably read
00:40:40
faster than I I wanted to tell you a
00:40:43
bit about early stage and how we
00:40:45
operational I said a tip you off to
00:40:48
snack and part because we'll have
00:40:51
discussions about that give some
00:40:54
background on health outcomes have
00:40:55
changed a little bit and then point out
00:40:58
the obvious that the these studies are
00:41:01
really reductionist and a and if we're
00:41:05
going to move further oh we we will and
00:41:08
try to test good ideas we need better
00:41:11
methods different methods for doing
00:41:13
trials many of those methods would do
00:41:16
would be breaking a mold breaking
00:41:19
deregulatory Mall and doing studies
00:41:22
with targeted designs identifying
00:41:25
patients up by phenotype metabolic Tina
00:41:28
typed by sequencing and the designing
00:41:32
trials with the fury of drug action in
00:41:34
mind and then being able to do just the
00:41:36
opposite oh what's been done in in in
00:41:41
me is trial or in in some of these
00:41:44
other trials and that is to do small.
00:41:46
But it's trials to be able to prove
00:41:50
that your role and have an that we the
00:41:53
people with the phenotype in question
00:41:57
so that's not just in the one trials
00:41:59
but bested trials in which patients are
00:42:02
signed the baskets based on their
00:42:03
genotype and they give in series rose
00:42:07
for so called umbrella trials in which
00:42:11
you detest the mode the the efficacy
00:42:13
based on the mode of action cross
00:42:16
diagnoses are without regard to
00:42:18
diagnoses but with regard to to
00:42:21
mechanism of action so so that's it so
00:42:23
thanks for bearing with me over over
00:42:25
these non two minutes late here over
00:42:28
this we're over these last few minutes
00:42:32
and even the really can see that this
00:42:34
is not here I wanted to to remind them
00:42:37
the miss one you'll be better quote I
00:42:41
really didn't say everything I said so
00:42:44
for me and also the point down to
00:42:47
really if you were here the the really
00:42:49
better manage the mets and you know the
00:42:52
mets are in the world series and the

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Conference Program

Introduction to the 12th Nestlé International Nutrition Symposium
Thomas Beck, NRC Director
22 Oct. 2015 · 8:57 a.m.
418 views
Introduction to Session I - Cognitive & Brain Development
Susan Gasser, Friedrich Miescher Institute, Basel, Switzerland
22 Oct. 2015 · 9:04 a.m.
The development of a healthy brain
Michael Gazzaniga, University of California, Santa Barbara, USA
22 Oct. 2015 · 9:16 a.m.
221 views
Q&A - The development of a healthy brain
Michael Gazzaniga, University of California, Santa Barbara, USA
22 Oct. 2015 · 9:56 a.m.
Early influences on brain development and epigenetics
Stephen G. Matthews, University of Toronto, Canada
22 Oct. 2015 · 10:49 a.m.
Q&A - Early influences on brain development and epigenetics
Stephen G. Matthews, University of Toronto, Canada
22 Oct. 2015 · 11:29 a.m.
Building the physiology of thought
Rebecca Saxe, Massachusetts Institute of Technology, Cambridge, USA
22 Oct. 2015 · 11:38 a.m.
154 views
Q&A - Building the physiology of thought
Rebecca Saxe, Massachusetts Institute of Technology, Cambridge, USA
22 Oct. 2015 · 12:10 p.m.
Introduction to Session II - Cognitive Decline
Kathinka Evers
22 Oct. 2015 · 2:02 p.m.
Brain health & brain diseases - future perspectives
Richard Frackowiak, CHUV University Hospital, Lausanne, Switzerland
22 Oct. 2015 · 2:11 p.m.
Alzheimer's disease: genome-wide clues for novel therapies
Rudolph E. Tanzi, Massachusetts General Hospital, Charlestown, USA
22 Oct. 2015 · 3:15 p.m.
Q&A - Alzheimer's disease: genome-wide clues for novel therapies
Rudolph E. Tanzi, Massachusetts General Hospital, Charlestown, USA
22 Oct. 2015 · 3:59 p.m.
Immunometabolic regulators of age-related inflammation
Vishwa D. Dixit, Yale School of Medicine, New Haven, USA
22 Oct. 2015 · 4:21 p.m.
Q&A - Immunometabolic regulators of age-related inflammation
Vishwa D. Dixit, Yale School of Medicine, New Haven, USA
22 Oct. 2015 · 4:59 p.m.
Introduction to Session III - Nutrition & Cognitive Development
Pierre Magistretti, KAUST, Thuwal, Saudi Arabia and EPFL, Lausanne, Switzerland
23 Oct. 2015 · 9 a.m.
Energy metabolism in long-term memory formation and enhancement
Cristina M. Alberini, The Center for Neural Science, New York University, USA
23 Oct. 2015 · 9:16 a.m.
129 views
Q&A - Energy metabolism in long-term memory formation and enhancement
Cristina M. Alberini, The Center for Neural Science, New York University, USA
23 Oct. 2015 · 9:53 a.m.
Building the costly human brain: implications for the evolution of slow childhood growth and the origins of diabetes
Christopher Kuzawa, Northwestern University, Evanston, USA
23 Oct. 2015 · 10:29 a.m.
Q&A - Building the costly human brain: implications for the evolution of slow childhood growth and the origins of diabetes
Christopher Kuzawa, Northwestern University, Evanston, USA
23 Oct. 2015 · 10:57 a.m.
Nutrition, growth and the developing brain
Prof. Maureen Black, University of Maryland, School of Medicine, Baltimore, USA
23 Oct. 2015 · 11:09 a.m.
Q&A - Nutrition, growth and the developing brain
Prof. Maureen Black, University of Maryland, School of Medicine, Baltimore, USA
23 Oct. 2015 · 11:49 a.m.
Introduction to Session IV - Decline & Nutritional Intervention
Tamas Bartfai, The Scripps Research Institute, La Jolla, USA
23 Oct. 2015 · 12:48 p.m.
On multi-domain approaches for prevention trials
Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden
23 Oct. 2015 · 1:04 p.m.
Q&A - On multi-domain approaches for prevention trials
Miia Kivipelto, MD, PhD, Karolinska Institutet
23 Oct. 2015 · 1:39 p.m.
Methodological challenges in Alzheimer clinical development
Lon S. Schneider, Keck School of Medicine of USC, Los Angeles, USA
23 Oct. 2015 · 1:49 p.m.
Q&A - Methodological challenges in Alzheimer clinical development
Lon S. Schneider, Keck School of Medicine of USC, Los Angeles, USA
23 Oct. 2015 · 2:32 p.m.
We are what we remember: memory and age related memory disorders
Eric R. Kandel, Columbia University, New York, USA
23 Oct. 2015 · 3:03 p.m.
138 views
Concluding Remarks
Stefan Catsicas, Chief Technology Officer, Nestlé SA
23 Oct. 2015 · 3:50 p.m.

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